Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers besides the classic shared epitope susceptibility sequences
Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers besides the classic shared epitope susceptibility sequences
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DOI：
10.1002/art.11366
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发表时间：
2004-01-01
影响因子：
--
通讯作者：
Yamamoto, K
中科院分区：
文献类型：
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作者：
Kochi, Y;Yamada, R;Yamamoto, K
客观的。通过键入HLA-DRB1等位基因和多个单一核苷酸多态性（SNP），在日本人群中检查了与类风湿关节炎（RA）敏感性相关的整个HLA区域（DRB1基因座以外）。为828例RA和1,032例对照组患者，对分型的HLA-DRB1等位基因和88个SNP进行了基因分型。评估了数据的连锁不平衡，并在存在或不存在疾病敏感性DRB1等位基因的情况下以两种方式分析了病例对照关联，以检测与Drb1等位基因相关的基因座。 HLA-DRB1等位基因 *0405， *0401， *0901， *0101， *1401， *1602， *0403和 *1405与日本人口中的RA显着相关。观察到最小的p值（p = 1.4 x 10（-27））与notch4基因的内含子SNP相关，这是由于与HLA-DRB1等位基因的强链连接不平衡所致。在2个SNP中观察到与HLA-DRB1共享表位相位无关的强大关联：一个在云母基因的内含子中，另一个在HLA-DQB2基因的内含子中。它们与RA的关联，独立于HLA-DRB1共享的表位等位基因，具有暗示性（P = 0.0024 [校正P（P-Corr）= 0.068，P = 0.00037 [P-Corr = 0.012]）。结论。这些发现表明，除了HLA-DRB1或其他DRB1（非共享表位，非*0901）等位基因以外的1个或更多其他基因座与RA敏感/保护有关。
Objective. To examine the entire HLA region for loci (other than the DRB1 locus) associated with rheumatoid arthritis (RA) susceptibility, by typing HLA-DRB1 alleles and multiple single-nucleotide polymorphisms (SNPs) in the Japanese population.Methods. The HLA-DRB1 alleles and 88 SNPs distributed over the HILA gene complex were genotyped, for 828 patients with RA and 1,032 control subjects. The data were evaluated for linkage disequilibrium, and case-control associations were analyzed in 2 ways, in the presence or absence of the disease-susceptibility DRB1 allele, to detect loci independent of the DRB1 allele.Results. HLA-DRB1 alleles *0405, *0401, *0901, *0101, *1401, *1602, *0403, and *1405 were significantly associated with RA in the Japanese population. The smallest P value (P = 1.4 x 10(-27)) was observed in association with an intronic SNP of the NOTCH4 gene, which was due to strong linkage disequilibrium with the HLA-DRB1 allele. A strong association that was independent of HLA-DRB1 shared epitope alleles was observed in 2 SNPs: one in the intron of the MICA gene, the other in the intron of the HLA-DQB2 gene. Their association with RA, independent of HLA-DRB1 shared epitope alleles, was suggestive (P = 0.0024 [corrected P (P-corr) = 0.068, and P = 0.00037 [P-corr = 0.012], respectively).Conclusion. These findings suggest that 1 or more other loci besides the HLA-DRB1 or other DRB1 (non-shared epitope, non-*0901) alleles are involved in RA susceptibility/protection.