与韩国人类风湿性关节炎易感性增加相关的PADI4基因功能性单倍型。

A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans.

作者信息

Kang Changsoo Paul, Lee Hye-Soon, Ju Hyoungseok, Cho Hyunmi, Kang Changwon, Bae Sang-Cheol

机构信息

Dept. of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Guseong-dong, Yuseong-gu, Daejeon 305-701, Korea.

出版信息

Arthritis Rheum. 2006 Jan;54(1):90-6. doi: 10.1002/art.21536.

DOI:10.1002/art.21536

PMID:16385500

Abstract

OBJECTIVE

Anticitrullinating autoantibodies are specific markers for rheumatoid arthritis (RA). A functional haplotype of 4 exonic single-nucleotide polymorphisms (SNPs) in a citrullinating enzyme, peptidylarginine deiminase 4 (PADI4), was shown to be associated with susceptibility to RA in a Japanese population and was shown to increase the stability of PADI4 messenger RNA. However, the association was not confirmed in 4 subsequent studies involving Caucasian RA patients living in the UK, a French Caucasian population, and a Spanish population. The aim of the current study was to investigate the association of SNPs in the PADI4 gene with RA in a Korean population.

METHODS

Four exonic SNPs of the PADI4 gene (padi4_89, padi4_90, padi4_92, and padi4_104) were genotyped in 545 unrelated patients with RA and 392 controls, using the MassArray SNP genotyping system. Allelic, genotypic, and haplotypic associations of the SNPs with RA susceptibility were examined using the chi-square test and multivariate logistic regression analyses.

RESULTS

Increased RA susceptibility was significantly associated with the minor alleles of padi4_89 (P = 2.3 x 10(-5)), padi4_90 (P = 2.3 x 10(-5)), padi4_92 (P = 2.1 x 10(-5)), and padi4_104 (P = 1.1 x 10(-3)) and the haplotype carrying the 4 minor alleles (P = 1.0 x 10(-4)). Genotypes carrying the minor alleles and HLA-DRB1 shared epitope (SE) alleles (P = 9.4 x 10(-21)) were also associated with increased RA susceptibility. The genotypic associations were sustained among individuals who did not carry any SE alleles, except in the case of padi4_104. Individuals carrying the risk SNPs and/or SE alleles were more susceptible to RA than were individuals carrying neither risk SNPs nor SE alleles.

CONCLUSION

The PADI4 SNPs and haplotypes are associated with RA susceptibility in Koreans. Thus, the association of PADI4 with RA may depend on genetic heterogeneity between Asians and Europeans.

摘要

目的

抗瓜氨酸化自身抗体是类风湿关节炎（RA）的特异性标志物。瓜氨酸化酶肽基精氨酸脱亚氨酶4（PADI4）中4个外显子单核苷酸多态性（SNP）的一个功能单倍型，在日本人群中显示与RA易感性相关，且显示可增加PADI4信使核糖核酸的稳定性。然而，在随后涉及居住在英国的白种人RA患者、法国白种人群体和西班牙人群体的4项研究中，这种关联未得到证实。本研究的目的是调查韩国人群中PADI4基因单核苷酸多态性与RA的关联。

方法

使用MassArray SNP基因分型系统，对545例无亲缘关系的RA患者和392例对照进行PADI4基因的4个外显子单核苷酸多态性（padi4_89、padi4_90、padi4_92和padi4_104）基因分型。使用卡方检验和多因素逻辑回归分析检查这些单核苷酸多态性与RA易感性的等位基因、基因型和单倍型关联。

结果

RA易感性增加与padi4_89（P = 2.3×10⁻⁵）、padi4_90（P = 2.3×10⁻⁵）、padi4_92（P = 2.1×10⁻⁵）和padi4_104（P = 1.1×10⁻³）的次要等位基因以及携带4个次要等位基因的单倍型（P = 1.0×10⁻⁴）显著相关。携带次要等位基因和HLA - DRB1共享表位（SE）等位基因的基因型（P = 9.4×10⁻²¹）也与RA易感性增加相关。除padi4_104外，在不携带任何SE等位基因的个体中，基因型关联仍然存在。携带风险单核苷酸多态性和/或SE等位基因的个体比既不携带风险单核苷酸多态性也不携带SE等位基因的个体更容易患RA。