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        "resumen" => "<span id="as0005" class="elsevierStyleSection elsevierViewall"><p id="sp0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Introdu&#231;&#227;o&#58;</span> 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><p id="sp0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Objectivos&#58;</span> 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><p id="sp0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Material e m&#233;todos&#58;</span> 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&#42;&#44; B&#42;&#44; C&#42;&#44; DRB1&#42;&#44; DQB1&#42; 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><p id="sp0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Resultados&#58;</span> Comparativamente com os controlos&#44; os doentes inclu&#237;dos apresentavam frequ&#234;ncias aumentadas de&#58; B&#42;08 &#40;10&#44;6&#37; <span class="elsevierStyleItalic">vs</span> 6&#44;1&#37;&#41;&#44; 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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><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;01 e DQB1&#42;02 &#40;38&#37; <span class="elsevierStyleItalic">vs</span> 18&#37;&#41;&#44; RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44;1&#44; IC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#91;1&#44;3&#59;3&#44;3&#93;&#44; p<span class="elsevierStyleInf">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;02&#46; O alelo DQB1&#42;03 est&#225; diminu&#237;do nos doentes que apresentam s&#237;ndroma ventilat&#243;ria obstrutiva&#44; RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;53&#44; IC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#91;0&#44;3&#59;0&#44;9&#93;&#44; p<span class="elsevierStyleInf">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#46; O alelo DRB1&#42;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; p<span class="elsevierStyleInf">c</span><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 <span class="elsevierStyleItalic">&#40;high&#41;</span> 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><p id="sp0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Conclus&#245;es&#58;</span> 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><p id="sp0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Rev Port Pneumol 2008&#59; XIV &#40;6</span>&#41;<span class="elsevierStyleBold">&#58; 727-746</span></p></span>"
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        "resumen" => "<span id="as0010" class="elsevierStyleSection elsevierViewall"><p id="sp0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Introduction&#58;</span> 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><p id="sp0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Aim&#58;</span> 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><p id="sp0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Material and methods&#58;</span> A total of 104 sarcoidosis patients were included&#46; Clinical presentation&#44; functional&#44; 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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><p id="sp0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Conclusions&#58;</span> 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><p id="sp0060" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Rev Port Pneumol 2008&#59; XIV &#40;6&#41;&#58; 727-746</span></p></span>"
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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)
Artigo Original/Original Article
Open Access
Estudo de polimorfismos genéticos do HLA (classes I e II) e do TNF-α em doentes com sarcoidose
HLA class I and II and TNF-α gene polymorphisms in sarcoidosis patients
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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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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.

Rev Port Pneumol 2008; XIV (6): 727-746

Palavras-chave:
Sacordoise
genética
HLA
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 methods 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.

Rev Port Pneumol 2008; XIV (6): 727-746

Key-words:
Sarcoidosis
genetics
HLA
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