Joint association of complement component 3 and CC-cytokine ligand2 (<i>CCL2</i>) or complement component 3 and <i>CFH</i> polymorphisms in age-related macular degeneration
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<i>Background</i>: To determine the joint effect of complement component 3(C3 R102G) with CC-cytokine ligand2 (<i>CCL2</i>-2518) or complement factor H (<i>CFH</i>) Y402H polymorphisms on advanced age-related macular degeneration (AMD). <i>Methods</i>: In this case-control study, 233 patients with advanced AMD and 159 unrelated healthy controls enrolled for evaluation. Selected polymorphisms were determined by polymerase chain reaction and restriction fragment length polymorphism. <i>Results</i>: A combination of AA <i>CCL2</i> (rs1024611) and GG C3 (R102G) genotypes resulted in a super-additivity of the risks: OR = 10.13, 95% CI 1.04–98.49, <i>p</i> = 0.04, adjusted OR = 7.74, 95% CI 0.71–84.75, <i>p</i> < 0.1, adjusted synergy indices: relative excess risk due to interaction (RERI) = 1.38, the attributable proportion due to interaction (AP) = 24.7% and the synergy index (S) = 1.43. Combination of at-risk genotypes of <i>CFH</i> Y402H and C3 R102G resulted in a strong super-additive risk: adjusted OR = 22.65, 95% CI 2.32–220.91, <i>p</i> = 0.007, adjusted AP = 90.4% and the S = 12.86. Attributable proportion of risk owing to C3-<i>CCL2</i> and C3-<i>CFH</i> interaction calculated at 25% and 90% for advanced AMD. <i>Conclusion</i>: We have previously shown a strong association of C3 (R102G) and <i>CFH</i> Y402H with AMD whereas no association was found for <i>CCL2</i>-2518. This study enclosed strong synergistic association of risk genotypes of C3 and <i>CFH</i> Y402H with AMD. We also revealed synergistic influence of <i>CCL2</i>-2518 and the at-risk genotype of the C3 in AMD with an estimated AP = 50.9% (adjusted AP = 24.7%). Present findings show that <i>CCL2</i>-2518 polymorphism is not an innocent bystander in AMD susceptibility when combined with the at-risk genotype of C3 (R102G).
<i>背景</i>：本研究旨在明确补体成分3（complement component 3, C3 R102G）分别与CC趋化因子配体2（CC chemokine ligand 2, CCL2-2518）、补体因子H（complement factor H, CFH Y402H）的基因多态性联合对晚期年龄相关性黄斑变性（advanced age-related macular degeneration, AMD）的共同效应。 <i>方法</i>：本病例对照研究共纳入233例晚期AMD患者与159名无关健康对照进行评估。采用聚合酶链式反应联合限制性片段长度多态性分析对目标基因多态性进行检测。 <i>结果</i>：CCL2（rs1024611）AA基因型与C3（R102G）GG基因型联合可引发风险的超相加效应：比值比（odds ratio, OR）=10.13，95%置信区间（confidence interval, CI）为1.04~98.49，p=0.04；校正后比值比（adjusted OR）=7.74，95%CI为0.71~84.75，p<0.1。校正后的协同指数包括：交互作用相对超额风险（relative excess risk due to interaction, RERI）=1.38、交互作用归因比例（attributable proportion due to interaction, AP）=24.7%、协同指数（synergy index, S）=1.43。CFH Y402H与C3 R102G的风险基因型联合可产生显著的超相加风险：校正后OR=22.65，95%CI为2.32~220.91，p=0.007，校正后AP=90.4%，S=12.86。针对晚期AMD，C3-CCL2与C3-CFH交互作用的风险归因比例分别为25%与90%。 <i>结论</i>：本团队既往研究已证实C3（R102G）与CFH Y402H与AMD存在显著关联，但未发现CCL2-2518与AMD存在关联。本研究进一步证实C3风险基因型与CFH Y402H联合与AMD存在显著协同关联。同时本研究还揭示，CCL2-2518与C3（R102G）风险基因型联合可对AMD产生协同影响，估算AP=50.9%（校正后AP=24.7%）。本研究结果表明，当与C3（R102G）风险基因型联合时，CCL2-2518基因多态性并非AMD易感性中的无辜旁观者，而是参与了疾病进程。
