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

<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> &lt; 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).