HLA区域单倍型对类风湿关节炎中抗环瓜氨酸肽抗体阳性的贡献，独立于HLA - DRB1。

Contribution of a haplotype in the HLA region to anti-cyclic citrullinated peptide antibody positivity in rheumatoid arthritis, independently of HLA-DRB1.

作者信息

Okada Yukinori, Yamada Ryo, Suzuki Akari, Kochi Yuta, Shimane Kenichi, Myouzen Keiko, Kubo Michiaki, Nakamura Yusuke, Yamamoto Kazuhiko

机构信息

Institute of Medical Science, University of Tokyo, Tokyo, Japan.

出版信息

Arthritis Rheum. 2009 Dec;60(12):3582-90. doi: 10.1002/art.24939.

DOI:10.1002/art.24939

PMID:19950296

Abstract

OBJECTIVE

To examine the risk of anti-cyclic citrullinated peptide (anti-CCP) antibody positivity in rheumatoid arthritis (RA) patients carrying certain haplotypes in the HLA region.

METHODS

A total of 1,389 Japanese patients with RA were genotyped for 30 single-nucleotide polymorphisms (SNPs) in the HLA region using commercial oligonucleotide arrays (from Perlegen or Affymetrix) as well as for HLA-DRB1 alleles using a sequence-specific polymerase chain reaction method. Stepwise logistic regression was used to select from among the 30 SNPs the ones that represented a risk of anti-CCP antibody positivity. Haplotypes of the selected SNPs were inferred using an expectation-maximization algorithm. Associations of individual SNPs were evaluated with the Cochran-Armitage test for trend. DRB1 alleles and haplotypes were evaluated with the chi-square test. Heterogeneities of risks among the shared epitope (SE) and non-SE HLA-DRB1 alleles were examined using the exact test. Haplotype associations that were independent of individual HLA-DRB1 alleles were evaluated using the likelihood ratio test.

RESULTS

Significant associations were found for 9 SNPs (smallest P value being 2.4x10(-8)) and in 4 HLA-DRB1 alleles (smallest P value being 2.0x10(-10) in DRB1*0405). Stepwise logistic regression selected 4 SNPs (rs9262638, rs7775228, rs4713580, and rs9277359). Among the 16 inferred haplotypes of these 4 SNPs, 6 indicated significant associations (smallest P value being 1.9x10(-11)). Risks among SE and non-SE alleles were significantly heterogeneous (P=0.0095 and P=9.8x10(-9), respectively), indicating the importance of stratification with individual DRB1 alleles rather than SE alleles. Conditional analysis of the risk associated with individual DRB1 alleles identified a risk haplotype that was independent of DRB1 (odds ratio 2.00 [95% confidence interval 1.44-2.79], P=2.6x10(-5)).

CONCLUSION

Heterogeneous risks of anti-CCP antibody positivity were confirmed among SE and non-SE alleles in our patient population. A risk haplotype in the HLA region that is independent of HLA-DRB1 was confirmed.

摘要

目的

研究携带人类白细胞抗原（HLA）区域特定单倍型的类风湿关节炎（RA）患者中抗环瓜氨酸肽（anti-CCP）抗体阳性的风险。

方法

使用商业寡核苷酸芯片（来自Perlegen或Affymetrix）对1389例日本RA患者进行HLA区域30个单核苷酸多态性（SNP）的基因分型，并使用序列特异性聚合酶链反应方法对HLA-DRB1等位基因进行基因分型。采用逐步逻辑回归从30个SNP中筛选出代表anti-CCP抗体阳性风险的SNP。使用期望最大化算法推断所选SNP的单倍型。使用Cochran-Armitage趋势检验评估单个SNP的关联性。使用卡方检验评估DRB1等位基因和单倍型。使用确切概率检验检查共享表位（SE）和非SE HLA-DRB1等位基因之间风险的异质性。使用似然比检验评估独立于单个HLA-DRB1等位基因的单倍型关联性。

结果

发现9个SNP存在显著关联（最小P值为2.4×10⁻⁸），4个HLA-DRB1等位基因存在显著关联（DRB1*0405中最小P值为2.0×10⁻¹⁰）。逐步逻辑回归筛选出4个SNP（rs9262638、rs7775228、rs4713580和rs9277359）。在这4个SNP的16种推断单倍型中，6种显示出显著关联（最小P值为1.9×10⁻¹¹）。SE和非SE等位基因之间的风险存在显著异质性（分别为P = 0.0095和P = 9.8×10⁻⁹），表明按单个DRB1等位基因而非SE等位基因进行分层的重要性。对与单个DRB1等位基因相关的风险进行条件分析，确定了一个独立于DRB1的风险单倍型（优势比2.00 [95%置信区间1.44 - 2.79]，P = 2.6×10⁻⁵）。