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        "resumen" => "<span class="elsevierStyleSectionTitle">Introduction</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Several factors suggest a genetic predisposition to sarcoidosis&#44; namely the recognition of race as a risk factor and the occurrence of familial clustering of cases&#46; Several studies have reported an association of sarcoidosis and HLA class I and especially class II alleles in different populations&#46;</p> <span class="elsevierStyleSectionTitle">Aim</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">HLA class I&#44; class II and TNF-&#945; genotyping in a group of sarcoidosis patients and its relation with clinical presentation and outcome&#46;</p> <span class="elsevierStyleSectionTitle">Material and methods</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A total of 104 sarcoidosis patients were included&#46; Clinical presentation&#44; functional&#44; radiology&#44; BAL findings and organ involvement were studied&#46; HLA&#8211; A<span class="elsevierStyleSup">&#42;</span>&#44; -B<span class="elsevierStyleSup">&#42;</span>&#44; -C<span class="elsevierStyleSup">&#42;</span>&#44; DRB1<span class="elsevierStyleSup">&#42;</span>&#44; DQB1<span class="elsevierStyleSup">&#42;</span> and TNF-&#945; were genotyped by molecular biology methods&#46; DNA was extracted from peripheral blood and PCR-SSP and PCR-reverse hybridisation me-thods were used&#46; Allele frequencies were compared with controls from the same region&#46; The X2 test was used for discrete values and the Kruskal-Wallis test for continuous values&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">When patients were compared with controls we noticed increased frequencies of B<span class="elsevierStyleSup">&#42;</span>08 &#40;10&#46;6&#37; vs&#46; 6&#46;1&#37;&#41;&#44; O&#46;R&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;8&#44; C&#46;I&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#91;1&#46;1&#59;3&#46;1&#93;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#59; DRB1<span class="elsevierStyleSup">&#42;</span>12 &#40;4&#46;3&#37; vs&#46; 1&#46;7&#37;&#41;&#44; O&#46;R&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;63&#44; C&#46;I&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#91;1&#46;1&#59;6&#46;1&#93;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#46; Patients with erythema nodosum have increased frequencies of the alleles DRB1<span class="elsevierStyleSup">&#42;</span>03 &#40;28&#37; vs&#46; 9&#46;3&#37;&#41;&#44; R&#46;R&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;39&#44; C&#46;I&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#91;1&#46;5&#59;3&#46;8&#93;&#44; p<span class="elsevierStyleInf">c</span>&#61;0&#46;01 and DQB1<span class="elsevierStyleSup">&#42;</span>02 &#40;38&#37; vs&#46; 18&#37;&#41;&#44; R&#46;R&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;1&#44; C&#46;I&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#91;1&#46;3&#59;3&#46;3&#93;&#44; p<span class="elsevierStyleInf">c</span>&#61;0&#46;02&#46; Allele DQB1<span class="elsevierStyleSup">&#42;</span>03 is decreased in patients with obstructive pattern R&#46;R&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;53&#44; C&#46;I&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#91;0&#46;3&#59;0&#46;9&#93;&#44; p<span class="elsevierStyleInf">c</span>&#61;0&#46;05&#46; Allele DRB1<span class="elsevierStyleSup">&#42;</span>15 is related to restrictive pattern and reduced diffusion capacity &#40;21&#46;1&#37; <span class="elsevierStyleItalic">vs</span>&#46; 6&#46;6&#37;&#41;&#44; R&#46;R&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;46&#44; C&#46;I&#46;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#91;1&#46;35&#59;4&#46;48&#93;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01 and &#40;18&#46;1&#37; <span class="elsevierStyleItalic">vs</span>&#46; 3&#46;8&#37;&#41;&#44; R&#46;R&#46;&#61;1&#46;87&#44; p<span class="elsevierStyleInf">c</span>&#61; 0&#46;05 respectively&#46; The TNF-&#945; A&#47;A &#40;high&#41; genotype is significantly associated with erythema nodosum &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;04&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">These data add support to the genetic association of HLA class I and II with sarcoidosis in terms of susceptibility&#44; type of presentation&#44; severity and outcome&#46; Moreover as previously described in other populations&#44; the TNF-&#945; A&#47;A &#40;high&#41; genotype has a significant association with erythema nodosum&#46;</p>"
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        "resumen" => "<span class="elsevierStyleSectionTitle">Introdu&#231;&#227;o</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A susceptibilidade gen&#233;tica na ocorr&#234;ncia da sarcoidose &#233; sugerida por alguns factores&#44; nomeadamente pela observa&#231;&#227;o de casos de agrega&#231;&#227;o familiar e a associa&#231;&#227;o da ra&#231;a a diferentes tipos de incid&#234;ncia e gravidade da doen&#231;a&#46; V&#225;rios estudos t&#234;m evidenciado a associa&#231;&#227;o da classe I e especialmente da classe II do sistema HLA com a susceptibilidade &#224; sarcoidose&#46;</p> <span class="elsevierStyleSectionTitle">Objectivos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Estudo dos polimorfismos gen&#233;ticos da classe I e II do sistema HLA e do TNF-&#945; num grupo de doentes com sarcoidose&#44; nomeadamente a sua influ&#234;ncia na susceptibilidade&#44; apresenta&#231;&#227;o cl&#237;nica e evolu&#231;&#227;o da doen&#231;a&#46;</p> <span class="elsevierStyleSectionTitle">Material e m&#233;todos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Foram inclu&#237;dos 104 doentes com sarcoidose&#44; tendo sido estudadas a apresenta&#231;&#227;o cl&#237;nica&#44; funcional&#44; radiol&#243;gica e os resultados do LBA&#46; Foram usados m&#233;todos de biologia molecular na genotipagem do HLA -A<span class="elsevierStyleSup">&#42;</span>&#44; B<span class="elsevierStyleSup">&#42;</span>&#44; C<span class="elsevierStyleSup">&#42;</span>&#44; DRB1<span class="elsevierStyleSup">&#42;</span>&#44; DQB1<span class="elsevierStyleSup">&#42;</span> e TNF -&#945;&#46; O ADN foi extra&#237;do do sangue perif&#233;rico e foram usados os m&#233;todos PCR -SSP e PCR -<span class="elsevierStyleItalic">reverse hibridization</span>&#46; As frequ&#234;ncias al&#233;licas foram comparadas com controlos da mesma regi&#227;o geogr&#225;fica pelo teste &#967;<span class="elsevierStyleSup">2</span>&#44; sendo usado o teste Kruskal-Wallis para vari&#225;veis cont&#237;nuas&#46;</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Comparativamente com os controlos&#44; os doentes inclu&#237;dos apresentavam frequ&#234;ncias aumentadas de&#58; B<span class="elsevierStyleSup">&#42;</span>08 &#40;10&#44;6&#37; <span class="elsevierStyleItalic">vs</span> 6&#44;1&#37;&#41;&#44; OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44;8&#44; IC&#61;&#91;1&#44;1&#59;3&#44;1&#93;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;02&#59; DRB1<span class="elsevierStyleSup">&#42;</span>12 &#40;4&#44;3&#37; <span class="elsevierStyleItalic">vs</span> 1&#44;7&#37;&#41;&#44; OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44;63&#44; IC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#91;1&#44;1&#59;6&#44;1&#93;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;03&#46; Os doentes com eritema nodoso apresentaram aumento das frequ&#234;ncias al&#233;licas de DRB1<span class="elsevierStyleSup">&#42;</span>03 &#40;28&#37; <span class="elsevierStyleItalic">vs</span> 9&#44;3&#37;&#41;&#44; RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44;39&#44; IC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#91;1&#44;5&#59;3&#44;8&#93;&#44; p<span class="elsevierStyleInf">c</span>&#61;0&#44;01 e DQB1<span class="elsevierStyleSup">&#42;</span>02 &#40;38&#37; vs 18&#37;&#41;&#44; RR&#61;2&#44;1&#44; IC&#61;&#91;1&#44;3&#59;3&#44;3&#93;&#44; p<span class="elsevierStyleInf">c</span>&#61;0&#44;02&#46; O alelo DQB1<span class="elsevierStyleSup">&#42;</span>03 est&#225; diminu&#237;do nos doentes que apresentam s&#237;ndroma ventilat&#243;ria obstrutiva&#44; RR&#61;0&#44;53&#44; IC&#61;&#91;0&#44;3&#59;0&#44;9&#93;&#44; p<span class="elsevierStyleInf">c</span>&#61;0&#44;05&#46; O alelo DRB1<span class="elsevierStyleSup">&#42;</span>15 encontra -se significativamente associado quer &#224; s&#237;ndroma ventilat&#243;ria restritiva quer &#224; diminui&#231;&#227;o da transfer&#234;ncia alveolocapilar &#40;21&#44;1&#37; <span class="elsevierStyleItalic">vs</span> 6&#44;6&#37;&#41;&#44; RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44;46&#44; IC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#91;1&#44;35&#59;4&#44;48&#93;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;01 e &#40;18&#44;1&#37; <span class="elsevierStyleItalic">vs</span> 3&#44;8&#37;&#41;&#44; RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44;87&#44; pc<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#44; respectivamente&#46; Por sua vez&#44; o gen&#243;tipo A&#47;A &#40;<span class="elsevierStyleItalic">high</span>&#41; do TNF -&#945; apresentou uma frequ&#234;ncia aumentada &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;04&#41; nos doentes com eritema nodoso&#46;</p> <span class="elsevierStyleSectionTitle">Conclus&#245;es</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Os resultados obtidos adicionam evid&#234;ncia ao facto de&#44; quer a classe I quer a classe II do sistema HLA influenciarem a susceptibilidade&#44; o tipo de apresenta&#231;&#227;o&#44; o grau de gravidade e a evolu&#231;&#227;o na sarcoidose&#46; Por outro lado&#44; o eritema nodoso parece relacionar -se com o gen&#243;tipo de elevada produ&#231;&#227;o de TNF -&#945;&#44; associa&#231;&#227;o esta j&#225; anteriormente descrita&#46;</p>"
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                      "titulo" => "ATS&#47;ERS&#47;WASOG Statement on Sarcoidosis"
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                        0 => array:2 [
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                            2 => "M&#46; Ando"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.160.2.ats4-99"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "1999"
                        "volumen" => "160"
                        "paginaInicial" => "736"
                        "paginaFinal" => "755"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10430755"
                            "web" => "Medline"
                          ]
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                ]
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                      "titulo" => "Sarcoidosis"
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                          "etal" => false
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                            0 => "M&#46;C&#46; Iannuzzi"
                            1 => "B&#46;A&#46; Rybicki"
                            2 => "A&#46;S&#46; Teirstein"
                          ]
                        ]
                      ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMra071714"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2007"
                        "volumen" => "357"
                        "paginaInicial" => "2153"
                        "paginaFinal" => "2165"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18032765"
                            "web" => "Medline"
                          ]
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                ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Sarcoidosis"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46;P&#46; Baughman"
                            1 => "E&#46;E&#46; Lower"
                            2 => "R&#46; du Bois"
                          ]
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(03)12888-7"
                      "Revista" => array:5 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2003"
                        "volumen" => "361"
                        "paginaInicial" => "1111"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12672326"
                            "web" => "Medline"
                          ]
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                      ]
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                  ]
                ]
              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetics ofn sarcoidosis&#59; candidate genes and genome scans"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46;C&#46; Iannuzzi"
                            1 => "B&#46;A&#46; Rybicki"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Proc Am Thorac Soc"
                        "fecha" => "2007"
                        "numero" => "4"
                        "paginaInicial" => "108"
                        "paginaFinal" => "116"
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib5"
              "etiqueta" => "5&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Familial aggregation of sarcoidosis&#46; A case control etiologic study of sarcoidosis &#40;ACCESS&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "B&#46;A&#46; Rybicki"
                            1 => "M&#46;C&#46; Iannuzzi"
                            2 => "M&#46;M&#46; Frederick"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Am J Repir Crit Care Med"
                        "fecha" => "2001"
                        "volumen" => "164"
                        "paginaInicial" => "2085"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib6"
              "etiqueta" => "6&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The HLA System"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Klein"
                            1 => "A&#46; Sato"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM200009073431006"
                      "Revista" => array:7 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2000"
                        "volumen" => "343"
                        "numero" => "10"
                        "paginaInicial" => "702"
                        "paginaFinal" => "709"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10974135"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            6 => array:3 [
              "identificador" => "bib7"
              "etiqueta" => "7&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Sarcoidosis and human leucocyte antigen class I and II genes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "B&#46;A&#46; Rybicki"
                            1 => "M&#46;C&#46; Iannuzzi"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/rccm.2401005"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2004"
                        "volumen" => "169"
                        "paginaInicial" => "665"
                        "paginaFinal" => "666"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15003948"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib8"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA antigens in sarcoidosis"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "D&#46; Brewerton"
                            1 => "C&#46; Cockburn"
                            2 => "D&#46; James"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Immunol"
                        "fecha" => "1977"
                        "volumen" => "27"
                        "paginaInicial" => "227"
                        "paginaFinal" => "229"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/849654"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib9"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA-B8 in sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "S&#46; Olenchock"
                            1 => "E&#46; Heise"
                            2 => "J&#46; Marz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Allergy"
                        "fecha" => "1981"
                        "volumen" => "47"
                        "paginaInicial" => "151"
                        "paginaFinal" => "153"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6455946"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib10"
              "etiqueta" => "10&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA antigens associated with sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "K&#46; Lenhart"
                            1 => "V&#46; Kolek"
                            2 => "A&#46; Bartova"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Dis Markers"
                        "fecha" => "1990"
                        "volumen" => "8"
                        "paginaInicial" => "23"
                        "paginaFinal" => "29"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2311346"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib11"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA-A&#44;B C antigens in pulmonary sarcoidosis in Polish population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46; Dubaniewicz"
                            1 => "Z&#46; Szczerkowska"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Immunol Ther Exp &#40;Warz&#41;"
                        "fecha" => "1999"
                        "volumen" => "47"
                        "numero" => "1"
                        "paginaInicial" => "55"
                        "paginaFinal" => "59"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA class I&#44; II III polymorphism in Italian patients with sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "L&#46; Pasturenzi"
                            1 => "M&#46; Martinetti"
                            2 => "M&#46; Cuccia"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Chest"
                        "fecha" => "1993"
                        "volumen" => "104"
                        "numero" => "4"
                        "paginaInicial" => "1170"
                        "paginaFinal" => "1175"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8404186"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib13"
              "etiqueta" => "13&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "&#8216;The sarcoidosis map&#8217;&#58; a joint survey of clinical and immunogenetic findings in two European countries"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "M&#46; Martinetti"
                            1 => "C&#46; Tinelli"
                            2 => "V&#46; Kolek"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.152.2.7633707"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "1995"
                        "volumen" => "152"
                        "paginaInicial" => "557"
                        "paginaFinal" => "564"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7633707"
                            "web" => "Medline"
                          ]
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                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib14"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human leukocyte antigen &#8211; DR alleles influence the clinical course of pulmonary sarcoidosis in asian Indians"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "S&#46; Sharma"
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                            2 => "R&#46; Pandey"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1165/rcmb.2003-0007OC"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Cell Mol Biol"
                        "fecha" => "2003"
                        "volumen" => "29"
                        "paginaInicial" => "225"
                        "paginaFinal" => "231"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12600814"
                            "web" => "Medline"
                          ]
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                ]
              ]
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            14 => array:3 [
              "identificador" => "bib15"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparative analysis of HLA class I antigens in pulmonary sarcoidosis and tuberculosis in the same ethnic group"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.4065/78.4.436"
                      "Revista" => array:7 [
                        "tituloSerie" => "Mayo Clin Proc"
                        "fecha" => "2003"
                        "volumen" => "78"
                        "numero" => "4"
                        "paginaInicial" => "436"
                        "paginaFinal" => "442"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12683696"
                            "web" => "Medline"
                          ]
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                  ]
                ]
              ]
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            15 => array:3 [
              "identificador" => "bib16"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Increased HLA--B7 antigen frequency in South Caroline blacks in association with sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "J&#46; McIntyre"
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                            2 => "C&#46; Loadholt"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Transplant Proc"
                        "fecha" => "1977"
                        "volumen" => "9"
                        "paginaInicial" => "173"
                        "paginaFinal" => "176"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/854962"
                            "web" => "Medline"
                          ]
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                    ]
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                ]
              ]
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            16 => array:3 [
              "identificador" => "bib17"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA-DR2 predicts susceptibility and disease chronicity in Irish sarcoidosis patients"
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                          "etal" => true
                          "autores" => array:3 [
                            0 => "R&#46;M&#46; Rutherford"
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                            2 => "M&#46; Kearns"
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Sarcoidosis Vasc Diffuse Lung Dis"
                        "fecha" => "2004"
                        "volumen" => "21"
                        "numero" => "3"
                        "paginaInicial" => "191"
                        "paginaFinal" => "198"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15554075"
                            "web" => "Medline"
                          ]
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                ]
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            ]
            17 => array:3 [
              "identificador" => "bib18"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of HLA-B8 with spontaneous resolution in sarcoidosis"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "M&#46; Smith"
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                            2 => "D&#46; Mitchell"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Thorax"
                        "fecha" => "1981"
                        "volumen" => "36"
                        "paginaInicial" => "296"
                        "paginaFinal" => "298"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7281099"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib19"
              "etiqueta" => "19&#46;"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human luekocyte antigen class I alleles and the disease course in sarcoidosis patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46; Grunewald"
                            1 => "A&#46; Eklund"
                            2 => "O&#46; Olerup"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/rccm.200303-459OC"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2004"
                        "volumen" => "169"
                        "paginaInicial" => "696"
                        "paginaFinal" => "702"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14656748"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib20"
              "etiqueta" => "20&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA class II genotyping of sarcoidosis patients in Hokkaido by PCR-RFLP"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "M&#46; Ishihara"
                            1 => "H&#46; Inoko"
                            2 => "K&#46; Suzuki"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Jpn J Ophthalmol"
                        "fecha" => "1996"
                        "volumen" => "40"
                        "paginaInicial" => "540"
                        "paginaFinal" => "543"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9130059"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib21"
              "etiqueta" => "21&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA serological and class II genotyping in sarcoidosis patients in Japan"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
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                            0 => "M&#46; Ishihara"
                            1 => "T&#46; Ishida"
                            2 => "H&#46; Inoko"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Jpn J Ophthalmol"
                        "fecha" => "1996"
                        "volumen" => "40"
                        "paginaInicial" => "86"
                        "paginaFinal" => "94"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8739505"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib22"
              "etiqueta" => "22&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic aspects of sarcoidosis ClassII histocompatibility antigens and a family study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "D&#46; Nowack"
                            1 => "K&#46;M&#46; Goebel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Intern Med"
                        "fecha" => "1987"
                        "volumen" => "147"
                        "paginaInicial" => "481"
                        "paginaFinal" => "483"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3827423"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib23"
              "etiqueta" => "23&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA -DRB1<span class="elsevierStyleSup">&#42;</span>1101&#58; a significant risk factor for sarcoidosis in blacks and whites"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "M&#46;D&#46; Rossman"
                            1 => "B&#46; Thomson"
                            2 => "M&#46; Frederick"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1086/378097"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Hum Genet"
                        "fecha" => "2003"
                        "volumen" => "73"
                        "paginaInicial" => "720"
                        "paginaFinal" => "735"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14508706"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib24"
              "etiqueta" => "24&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Sarcoidosis susceptibility and resistance HLA-DQB1 alleles in African Americans"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "M&#46; Iannuzzi"
                            1 => "M&#46; Maliarik"
                            2 => "L&#46; Poisson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2003"
                        "volumen" => "1670"
                        "paginaInicial" => "1225"
                        "paginaFinal" => "1231"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib25"
              "etiqueta" => "25&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "J&#46; Grutters"
                            1 => "H&#46; Sato"
                            2 => "K&#46; Welsh"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Cell Mol Biol"
                        "fecha" => "2003"
                        "volumen" => "29"
                        "paginaInicial" => "S59"
                        "paginaFinal" => "S62"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14503556"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib26"
              "etiqueta" => "26&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA -DQB1<span class="elsevierStyleSup">&#42;</span>0602-DRB1<span class="elsevierStyleSup">&#42;</span>150101"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "C&#46;E&#46; Voorter"
                            1 => "M&#46; Drent"
                            2 => "E&#46;M&#46; Van den Berger-Loonen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.humimm.2005.04.003"
                      "Revista" => array:7 [
                        "tituloSerie" => "Hum Immunol"
                        "fecha" => "2005"
                        "volumen" => "66"
                        "numero" => "7"
                        "paginaInicial" => "826"
                        "paginaFinal" => "835"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16112030"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib27"
              "etiqueta" => "27&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The major histocompatibility complex gene region and sarcoidosis susceptibility in African Americans"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "B&#46;A&#46; Rybicki"
                            1 => "M&#46;J&#46; Maliarik"
                            2 => "L&#46;M&#46; Poisson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/rccm.2112060"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2003"
                        "volumen" => "167"
                        "paginaInicial" => "444"
                        "paginaFinal" => "449"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12554629"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib28"
              "etiqueta" => "28&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA &#8211; DQB1<span class="elsevierStyleSup">&#42;</span>0201&#58; a marker for good prognosis in british and dutch patients with sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "H&#46; Sato"
                            1 => "J&#46; Grutters"
                            2 => "P&#46; Pantelidis"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1165/rcmb.4782"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Cell Mol Biol"
                        "fecha" => "2002"
                        "volumen" => "27"
                        "paginaInicial" => "406"
                        "paginaFinal" => "411"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12356573"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib29"
              "etiqueta" => "29&#46;"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Grutters JC&#44; Ruven HJT&#44; Sato H&#44; <span class="elsevierStyleItalic">et al</span>&#46; MHC haplotype analysis in Dutch sarcoidosis patients presenting with L&#246;fgren&#39;s syndrome&#46; <span class="elsevierStyleItalic">In</span>&#58; &#40;Ed&#46;&#41;&#46; Genetic polymorphisms and phenotypes in sarcoidosis&#46; Utrecht&#44; Thesis University Utrech&#44; 2003&#58; 85-96&#46;"
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib30"
              "etiqueta" => "30&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of tumor necrosis factor-alpha&#44; lymphotoxin-alpha and HLA-DRB1 gene polymorphisms with Lofgren&#39;s syndrome in Czech patients with sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "F&#46; Mrazek"
                            1 => "L&#46;I&#46; Holla"
                            2 => "B&#46; Hutyrova"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1399-0039.2005.00370.x"
                      "Revista" => array:7 [
                        "tituloSerie" => "Tissue Antigens"
                        "fecha" => "2005"
                        "volumen" => "65"
                        "numero" => "2"
                        "paginaInicial" => "163"
                        "paginaFinal" => "171"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15713215"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib31"
              "etiqueta" => "31&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA--DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "M&#46; Berlin"
                            1 => "A&#46; Fogdell -Hahn"
                            2 => "O&#46; Olerup"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.156.5.9704069"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "1997"
                        "volumen" => "156"
                        "paginaInicial" => "1601"
                        "paginaFinal" => "1605"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9372682"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib32"
              "etiqueta" => "32&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Analysis of IL-6 and IL1A gene polymorphisms in UK and Dutch patients with sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "J&#46;C&#46; Grutters"
                            1 => "H&#46; Sato"
                            2 => "P&#46; Pantelidis"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Sarcoidosis Vas Diffuse Lung Dis"
                        "fecha" => "2003"
                        "volumen" => "20"
                        "numero" => "1"
                        "paginaInicial" => "20"
                        "paginaFinal" => "27"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib33"
              "etiqueta" => "33&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetics of sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "P&#46; Spagnolo"
                            1 => "R&#46;M&#46; du Bois"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.clindermatol.2007.03.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clinics in Dermatology"
                        "fecha" => "2007"
                        "volumen" => "25"
                        "paginaInicial" => "242"
                        "paginaFinal" => "249"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17560301"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib34"
              "etiqueta" => "34&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms at position &#8211; 308 in the promoter region of the TNF-alpha and in the first intron of the TNF-beta genes and spontaneous and lipopolysaccharide-induced TNF-alpha release in sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "A&#46; Somoskovi"
                            1 => "G&#46; Zissel"
                            2 => "U&#46; Seitzer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1006/cyto.1999.0498"
                      "Revista" => array:7 [
                        "tituloSerie" => "Cytokine"
                        "fecha" => "1999"
                        "volumen" => "11"
                        "numero" => "11"
                        "paginaInicial" => "882"
                        "paginaFinal" => "887"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10547277"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib35"
              "etiqueta" => "35&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Increased frequency of the uncommon tumor necrosis factor--857T allele in British and Dutch patients with sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "J&#46;C&#46; Grutters"
                            1 => "H&#46; Sato"
                            2 => "P&#46; Pantelidis"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.165.8.200110-0320"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2002"
                        "volumen" => "165"
                        "paginaInicial" => "1119"
                        "paginaFinal" => "1124"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11956055"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib36"
              "etiqueta" => "36&#46;"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Grutters JC&#44; Ruven HJT&#44; Sato H&#44; et al&#46; TNF promotor haplotypes associate with clinical phenotypes and prognosis in sarcoidosis&#46; In&#58; &#40;Ed&#46;&#41;&#46; Genetic polymorphisms and phenotypes in sarcoidosis&#46; Utrecht&#44; Thesis University Utrecht&#59; 2003&#58; 49-66&#46;"
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib37"
              "etiqueta" => "37&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of tumor necrosis factor-&#945;&#44; lymphotoxin-&#945; and DRB1 gene polymorphisms with L&#246;fgren&#39;s syndrome in Czech patients with sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:10 [
                            0 => "F&#46; Mrazek"
                            1 => "L&#46;I&#46; Holla"
                            2 => "B&#46; Hutyrova"
                            3 => "V&#46; Znojil"
                            4 => "A&#46; Vasku"
                            5 => "V&#46; Kolek"
                            6 => "K&#46;I&#46; Welsh"
                            7 => "J&#46; Vacha"
                            8 => "R&#46;M&#46; du Bois"
                            9 => "M&#46; Petrek"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1399-0039.2005.00370.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Tissue Antigens"
                        "fecha" => "2005"
                        "volumen" => "65"
                        "paginaInicial" => "163"
                        "paginaFinal" => "717"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15713215"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib38"
              "etiqueta" => "38&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tumour necrosis factor alpha promotor gene polymorphism in sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "U&#46; Seitzer"
                            1 => "C&#46; Swider"
                            2 => "F&#46; Stuber"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1006/cyto.1997.0224"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cytokine"
                        "fecha" => "1997"
                        "volumen" => "9"
                        "paginaInicial" => "787"
                        "paginaFinal" => "790"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9344512"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib39"
              "etiqueta" => "39&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA and sarcoidosis&#58; new pathogenic insights"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46; Martinetti"
                            1 => "M&#46; Luisetti"
                            2 => "M&#46; Cuccia"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Sarcoidosis Vasc Diffuse Lung Dis"
                        "fecha" => "2002"
                        "paginaInicial" => "19"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib40"
              "etiqueta" => "40&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tumour necrosis factor-alpha promoter polymorphism in erythema nodosum"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "S&#46; Labunski"
                            1 => "G&#46; Posern"
                            2 => "S&#46; Ludwig"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Acta Derm Venereol"
                        "fecha" => "2001"
                        "volumen" => "81"
                        "numero" => "1"
                        "paginaInicial" => "18"
                        "paginaFinal" => "21"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11411907"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib41"
              "etiqueta" => "41&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The gene polymorphism of tumour necrosis factor-beta&#44; but not that of tumour necrosis factor-alpha&#44; is associated with prognosis of sarcoidosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "E&#46; Yamaguchi"
                            1 => "A&#46; Itoh"
                            2 => "N&#46; Hizawa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Chest"
                        "fecha" => "2001"
                        "volumen" => "119"
                        "numero" => "3"
                        "paginaInicial" => "753"
                        "paginaFinal" => "761"
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Vol. 14. Issue 6.
Pages 727-746 (November - December 2008)
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Vol. 14. Issue 6.
Pages 727-746 (November - December 2008)
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HLA class I and II and TNF-α gene polymorphisms in sarcoidosis patients
Estudo de polimorfismos genéticos do HLA (classes I e II) e do TNF-α em doentes com sarcoidose
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António Morais1, Helena Alves2, Bruno Lima2, Luís Delgado3, Ricardo Gonçalves2, Sandra Tafulo2
1 Serviço de Pneumologia do Hospital São João, Porto / Pulmonology Unit, Hospital São João, Porto
2 Centro de Histocompatibilidade do Norte / Histocompatability Centre of the North
3 Serviço de Imunologia da Faculdade de Medicina do Porto / Pulmonology Unit, Porto Faculty of Medicine
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Abstract
Introduction

Several factors suggest a genetic predisposition to sarcoidosis, namely the recognition of race as a risk factor and the occurrence of familial clustering of cases. Several studies have reported an association of sarcoidosis and HLA class I and especially class II alleles in different populations.

Aim

HLA class I, class II and TNF-α genotyping in a group of sarcoidosis patients and its relation with clinical presentation and outcome.

Material and methods

A total of 104 sarcoidosis patients were included. Clinical presentation, functional, radiology, BAL findings and organ involvement were studied. HLA– A*, -B*, -C*, DRB1*, DQB1* and TNF-α were genotyped by molecular biology methods. DNA was extracted from peripheral blood and PCR-SSP and PCR-reverse hybridisation me-thods were used. Allele frequencies were compared with controls from the same region. The X2 test was used for discrete values and the Kruskal-Wallis test for continuous values.

Results

When patients were compared with controls we noticed increased frequencies of B*08 (10.6% vs. 6.1%), O.R.=1.8, C.I.=[1.1;3.1], p=0.02; DRB1*12 (4.3% vs. 1.7%), O.R.=2.63, C.I.=[1.1;6.1], p=0.03. Patients with erythema nodosum have increased frequencies of the alleles DRB1*03 (28% vs. 9.3%), R.R.=2.39, C.I.=[1.5;3.8], pc=0.01 and DQB1*02 (38% vs. 18%), R.R.=2.1, C.I.=[1.3;3.3], pc=0.02. Allele DQB1*03 is decreased in patients with obstructive pattern R.R.=0.53, C.I.=[0.3;0.9], pc=0.05. Allele DRB1*15 is related to restrictive pattern and reduced diffusion capacity (21.1% vs. 6.6%), R.R.=2.46, C.I.=[1.35;4.48], p=0.01 and (18.1% vs. 3.8%), R.R.=1.87, pc= 0.05 respectively. The TNF-α A/A (high) genotype is significantly associated with erythema nodosum (p=0.04).

Conclusions

These data add support to the genetic association of HLA class I and II with sarcoidosis in terms of susceptibility, type of presentation, severity and outcome. Moreover as previously described in other populations, the TNF-α A/A (high) genotype has a significant association with erythema nodosum.

Key-words:
Sarcoidosis
genetics
HLA
Resumo
Introdução

A susceptibilidade genética na ocorrência da sarcoidose é sugerida por alguns factores, nomeadamente pela observação de casos de agregação familiar e a associação da raça a diferentes tipos de incidência e gravidade da doença. Vários estudos têm evidenciado a associação da classe I e especialmente da classe II do sistema HLA com a susceptibilidade à sarcoidose.

Objectivos

Estudo dos polimorfismos genéticos da classe I e II do sistema HLA e do TNF-α num grupo de doentes com sarcoidose, nomeadamente a sua influência na susceptibilidade, apresentação clínica e evolução da doença.

Material e métodos

Foram incluídos 104 doentes com sarcoidose, tendo sido estudadas a apresentação clínica, funcional, radiológica e os resultados do LBA. Foram usados métodos de biologia molecular na genotipagem do HLA -A*, B*, C*, DRB1*, DQB1* e TNF -α. O ADN foi extraído do sangue periférico e foram usados os métodos PCR -SSP e PCR -reverse hibridization. As frequências alélicas foram comparadas com controlos da mesma região geográfica pelo teste χ2, sendo usado o teste Kruskal-Wallis para variáveis contínuas.

Resultados

Comparativamente com os controlos, os doentes incluídos apresentavam frequências aumentadas de: B*08 (10,6% vs 6,1%), OR=1,8, IC=[1,1;3,1], p=0,02; DRB1*12 (4,3% vs 1,7%), OR=2,63, IC=[1,1;6,1], p=0,03. Os doentes com eritema nodoso apresentaram aumento das frequências alélicas de DRB1*03 (28% vs 9,3%), RR=2,39, IC=[1,5;3,8], pc=0,01 e DQB1*02 (38% vs 18%), RR=2,1, IC=[1,3;3,3], pc=0,02. O alelo DQB1*03 está diminuído nos doentes que apresentam síndroma ventilatória obstrutiva, RR=0,53, IC=[0,3;0,9], pc=0,05. O alelo DRB1*15 encontra -se significativamente associado quer à síndroma ventilatória restritiva quer à diminuição da transferência alveolocapilar (21,1% vs 6,6%), RR=2,46, IC=[1,35;4,48], p=0,01 e (18,1% vs 3,8%), RR=1,87, pc=0,05, respectivamente. Por sua vez, o genótipo A/A (high) do TNF -α apresentou uma frequência aumentada (p=0,04) nos doentes com eritema nodoso.

Conclusões

Os resultados obtidos adicionam evidência ao facto de, quer a classe I quer a classe II do sistema HLA influenciarem a susceptibilidade, o tipo de apresentação, o grau de gravidade e a evolução na sarcoidose. Por outro lado, o eritema nodoso parece relacionar -se com o genótipo de elevada produção de TNF -α, associação esta já anteriormente descrita.

Palavras-chave:
Sacordoise
genética
HLA
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Bibliography/Bibliografia
[1.]
G.W. Hunninghake, U. Costabel, M. Ando.
ATS/ERS/WASOG Statement on Sarcoidosis.
Am J Respir Crit Care Med, 160 (1999), pp. 736-755
[2.]
M.C. Iannuzzi, B.A. Rybicki, A.S. Teirstein.
Sarcoidosis.
N Engl J Med, 357 (2007), pp. 2153-2165
[3.]
R.P. Baughman, E.E. Lower, R. du Bois.
Sarcoidosis.
[4.]
M.C. Iannuzzi, B.A. Rybicki.
Genetics ofn sarcoidosis; candidate genes and genome scans.
Proc Am Thorac Soc, (2007), pp. 108-116
[5.]
B.A. Rybicki, M.C. Iannuzzi, M.M. Frederick, et al.
Familial aggregation of sarcoidosis. A case control etiologic study of sarcoidosis (ACCESS).
Am J Repir Crit Care Med, 164 (2001), pp. 2085
[6.]
J. Klein, A. Sato.
The HLA System.
N Engl J Med, 343 (2000), pp. 702-709
[7.]
B.A. Rybicki, M.C. Iannuzzi.
Sarcoidosis and human leucocyte antigen class I and II genes.
Am J Respir Crit Care Med, 169 (2004), pp. 665-666
[8.]
D. Brewerton, C. Cockburn, D. James, et al.
HLA antigens in sarcoidosis.
Clin Exp Immunol, 27 (1977), pp. 227-229
[9.]
S. Olenchock, E. Heise, J. Marz, et al.
HLA-B8 in sarcoidosis.
Ann Allergy, 47 (1981), pp. 151-153
[10.]
K. Lenhart, V. Kolek, A. Bartova.
HLA antigens associated with sarcoidosis.
Dis Markers, 8 (1990), pp. 23-29
[11.]
A. Dubaniewicz, Z. Szczerkowska.
HLA-A,B C antigens in pulmonary sarcoidosis in Polish population.
Arch Immunol Ther Exp (Warz), 47 (1999), pp. 55-59
[11.]
L. Pasturenzi, M. Martinetti, M. Cuccia.
HLA class I, II III polymorphism in Italian patients with sarcoidosis.
Chest, 104 (1993), pp. 1170-1175
[13.]
M. Martinetti, C. Tinelli, V. Kolek, et al.
‘The sarcoidosis map’: a joint survey of clinical and immunogenetic findings in two European countries.
Am J Respir Crit Care Med, 152 (1995), pp. 557-564
[14.]
S. Sharma, A. Balamurugan, R. Pandey, et al.
Human leukocyte antigen – DR alleles influence the clinical course of pulmonary sarcoidosis in asian Indians.
Am J Respir Cell Mol Biol, 29 (2003), pp. 225-231
[15.]
A. Dubaniewicz, Z. Szczerkowska, A. Hoppe.
Comparative analysis of HLA class I antigens in pulmonary sarcoidosis and tuberculosis in the same ethnic group.
Mayo Clin Proc, 78 (2003), pp. 436-442
[16.]
J. McIntyre, K. Mckee, C. Loadholt, et al.
Increased HLA--B7 antigen frequency in South Caroline blacks in association with sarcoidosis.
Transplant Proc, 9 (1977), pp. 173-176
[17.]
R.M. Rutherford, M.H. Brutshe, M. Kearns, et al.
HLA-DR2 predicts susceptibility and disease chronicity in Irish sarcoidosis patients.
Sarcoidosis Vasc Diffuse Lung Dis, 21 (2004), pp. 191-198
[18.]
M. Smith, C. Turton, D. Mitchell, et al.
Association of HLA-B8 with spontaneous resolution in sarcoidosis.
Thorax, 36 (1981), pp. 296-298
[19.]
J. Grunewald, A. Eklund, O. Olerup.
Human luekocyte antigen class I alleles and the disease course in sarcoidosis patients.
Am J Respir Crit Care Med, 169 (2004), pp. 696-702
[20.]
M. Ishihara, H. Inoko, K. Suzuki, et al.
HLA class II genotyping of sarcoidosis patients in Hokkaido by PCR-RFLP.
Jpn J Ophthalmol, 40 (1996), pp. 540-543
[21.]
M. Ishihara, T. Ishida, H. Inoko, et al.
HLA serological and class II genotyping in sarcoidosis patients in Japan.
Jpn J Ophthalmol, 40 (1996), pp. 86-94
[22.]
D. Nowack, K.M. Goebel.
Genetic aspects of sarcoidosis ClassII histocompatibility antigens and a family study.
Arch Intern Med, 147 (1987), pp. 481-483
[23.]
M.D. Rossman, B. Thomson, M. Frederick, et al.
HLA -DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites.
Am J Hum Genet, 73 (2003), pp. 720-735
[24.]
M. Iannuzzi, M. Maliarik, L. Poisson, et al.
Sarcoidosis susceptibility and resistance HLA-DQB1 alleles in African Americans.
Am J Respir Crit Care Med, 1670 (2003), pp. 1225-1231
[25.]
J. Grutters, H. Sato, K. Welsh, et al.
Am J Respir Cell Mol Biol, 29 (2003), pp. S59-S62
[26.]
C.E. Voorter, M. Drent, E.M. Van den Berger-Loonen.
Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA -DQB1*0602-DRB1*150101.
Hum Immunol, 66 (2005), pp. 826-835
[27.]
B.A. Rybicki, M.J. Maliarik, L.M. Poisson.
The major histocompatibility complex gene region and sarcoidosis susceptibility in African Americans.
Am J Respir Crit Care Med, 167 (2003), pp. 444-449
[28.]
H. Sato, J. Grutters, P. Pantelidis, et al.
HLA – DQB1*0201: a marker for good prognosis in british and dutch patients with sarcoidosis.
Am J Respir Cell Mol Biol, 27 (2002), pp. 406-411
[29.]
Grutters JC, Ruven HJT, Sato H, et al. MHC haplotype analysis in Dutch sarcoidosis patients presenting with Löfgren's syndrome. In: (Ed.). Genetic polymorphisms and phenotypes in sarcoidosis. Utrecht, Thesis University Utrech, 2003: 85-96.
[30.]
F. Mrazek, L.I. Holla, B. Hutyrova, et al.
Association of tumor necrosis factor-alpha, lymphotoxin-alpha and HLA-DRB1 gene polymorphisms with Lofgren's syndrome in Czech patients with sarcoidosis.
Tissue Antigens, 65 (2005), pp. 163-171
[31.]
M. Berlin, A. Fogdell -Hahn, O. Olerup, et al.
HLA--DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis.
Am J Respir Crit Care Med, 156 (1997), pp. 1601-1605
[32.]
J.C. Grutters, H. Sato, P. Pantelidis, et al.
Analysis of IL-6 and IL1A gene polymorphisms in UK and Dutch patients with sarcoidosis.
Sarcoidosis Vas Diffuse Lung Dis, 20 (2003), pp. 20-27
[33.]
P. Spagnolo, R.M. du Bois.
Genetics of sarcoidosis.
Clinics in Dermatology, 25 (2007), pp. 242-249
[34.]
A. Somoskovi, G. Zissel, U. Seitzer, et al.
Polymorphisms at position – 308 in the promoter region of the TNF-alpha and in the first intron of the TNF-beta genes and spontaneous and lipopolysaccharide-induced TNF-alpha release in sarcoidosis.
Cytokine, 11 (1999), pp. 882-887
[35.]
J.C. Grutters, H. Sato, P. Pantelidis, et al.
Increased frequency of the uncommon tumor necrosis factor--857T allele in British and Dutch patients with sarcoidosis.
Am J Respir Crit Care Med, 165 (2002), pp. 1119-1124
[36.]
Grutters JC, Ruven HJT, Sato H, et al. TNF promotor haplotypes associate with clinical phenotypes and prognosis in sarcoidosis. In: (Ed.). Genetic polymorphisms and phenotypes in sarcoidosis. Utrecht, Thesis University Utrecht; 2003: 49-66.
[37.]
F. Mrazek, L.I. Holla, B. Hutyrova, V. Znojil, A. Vasku, V. Kolek, K.I. Welsh, J. Vacha, R.M. du Bois, M. Petrek.
Association of tumor necrosis factor-α, lymphotoxin-α and DRB1 gene polymorphisms with Löfgren's syndrome in Czech patients with sarcoidosis.
Tissue Antigens, 65 (2005), pp. 163-717
[38.]
U. Seitzer, C. Swider, F. Stuber, et al.
Tumour necrosis factor alpha promotor gene polymorphism in sarcoidosis.
Cytokine, 9 (1997), pp. 787-790
[39.]
M. Martinetti, M. Luisetti, M. Cuccia.
HLA and sarcoidosis: new pathogenic insights.
Sarcoidosis Vasc Diffuse Lung Dis, (2002), pp. 19
[40.]
S. Labunski, G. Posern, S. Ludwig, et al.
Tumour necrosis factor-alpha promoter polymorphism in erythema nodosum.
Acta Derm Venereol, 81 (2001), pp. 18-21
[41.]
E. Yamaguchi, A. Itoh, N. Hizawa, et al.
The gene polymorphism of tumour necrosis factor-beta, but not that of tumour necrosis factor-alpha, is associated with prognosis of sarcoidosis.
Chest, 119 (2001), pp. 753-761
[42.]
N. Takashigue, T.K. Naruse, A. Matsumori, et al.
Genetic polymorphisms at tumour necrosis factor loci (TNFA and TNFB) in cardiac sarcoidosis.
Tissue Antigens, 54 (1999), pp. 191-193
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