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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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