基于家系探讨基因、环境的相互作用对中国汉族人群IgA肾病易感性的影响

IgA nephropathy (IgAN) is the most common primary glomerulonephritis throughout the world. About 20 to 30% patients with IgAN progress to require renal replacement therapy within 10 to 20 years after onset, however, the pathogenesis of IgAN is unknown. Accumulating evidences indicate that genetic and environmental factors are considered to be involved in the pathogenesis of IgAN. The best 7 SNP predictive model for IgAN based on a recent GWAS and combined with meta analysis with risk-score modeling could explains nearly 5% of variation in disease risk. However, few information was known about the interaction effect of the 7 SNP and environmental factors on the pathogensis of IgAN. About 500 IgAN and their first-degree relatives were recruited in our study. Haplotype Relative Risk (HRR) and transmission disequilibrium test (TDT) were using to verification the 7 SNP predict the risk of IgA nephropathy in the Chinese population. Collected the environment exposure of the patients and their family members, MDR (multifactor dimensionality reduction method) was applied with analysis of SNP-SNP and SNP-environment interaction of susceptibility to IgA nephropathy.This finding will propose a molecule genetic mechanism, screening high risk group in the population with IgAN.

IgA肾病是全世界发病范围最广的原发性肾小球疾病，是引起终末期尿毒症最常见的病因之一，然而IgA肾病的发病机制目前尚不完全清楚，研究认为遗传及环境因素起重要作用。最近GWAS研究结合荟萃分析显示有7个SNP位点可以预测IgA肾病的发病风险，但尚无文献报道这7个SNP位点与环境的交互作用对IgA肾病发病风险的预测。本研究拟根据GWAS研究结果，以家庭为对照，收集IgA肾病患者500例及家庭成员，采用单倍体危险度（HRR）和传递不平衡检验（TDT）验证7个SNP位点对中国人群IgA肾病发病风险的预测。同时结合患者及家庭成员环境因素的采集，采用MDR（多因子降维法）分析SNP-SNP及SNP-环境交互作用对IgA肾病易感性的影响。研究结果对阐明IgA肾病发生的分子遗传机制、筛检IgA肾病高危人群、预防IgA肾病发生具有重要指导意义。

收集IgA肾病患者521例，正常对照组535例，验证 GWAS研究结果（预测IgA肾病疾病风险模型的7个SNP位点）对中国西部地区IgA肾病易感性的影响。采用MDR方法分析SNP-SNP之间的相互作用对IgAN肾病易感性的影响。收集到459例IgAN患者收集到完整的临床及病理资料，315例患者收集到临床随访资料，分析了7个SNP位点及不同遗传模型对IgAN肾病临床表型及病理特点及预后的关系。研究结果显示：经过严格的Bonferroni校正，7个SNP位点与IgA肾病的发病率不相关。rs2856717T/C, rs9275596C/T ,rs2412971A/G 之间的相互作用与IgAN的发病可能相关。rs2856717 T/C的T等位基因在隐性遗传模式下（TT vs TC+ CC）可能与IgA肾病的肾功能下降关联(p = 0.008, Pc = 0.056, odds ratio [OR] = 1.527)。 rs9275596 的T 等位基因在显性及累加遗传模型下与IgAN肾病的肉眼血尿相关。 P值分别为(p < 0.001, Pc = 0.007, OR = 2.983) ,(p < 0.001, Pc = 0.007, OR = 2.17)。 Kaplan–Meier survival 分析显示 rs2856717等位基因的TT+TC基因型与CC基因型相比肾脏存活率更低。(85.1% vs. 92.7%, p = 0.046). 本研究首次发现rs2856717 位点与IgAN肾病的临床特点及不良预后相关。为今后在功能上验证该基因在IgAN肾病发病机制中起的作用奠定了理论基础.