对日本类风湿性关节炎患者单核苷酸多态性的分析表明，除了经典的共享表位易感性序列外，还有其他易感性标记。

Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers besides the classic shared epitope susceptibility sequences.

作者信息

Kochi Yuta, Yamada Ryo, Kobayashi Kyoko, Takahashi Atsushi, Suzuki Akari, Sekine Akihiro, Mabuchi Akihiko, Akiyama Fumihiro, Tsunoda Tatsuhiko, Nakamura Yusuke, Yamamoto Kazuhiko

机构信息

University of Tokyo, Tokyo, Japan.

出版信息

Arthritis Rheum. 2004 Jan;50(1):63-71. doi: 10.1002/art.11366.

DOI:10.1002/art.11366

PMID:14730600

Abstract

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 HLA 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.

摘要

目的

通过对日本人群的HLA - DRB1等位基因和多个单核苷酸多态性（SNP）进行分型，检测整个HLA区域中与类风湿关节炎（RA）易感性相关的基因座（DRB1基因座除外）。

方法

对828例RA患者和1032例对照者进行HLA - DRB1等位基因及分布于HLA基因复合体的88个SNP的基因分型。评估数据的连锁不平衡情况，并在存在或不存在疾病易感性DRB1等位基因的情况下，以两种方式分析病例对照关联，以检测独立于DRB1等位基因的基因座。

结果

在日本人群中，HLA - DRB1等位基因*0405、*0401、*0901、*0101、*1401、*1602、0403和1405与RA显著相关。与NOTCH4基因内含子SNP相关的P值最小（P = 1.4×10⁻²⁷），这是由于与HLA - DRB1等位基因存在强连锁不平衡。在两个SNP中观察到与HLA - DRB1共享表位等位基因无关的强关联：一个在MICA基因内含子中，另一个在HLA - DQB2基因内含子中。它们与RA的关联独立于HLA - DRB1共享表位等位基因，具有提示意义（分别为P = 0.0024 [校正P（P(corr)）= 0.068]和P = 0.00037 [P(corr) = 0.012]）。