Caracterização HLA na população portuguesa de doentes com espondilite anquilosante
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2010
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Introdução: A Espondilite Anquilosante (EA) é uma doença reumática inflamatória com um componente hereditário muito significativo e com uma prevalência global muito similar à artrite reumatóide. A forte associação com o alelo HLA-B27 é conhecida desde a década de 70. Existem evidências de que múltiplos genes MHC e não MHC possam exercer influência em diferentes aspectos da doença.
Objectivos: A presente investigação teve como principais objectivos investigar as associações individuais de alelos HLA classe I/II e de haplotipos MHC estendidos (HLA-A/B*27/-Cw/-DRB1/-DQB1) com a susceptibilidade e com características fenotípicas da EA. Determinar a frequência dos subtipos B*27 na população Portuguesa, estabelecendo possíveis associações entre estes polimorfismos e a doença.
Métodos: Recrutaram-se 188 pacientes em vários centros de reumatologia nacionais segundo os critérios de Nova Iorque modificados (1984). O grupo controlo (n=189) foi seleccionado a partir do registo nacional de dadores de medula óssea do Centro de Histocompatibilidade do Sul. Neste estudo, apenas indivíduos HLA-B27 positivos (doentes e controlos) foram considerados. Ambos os grupos foram genotipados para os loci HLA-A, -B, -Cw, -DRB1 e -DQB1 através da PCR-rSSOP. A alta resolução foi realizada de forma a determinar os subtipos B*27 num subgrupo de 138 doentes e 189 controlos. Os haplotipos foram estimados pelo algoritmo EM, do software Arlequim v3.11. As comparações caso-controlo foram efectuadas através de tabelas de contingência; as associações entre características clínicas e genéticas foram determinadas através de regressões lineares e logísticas binomiais, utilizando o software Stata10.1.
Resultados: Não se observaram associações entre os loci HLA em estudo e a susceptibilidade para a EA. Na nossa população, os alelos B*27 relacionados com a doença aparecem frequentemente associados com o haplotipo: A*02/B*27/Cw*02/DRB1*01/DQB1*05 (p=0,000; OR=39,06; IC 95% [2,34-651]). As correlações entre variáveis clínicas e genéticas efectuadas revelaram a presença de vários alelos e haplotipos associados com as características fenotípicas da doença. O haplotipo A*02/B*27/Cw*01/DRB1*08/DQB1*04 e o alelo DQB1*04 parecem exercer um efeito “protector” em relação à gravidade, repercussão funcional e radiológica. Os alelos B*2705 e B*2702 foram os subtipos mais frequentes na população Portuguesa, neste caso não se verificaram diferenças significativas na distribuição dos subtipos B*27 entre grupo de doentes e controlos.
Conclusões: Na população Portuguesa identificou-se um haplotipo capaz de conferir susceptibilidade para a doença, assim como, um haplotipo e um alelo que aparentemente poderão conferir menor gravidade da doença. Reafirma-se a importância do alelo DRB1*08 como factor de risco para uveíte. Os subtipos B*27 encontrados na nossa população estão em concordância com os que são referenciados na literatura para populações Caucasianas. A identificação e descrição de variantes genéticas em genes-alvo poderão contribuir para a caracterização da susceptibilidade para esta doença, assim como para a definição de modelos de prognóstico e de terapia.
Introduction: The Ankylosing Spondylitis (AS) is an inflammatory rheumatic disease with a significant hereditary component, and with an overall prevalence very similar to rheumatoid arthritis. The strong association with the HLA-B27 allele has been known since the '70s. There is evidence that multiple MHC and non MHC genes may influence on different aspects of the disease. Objectives: This study aims to investigate the individual associations of HLA class I/II and MHC extended haplotypes (HLA-A/B*27/-Cw/-DRB1/-DQB1) with susceptibility and phenotypic features of AS. In addition to determine the frequency of B*27 subtypes in the Portuguese population and establish possible associations between these polymorphisms and disease. Methods: A total of 188 patients were recruited in several rheumatology outpatient clinics from different areas of the country, according to the modified New York (1984). The control group (n=189) were randomly selected from the bone marrow donors registry of Centro de Histocompatibilidade do Sul. In this study, only HLA-B27 positive individuals (patients and controls) were considered. Both groups were genotyped for the loci HLA-A, -B, -Cw, -DRB1 and -DQB1 by PCR-rSSOP. The high resolution was performed to determine the B*27 subtypes in a subgroup of 138 patients and 189 controls. The extended HLA haplotypes were estimated by EM algorithm using the Arlequin v3.11 software. The case-control comparisons were made using contingency tables; the associations between clinical and genetic characteristics were determined through linear regression and logistic binomial, using the Stata10.1 software. Results: No association was seen between HLA loci and AS. In our population, the B*27 alleles conferring susceptibility to AS appear to be more frequently carried by the haplotypes A*02/B*27/Cw*02/DRB1*01/DQB1*05 (p=0,000; OR=39,06; IC 95% [2,34-651]). Correlations between clinical and genetic features revealed the presence of multiples alleles and haplotypes associated with phenotypic features of the disease. The haplotype A*02/B*27/Cw*01/DRB1*08/DQB1*04 and DQB1*04 seems to confer protection for the severity, functional and radiological repercussion. The B*2705 and B*2702 subtypes were the most frequent in the Portuguese population; no significant difference was found in the distribution of these B*27 subtypes between AS patients and controls. Conclusions: We identified, in the Portuguese population, a haplotype that seems to confer susceptibility to disease. In addition we identified a haplotype and an allele that apparently may have a protective role in disease severity. We confirm the importance of the DRB1*08 allele as a risk factor for uveitis. The B*27 subtypes found in our population are in agreement with those reported in the literature for Caucasian populations. The identification of genetic variants of target genes could be very useful in the characterization of susceptibility to the disease and establishing models of prognosis and guidance of therapy.
Introduction: The Ankylosing Spondylitis (AS) is an inflammatory rheumatic disease with a significant hereditary component, and with an overall prevalence very similar to rheumatoid arthritis. The strong association with the HLA-B27 allele has been known since the '70s. There is evidence that multiple MHC and non MHC genes may influence on different aspects of the disease. Objectives: This study aims to investigate the individual associations of HLA class I/II and MHC extended haplotypes (HLA-A/B*27/-Cw/-DRB1/-DQB1) with susceptibility and phenotypic features of AS. In addition to determine the frequency of B*27 subtypes in the Portuguese population and establish possible associations between these polymorphisms and disease. Methods: A total of 188 patients were recruited in several rheumatology outpatient clinics from different areas of the country, according to the modified New York (1984). The control group (n=189) were randomly selected from the bone marrow donors registry of Centro de Histocompatibilidade do Sul. In this study, only HLA-B27 positive individuals (patients and controls) were considered. Both groups were genotyped for the loci HLA-A, -B, -Cw, -DRB1 and -DQB1 by PCR-rSSOP. The high resolution was performed to determine the B*27 subtypes in a subgroup of 138 patients and 189 controls. The extended HLA haplotypes were estimated by EM algorithm using the Arlequin v3.11 software. The case-control comparisons were made using contingency tables; the associations between clinical and genetic characteristics were determined through linear regression and logistic binomial, using the Stata10.1 software. Results: No association was seen between HLA loci and AS. In our population, the B*27 alleles conferring susceptibility to AS appear to be more frequently carried by the haplotypes A*02/B*27/Cw*02/DRB1*01/DQB1*05 (p=0,000; OR=39,06; IC 95% [2,34-651]). Correlations between clinical and genetic features revealed the presence of multiples alleles and haplotypes associated with phenotypic features of the disease. The haplotype A*02/B*27/Cw*01/DRB1*08/DQB1*04 and DQB1*04 seems to confer protection for the severity, functional and radiological repercussion. The B*2705 and B*2702 subtypes were the most frequent in the Portuguese population; no significant difference was found in the distribution of these B*27 subtypes between AS patients and controls. Conclusions: We identified, in the Portuguese population, a haplotype that seems to confer susceptibility to disease. In addition we identified a haplotype and an allele that apparently may have a protective role in disease severity. We confirm the importance of the DRB1*08 allele as a risk factor for uveitis. The B*27 subtypes found in our population are in agreement with those reported in the literature for Caucasian populations. The identification of genetic variants of target genes could be very useful in the characterization of susceptibility to the disease and establishing models of prognosis and guidance of therapy.
Descrição
Dissertação de Mestrado em Genética Molecular, Comparativa e Tecnológica
Palavras-chave
Espondilite Anquilosante , Alelos , Haplotipos , MHC , HLA-B27