Department of Rheumatology, Institute of Medicine, University of Debrecen Medical and Health Science Center, Nagyerdei str 98, Debrecen, 4032, Hungary.
Clin Rev Allergy Immunol. 2013 Oct;45(2):170-9. doi: 10.1007/s12016-012-8346-7.
The "Bermuda triangle" of genetics, environment and autoimmunity is involved in the pathogenesis of rheumatoid arthritis (RA). Various aspects of genetic contribution to the etiology, pathogenesis and outcome of RA are discussed in this review. The heritability of RA has been estimated to be about 60 %, while the contribution of HLA to heritability has been estimated to be 11-37 %. Apart from known shared epitope (SE) alleles, such as HLA-DRB101 and DRB104, other HLA alleles, such as HLA-DRB113 and DRB115 have been linked to RA susceptibility. A novel SE classification divides SE alleles into S1, S2, S3P and S3D groups, where primarily S2 and S3P groups have been associated with predisposition to seropositive RA. The most relevant non-HLA gene single nucleotide polymorphisms (SNPs) associated with RA include PTPN22, IL23R, TRAF1, CTLA4, IRF5, STAT4, CCR6, PADI4. Large genome-wide association studies (GWAS) have identified more than 30 loci involved in RA pathogenesis. HLA and some non-HLA genes may differentiate between anti-citrullinated protein antibody (ACPA) seropositive and seronegative RA. Genetic susceptibility has also been associated with environmental factors, primarily smoking. Some GWAS studies carried out in rodent models of arthritis have confirmed the role of human genes. For example, in the collagen-induced (CIA) and proteoglycan-induced arthritis (PgIA) models, two important loci - Pgia26/Cia5 and Pgia2/Cia2/Cia3, corresponding the human PTPN22/CD2 and TRAF1/C5 loci, respectively - have been identified. Finally, pharmacogenomics identified SNPs or multiple genetic signatures that may be associated with responses to traditional disease-modifying drugs and biologics.
遗传学、环境和自身免疫的“百慕大三角”与类风湿关节炎（RA）的发病机制有关。本文讨论了遗传因素在 RA 的病因、发病机制和转归中的各个方面。RA 的遗传率估计约为 60%，而 HLA 对遗传率的贡献估计为 11-37%。除了已知的共享表位（SE）等位基因，如 HLA-DRB101 和 DRB104 外，其他 HLA 等位基因，如 HLA-DRB113 和 DRB115 也与 RA 的易感性有关。一种新的 SE 分类将 SE 等位基因分为 S1、S2、S3P 和 S3D 组，其中主要的 S2 和 S3P 组与血清阳性 RA 的易感性有关。与 RA 相关的最相关的非 HLA 基因单核苷酸多态性（SNP）包括 PTPN22、IL23R、TRAF1、CTLA4、IRF5、STAT4、CCR6、PADI4。全基因组关联研究（GWAS）已确定 30 多个与 RA 发病机制相关的位点。HLA 和一些非 HLA 基因可能区分抗瓜氨酸蛋白抗体（ACPA）阳性和阴性 RA。遗传易感性也与环境因素有关，主要是吸烟。一些在关节炎啮齿动物模型中进行的 GWAS 研究证实了人类基因的作用。例如，在胶原诱导（CIA）和蛋白聚糖诱导关节炎（PgIA）模型中，已经确定了两个重要的位点-Pgia26/Cia5 和 Pgia2/Cia2/Cia3，分别对应人类 PTPN22/CD2 和 TRAF1/C5 位点。最后，药物基因组学确定了可能与传统疾病修饰药物和生物制剂反应相关的 SNP 或多个遗传特征。
