Complement factor H‑related 3 (CFHR3) belongs to the human factor H protein family and is associated with various human diseases, including nephropathy, age‑related macular degeneration and atypical hemolytic uremic syndrome.
Using a panel of 8854 SNPs associated with AAMD at p-values ≤5.0E-7 from a cohort of >30,000 elderly people, we identified SNPs in miRNA target-encoding constituents of: (1) regulator of complement activation (RCA) genes (rs390679, CFHR1, p≤2.14E-214 ; rs12140421, CFHR3, p≤4.63E-29); (2) genes of major histocompatibility complex (MHC) loci (rs4151672, CFB, p≤8.91E-41 ; rs115404146, HLA-C, p≤6.32E-12 ; rs1055821, HLA-B, p≤1.93E-9 ; rs1063355, HLA-DQB1, p≤6.82E-14); and (3) genes of the 10q26 AAMD locus (rs1045216, PLEKHA1, p≤4.17E-142 ; rs2672603, ARMS2, p≤7.14E-46).
The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD.
Copy number variations in regulators of complement activation genes (CFHR1 and CFHR3) and glutathione S transferase genes (GSTM1 and GSTT1) have been associated with AMD, and several additional loci have been identified as regions of potential interest but require further evaluation.
However, significant association was identified for the CFHR3-1 deletion in AMD cases (p = 2.38 × 10(-12)) OR = 0.31, CI-0.95 (0.23-0.44), for both neovascular disease (nAMD) (p = 8.3 × 10(-9)) OR = 0.36 CI-0.95 (0.25-0.52) and geographic atrophy (GA) (p = 1.5 × 10(-6)) OR = 0.36 CI-0.95 (0.25-0.52) compared to controls.
Additionally, 698 CNPs showed significant differences with false discovery rate (FDR)<0.01 among the 10 populations and these loci overlap with known disease-associated or pharmacogenetic-related genes such as CFHR3 and CFHR1 (age related macular degeneration), GSTTI (metabolism of various carcinogenic compounds and cancers) and UGT2B17 (prostate cancer and graft-versus-host disease).
This study showed that CFH was more likely to be AMD susceptibility gene at Chr.1q31 based on the finding that the CFHR1 and CFHR3 deletion was not polymorphic in the cohort of this study, and none of the SNPs that were significantly associated with AMD in a white population in C2, CFB, and C3 genes showed a significant association with AMD.
Thus, deficiency of CFHR3 and CFHR1 results in a loss of complement control but enhances local regulation by factor H. Our findings allude to a critical balance between the complement regulators CFHR3, CFHR1 and factor H and further emphasize the central role of complement regulation in AMD pathology.
Subsequently, genetic studies revealed highly significant statistical associations between AMD and variants of several complement pathway-associated genes including: Complement factor H (CFH), complement factor H-related 1 and 3 (CFHR1 and CFHR3), complement factor B (CFB), complement component 2 (C2), and complement component 3 (C3).
However deletion of a chromosomal segment in the Factor H gene cluster on human chromosome 1, which results in the deficiency of the terminal pathway regulator CFHR1, and of the putative complement regulator CFHR3 has a protective effect for development of AMD.