rs1061170 — CFH Y402H

CFH Y402H — The Strongest Genetic Risk Factor for Macular Degeneration

The CFH Y402H variant (also called Tyr402His) is the single most important genetic contributor to age-related macular degeneration¹¹ age-related macular degeneration
AMD is the leading cause of irreversible blindness in people over 50 in developed countries, a progressive disease that destroys the sharp central vision needed for reading and driving. Complement Factor H is a negative regulator of the alternative complement pathway, acting as a brake on inflammatory responses. The Y402H substitution — replacing tyrosine with histidine at position 402 — sits within a critical binding domain where CFH interacts with C-reactive protein and glycosaminoglycans on cell surfaces, particularly in the retina.

The Mechanism

The histidine variant at position 402 reduces CFH's ability to bind to heparan sulfate and other glycosaminoglycans²² heparan sulfate and other glycosaminoglycans
These molecules coat the surface of retinal pigment epithelium cells and Bruch's membrane, where CFH normally regulates complement activation in Bruch's membrane and on retinal pigment epithelium cells. This impaired binding means CFH-402H cannot effectively suppress complement activation at these sites, leading to chronic low-grade inflammation in the macula. The 402H variant also binds less effectively to malondialdehyde³³ malondialdehyde
MDA is a lipid peroxidation product that accumulates with aging and oxidative stress, a common lipid peroxidation product that accumulates in drusen — the hallmark yellow deposits beneath the retina in AMD. The result is uncontrolled complement-mediated damage to photoreceptors and retinal pigment epithelium, culminating in geographic atrophy (dry AMD) or choroidal neovascularization (wet AMD).

The Evidence

The CFH Y402H association with AMD represents one of the most robust findings in complex disease genetics. The Rotterdam Study⁴⁴ The Rotterdam Study
5,681 participants with up to 10 years of follow-up found that CC homozygotes have an 11-fold increased risk of late AMD compared to TT individuals, with cumulative risks of vision-threatening disease by age 95 reaching 48.3% for CC, 42.6% for TC, and 21.9% for TT. Population-attributable risk was calculated at 54%, meaning more than half of AMD cases in populations of European descent can be traced to this variant. A systematic meta-analysis⁵⁵ A systematic meta-analysis
Combined data from 26 studies confirmed a multiplicative model where each C allele increases AMD odds by approximately 2.5-fold, with highly consistent effects across Caucasian populations.

The variant's clinical significance extends to treatment response. A meta-analysis of anti-VEGF therapy⁶⁶ A meta-analysis of anti-VEGF therapy
Included 1,510 patients with neovascular AMD for wet AMD demonstrated that CC homozygotes respond 1.68-fold more poorly than TT individuals, requiring more frequent injections and achieving smaller visual acuity gains. Patients with CC genotype⁷⁷ Patients with CC genotype
Analysis from multiple treatment cohorts required a mean of 10.8 intravitreal injections over 12 months versus 7.2 for TC/TT genotypes. The strength of association varies substantially by ethnicity: highly significant in Europeans (C allele frequency ~36%), weaker in East Asian populations⁸⁸ East Asian populations
C allele frequency ~7% in Japanese and Korean cohorts where other variants like CFH I62V (rs800292) play a larger role.

Practical Implications

If you carry one or two C alleles, your AMD risk is meaningfully elevated, but AMD is not inevitable — onset typically occurs after age 60, and environmental factors modulate risk substantially. The most critical modifiable factor is smoking: smokers with CC genotype⁹⁹ smokers with CC genotype
Rotterdam Study data have a 34-fold increased risk compared to TT non-smokers, versus 11-fold for CC non-smokers. Quitting smoking at any age reduces risk, and the benefit applies regardless of genotype.

For CC homozygotes and high-risk TC heterozygotes, annual dilated eye exams starting at age 50 are prudent, with more frequent monitoring (every 6 months) if early drusen or pigmentary changes appear. Self-monitoring with an Amsler grid¹⁰¹⁰ Self-monitoring with an Amsler grid
A simple checkerboard pattern test that can detect early distortions in central vision at home can catch sudden changes indicating conversion to wet AMD, where urgent treatment can preserve vision. AREDS2 supplementation (vitamin C, vitamin E, zinc, copper, lutein, and zeaxanthin) reduces progression risk by approximately 25% in individuals with intermediate AMD, though evidence for benefit in those without existing disease is weaker.

Dietary patterns matter: high dietary intake of antioxidants¹¹¹¹ high dietary intake of antioxidants
Includes leafy greens, fatty fish rich in omega-3s from foods — particularly leafy greens, fatty fish rich in omega-3s, and colorful vegetables high in lutein and zeaxanthin — has been associated with reduced AMD risk even in those with high-risk CFH genotypes. Blue light exposure from screens is often cited as a concern, but evidence is weak; far more important is ultraviolet protection¹²¹² ultraviolet protection
Chronic UV exposure contributes to oxidative damage in the retina through high-quality sunglasses that block UV rays.

If you develop wet AMD, expect more aggressive treatment if you're a CC homozygote — you'll likely need more frequent anti-VEGF injections and closer monitoring. Emerging complement inhibitors targeting the alternative pathway are in late-stage trials and may offer genotype-specific benefits for CFH variant carriers in the coming years.

Interactions

CFH Y402H interacts multiplicatively with variants in ARMS2 (rs10490924 A69S), the second major AMD risk locus. Individuals with high-risk alleles at both loci¹³¹³ Individuals with high-risk alleles at both loci
Both CFH CC and ARMS2 TT genotypes — CFH CC plus ARMS2 TT (risk allele) — have synergistically elevated AMD risk exceeding the product of individual effects, suggesting convergent pathways in complement activation and extracellular matrix regulation. Interestingly, RMD subtype of AMD¹⁴¹⁴ RMD subtype of AMD
Reticular macular disease, characterized by yellow interlacing networks in the macula shows an inverse association with CFH 402H but positive association with ARMS2 69S, hinting at distinct pathogenic mechanisms within the AMD spectrum.

The gene-environment interaction with smoking is particularly striking: the combination of CFH risk alleles and smoking¹⁵¹⁵ the combination of CFH risk alleles and smoking
Data from multiple cohorts including Rotterdam Study amplifies risk far beyond additive expectations, likely because cigarette smoke components directly activate the complement cascade and generate oxidative stress that overwhelms the already-impaired regulatory capacity of CFH-402H. Other CFH variants including rs1410996 and rs800292 show complex haplotype effects and may refine risk prediction when considered jointly with Y402H.

Compound implications involving CFH Y402H and ARMS2 rs10490924 should be considered when both variants are present, as the combined risk profile may warrant earlier screening and more aggressive preventive measures than either variant alone would suggest.