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摘要: 迄今为止，大样本遗传关联研究尤其是全基因组关联研究(genome-wide association study，GWAS)发现并且确认了大量与类风湿性关节炎(rheumatoid arthritis，RA)遗传易感性相关的基因/区域，但是这些已经发现的遗传因素尚不足以完全解释RA的遗传度，而基因-基因交互作用是尚未被发现的遗传度的重要组成部分。实际上，基因间交互作用研究一直是RA遗传流行病学研究的一个重要方向，这类研究为深入认识RA的遗传基础和发病生物学机制提供了重要线索，也为RA发病风险预测和疾病预防提供了科学参考依据。本文将对RA基因-基因交互作用研究进展进行综述，从而为今后开展相关研究提供参考。Abstract: To date, multiple genetic susceptible genes/loci associated with rheumatoid arthritis (RA) have been identified and confirmed through large-scale genetic association studies and genome-wide association study (GWAS). However, the heritability of RA could be not fully explained by these genetic factors, and gene-gene interaction might account for part of the missing heritability. Indeed, genetic interaction study is a critical research direction in the field of genetic epidemiology of RA, and these studies have provided novel insights into the genetic basis and pathogenesis of RA. Additionally, these studies have also provided scientific reference for risk prediction and prevention of RA. This review is aimed to present a summary of recent progress in genetic interaction study of RA, thus implicate further research in this field.
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Key words:
- Rheumatoid arthritis /
- Genetic susceptibility /
- Gene-gene interaction
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表 1 RA中功能相关基因之间的交互作用研究
Table 1. Studies of the interaction between functionally related genes in RA
第一作者 发表时间(年) 人种 基因 研究结果 Martínez A[35] 2006 西班牙人 NFκB1与FCRL3 在NFκB1-94ins/del ATTG位点杂合子而非纯合子者中发现FCRL3-169位点与RA相关。 Julià A[36] 2007 西班牙人 IL6与IL4I1 多因子降维法分析发现IL6 rs1800797位点与IL4I1 rs1290754位点之间存在交互作用(验证样本准确度为0.60；OR=2.23，95% CI：1.51~3.28；P < 0.02)。 McKinney C[37] 2008 新西兰人和英国人 CCL3L1与CCR5 同时携带CCL3L1至少3个拷贝数与CCR5△32纯合子者发病风险高，但是未做相加模型交互作用的假设检验。 Marinou I[38] 2009 英国人 SELS与IL1β、IL6、TNF 在IL1β -511基因型为AA而非GA/GG者中SELS-105A等位基因在显性遗传模型下与RA发病相关，且层间异质性检验有统计学意义。未发现SELS与IL6、TNF间存在交互作用。 Assmann G[39] 2009 德国人 MDM2与p53 MDM2 SNP309位点与p53 P72R位点存在相乘模型交互作用。 Marinou I[40] 2008 英国人 IL-4、IL-4R与IL-13 IL-4R Q551R位点的A等位基因在显性遗传模型下与RA的关联强度在携带IL-13-1112位点不同基因型(TT/CT/CC)的个体中存在统计学差异，然而经过校正后无统计学差异。 Kawasaki A[41] 2010 日本人 TNFAIP3与TNIP1 未发现TNFAIP3 rs2230926位点与TNIP1 rs7708392位点之间存在相乘模型交互作用。 Perdigones N[42] 2010 西班牙人 TNFRSF14与TNFRSF6B 第一阶段研究、第二阶段研究及合并研究均发现在TNFRSF6B rs4809330位点基因型为GG而非GA/AA者中TNFRSF14 rs668486位点G等位基因与RA发病有关，且层间异质性检验有统计学意义。 Deshmukh HA[43] 2011 哥伦比亚人 MMEL1、CD244、KIAA1109、
ADAD1、CDK6、C8orf13-BLK、
PHF19-TRAF1、TRAF1-C5、
DKFZ、KIF5A、SH2B3、
C12orf30、CLEC16A、ITGAM、
CD226与CD40MMEL1 rs3890745位点与C80rf13-BLK rs13277113位点存在相乘模型交互作用。 Génin E[44] 2013 法国人、日本人和西班牙人 BANK1与BLK 在欧洲人群RA中BANK1 rs3733197位点与BLK rs13277113位点存在相乘模型交互作用；在西班牙人群及欧洲人群中，BANK1 rs3733197位点G等位基因仅在BLK rs13277113位点基因型为GG者中与RA有关；多因子降维法发现在欧洲人群而非日本人群RA中BANK1 rs3733197位点与BLK rs13277113位点存在交互作用。 Kim K[45] 2013 韩国人 IRF5与STAT4 IRF5 rs77571059位点与STAT4 rs16833215位点存在相乘模型交互作用。 Lee SH[46] 2014 韩国人 CTLA4、CD28、CD40、CD40LG与CD86 多因子降维法分析发现CD40LG -3458 T＞G与CD86 -3479 T＞G之间存在交互作用。 
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