rs114645367 (CFH): Age-Related Macular Degeneration

Key takeaways

• rs114645367 sits in the CFH region on chromosome 1, home to the strongest-known genetic risk signals for age-related macular degeneration (AMD)
• People with AMD show elevated blood levels of FHR-1, FHR-2, FHR-3, and FHR-4A proteins, while the main complement regulator FH remains unchanged, pointing to FHR proteins as key disease drivers
• Eight independent AMD-associated signals have been identified at this locus in a cohort of more than 33,000 individuals
• Rare variants in neighboring CFHR2 and CFHR5 genes independently raise AMD risk and reduce FHR-2 and FHR-5 protein levels
• This variant is understood in the context of locus-level findings; its specific individual effect size has not been reported in the available evidence

What the research says A study measuring all five FHR (complement factor H-related) protein concentrations in 202 controls and 216 individuals with AMD found that FHR-1 (p = 1.84 × 10^-6), FHR-2 (p = 1.47 × 10^-4), FHR-3 (p = 1.05 × 10^-5), and FHR-4A (p = 1.22 × 10^-²) were each significantly elevated in AMD, while factor H (FH - the main alternative complement pathway regulator encoded by CFH) concentrations were unchanged. In a larger International AMD Genomics Consortium cohort of 17,596 controls and 15,894 AMD cases, common haplotypes at the CFH locus (chromosome 1q31.3, encompassing CFH and the CFHR1-CFHR5 genes) strongly associated with FHR protein concentrations - for instance, the p.Tyr402His variant in CFH correlated with FHR-2 levels at p = 3.68 × 10^-¹^7. Low-frequency protein-altering variants in CFHR2 and CFHR5 independently associated with AMD risk at this locus (p = 5.03 × 10^-³ and p = 2.81 × 10^-6, respectively) and reduced or abolished FHR-2 and FHR-5 protein concentrations.

Reported associations

• Age-related macular degeneration: The locus harbors eight independent AMD-associated signals; the most severe coding variant here, p.Arg1210Cys in CFH (rs121913059), carries an odds ratio of 20.28 in a cohort of 17,596 controls and 15,894 AMD cases
• FHR-1 blood concentration: Significantly elevated in AMD (p = 1.84 × 10^-6; cohort of 202 controls and 216 AMD individuals)
• FHR-2 blood concentration: Elevated in AMD (p = 1.47 × 10^-4); the p.Tyr402His variant in CFH correlates with FHR-2 levels at p = 3.68 × 10^-¹^7
• FHR-3 blood concentration: Elevated in AMD (p = 1.05 × 10^-5)
• FHR-4A blood concentration: Elevated in AMD (p = 1.22 × 10^-²)
• FHR-5 blood concentration: Reduced or absent with low-frequency CFHR5 protein-altering variants that independently associate with AMD (p = 2.81 × 10^-6)

Evidence quality Evidence derives from a 2021 paper in the American Journal of Human Genetics (Lorés-Motta et al.) combining a protein-measurement cohort (202 controls, 216 AMD individuals) with the IAMDGC genetic cohort (17,596 controls, 15,894 AMD cases). CFHR2 and CFHR5 associations were established independently of all 52 previously reported GWAS signals at this locus, and the CFHR5 result reaches p = 2.81 × 10^-6. Tissue localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen (the hallmark deposits of early AMD) provides mechanistic support for the protein-level findings. Notably, rs114645367 is not named among the explicitly listed index variants in the provided study text; the evidence base for this specific rsID is therefore inferred from locus-level findings rather than a directly reported variant-level association, and should be interpreted with that caveat. No conflicting findings were described within the study itself.

Lifestyle considerations No lifestyle considerations on file for this variant.