Jean S, Quelvennec E, Alizadeh M, Guggenbuhl P, Birebent B, Perdriger A, Grosbois B, Pawlotsky P Y, Semana G
Laboratoire Universitaire d'Immunologie, ETS Bretagne Est, CHRU Fontenoy, Rennes, France.
Clin Exp Rheumatol. 1998 Nov-Dec;16(6):725-8.
Sjögren's syndrome (SS) is a chronic autoimmune disease with a genetic component. Among the genetic factors, the role of HLA class II genes has been suggested and a positive association with DRB1*03 allele has been described. However, there is no consensus on a unique HLA locus for this disease nor on the role of the HLA gene product in the disease. The aim of this study was to analyse prospectively MHC region involvement in the genetic susceptibility to SS by studying DRB1, DQB1, DPB1, TAP1, TAP2 genes and TNF microsatellites in a population of 45 primary SS patients.
All the polymorphisms studied were analysed at the genomic level using PCR-based methodologies.
Concerning HLA class II alleles, the highest relative risk to develop the disease was associated with the DRB115-DRB10301 heterozygous genotype (17.8% vs 3.5% in controls - pc < 0.005, OR = 5.96). Analysing other genes located on the same region allowed us to further determine the DRB1 haplotypes at risk. For instance, the DRB10301 haplotype involved in the genetic susceptibility to SS was more often associated with the DPB1 0201 and TNF-a2 alleles in SS patients than in controls. Moreover, all the DRB115-DRB10301 SS patients were TAP1-0101, TAP2-0101 homozygous, allowing us to deduce the extended genotype at risk as DRB115, TAP1-0101, TAP2-0101/DRB10301, TAP1-0101, TAP2-0101 which was carried by only 3 controls out of the 130 tested (p < 0.01, OR = 6.68).
This study confirmed the role of the MHC region in the susceptibility to Sjögren's disease, and for the first time suggests a synergistic interaction between two HLA-DRB1 extended haplotypes in the genetic mechanisms controlling the disease.
干燥综合征（SS）是一种具有遗传因素的慢性自身免疫性疾病。在遗传因素中，已提出人类白细胞抗原（HLA）Ⅱ类基因的作用，并描述了其与DRB1*03等位基因的正相关。然而，对于该疾病的独特HLA基因座以及HLA基因产物在疾病中的作用尚无共识。本研究的目的是通过研究45例原发性干燥综合征患者群体中的DRB1、DQB1、DPB1、TAP1、TAP2基因和肿瘤坏死因子（TNF）微卫星，前瞻性分析MHC区域在干燥综合征遗传易感性中的作用。
使用基于聚合酶链反应（PCR）的方法在基因组水平分析所有研究的多态性。
关于HLAⅡ类等位基因，患该疾病的最高相对风险与DRB115 - DRB10301杂合基因型相关（对照组为3.5%，患者组为17.8% - pc < 0.005，比值比（OR）= 5.96）。分析位于同一区域的其他基因使我们能够进一步确定有风险的DRB1单倍型。例如，与干燥综合征遗传易感性相关的DRB10301单倍型在干燥综合征患者中比在对照组中更常与DPB10201和TNF - a2等位基因相关。此外，所有DRB115 - DRB10301干燥综合征患者均为TAP1 - 0101、TAP2 - 0101纯合子，这使我们能够推断出有风险的扩展基因型为DRB115，TAP1 - 0101，TAP2 - 0101/DRB10301，TAP1 - 0101，TAP2 - 0101，在130名检测的对照组中只有3名携带该基因型（p < 0.01，OR = 6.68）。
本研究证实了MHC区域在干燥综合征易感性中的作用，并首次表明在控制该疾病的遗传机制中，两种HLA - DRB1扩展单倍型之间存在协同相互作用。
