rs1831282 — CFH

CFH rs1831282 — An Intronic Complement Haplotype Variant in the AMD Risk Locus

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in adults over 65 worldwide, and the complement factor H gene (CFH) harbors the strongest known genetic risk signals for this disease. rs1831282 is an intronic variant located at chromosome 1q31.3, position 196,704,862 (GRCh38), within the CFH gene — lying between the well-characterized Y402H coding variant (rs1061170) and the synonymous haplotype tag rs2274700. In the Naj et al. 2013 GWAS¹¹ Naj et al. 2013 GWAS
Genetic factors in nonsmokers with AMD revealed through genome-wide gene-environment interaction analysis. Ann Hum Genet. 2013, rs1831282 reached genome-wide significance within the CFH region (P=7.51×10⁻³⁰), with GWAS Catalog recording odds ratios of 2.38–2.63 per C allele copy for AMD risk.

Unusually for an AMD risk variant, the common (major) allele at rs1831282 is the risk allele. The C allele occurs at approximately 60% global frequency and tags the complement-dysregulation haplotype, while the rarer A allele (~40%) is the GRCh38 reference and the protective allele. This means the majority of the population — particularly East Asians (~94% C allele frequency) — carry at least one copy of the AMD-risk allele at this locus.

The Mechanism

CFH encodes the primary fluid-phase and cell-surface brake on the alternative complement pathway²² alternative complement pathway
the complement system's continuously active arm that must be tightly regulated to avoid attacking healthy tissue; CFH accelerates breakdown of the C3 convertase (C3bBb) to prevent amplification cascades. The retinal pigment epithelium (RPE) and Bruch's membrane sit at the interface between the retinal photoreceptors and the choriocapillaris blood supply — and they depend heavily on CFH to suppress chronic, low-grade complement activation driven by accumulated oxidized lipids, cellular debris, and advanced glycation end-products that accumulate with normal aging.

rs1831282 does not alter the CFH protein sequence. Its AMD association arises through linkage disequilibrium³³ linkage disequilibrium
the tendency for alleles at nearby positions to be inherited together; high LD means variants track one another across generations with functionally important nearby variants. The C allele marks the same complement-dysregulation haplotype block captured by rs1329428, rs2274700, and (to a lesser extent) rs1061170 — all of which are associated with reduced CFH protective function at retinal surfaces. Li et al. 2006⁴⁴ Li et al. 2006
CFH haplotypes without the Y402H coding variant show strong association with AMD susceptibility. Nat Genet. 2006 demonstrated that noncoding CFH variants carry AMD risk independently of Y402H, explaining why intronic variants like rs1831282 show genome-wide significance even in the absence of amino acid changes.

The Evidence

The primary evidence for rs1831282 comes from the Naj et al. 2013 genome-wide analysis⁵⁵ Naj et al. 2013 genome-wide analysis
1,207 AMD cases and 686 controls of Caucasian ancestry; 668,238 SNPs genotyped, which identified three genome-wide significant AMD loci: CFH (P=7.51×10⁻³⁰), ARMS2 (P=1.94×10⁻²³), and RDBP/CFB/C2 (P=4.37×10⁻¹⁰). The GWAS Catalog records two separate analysis sets from this study, both pointing to rs1831282 in the CFH region — one with OR=2.38 (95% CI 2.08–2.78, P=1×10⁻³¹) and one with OR=2.63 (95% CI 2.17–3.13, P=9×10⁻²⁴), with risk allele frequencies of 0.53–0.55 — consistent with the C allele carrying the risk signal.

The landmark Klein et al. 2005 Science paper⁶⁶ landmark Klein et al. 2005 Science paper
Complement factor H polymorphism in age-related macular degeneration. Science. 2005 established CFH as the primary AMD gene through a genome-wide scan of 116,204 SNPs in 96 cases and 50 controls, finding the intronic CFH variant rs380390 as the lead signal. Homozygous risk carriers showed 7.4-fold increased AMD odds (95% CI 2.9–19). rs1831282, located in the same CFH gene, resides within the haplotype block that Klein et al. and subsequent fine-mapping studies have identified as carrying multiple independent AMD risk signals.

As of 2025, emerging complement-targeted therapies for AMD — including the C3 inhibitor pegcetacoplan and the C5 inhibitor avacincaptad pegol — make CFH genotyping increasingly relevant. Heesterbeek et al. 2020⁷⁷ Heesterbeek et al. 2020
797 AMD patients, 945 controls; complement activation quantified across AMD disease stages. Invest Ophthalmol Vis Sci. 2020 found that CFH variants predict complement activation levels, supporting the use of genetic stratification to identify patients most likely to benefit from complement inhibitor therapy.

Practical Actions

For CC homozygotes — approximately 36% of the global population — this intronic CFH variant contributes to elevated AMD risk through the same complement-dysregulation mechanism as Y402H and other CFH haplotype markers. The additive architecture of the CFH locus means risk compounds across these variants, so individuals with multiple CFH risk alleles should prioritize early retinal monitoring. Supplementation with lutein, zeaxanthin, and omega-3 fatty acids has a documented evidence base for AMD risk reduction across all CFH haplotype risk genotypes.

Interactions

rs1831282 lies within the CFH haplotype block also tagged by rs1329428, rs2274700, and rs551397. These variants are in partial to moderate linkage disequilibrium with each other and with the Y402H coding variant (rs1061170). The risk signal from rs1831282 partially overlaps with — but is not fully interchangeable with — Y402H: Li et al. 2006⁸⁸ Li et al. 2006
Nat Genet. 2006 showed noncoding CFH haplotypes carry AMD risk independently of Y402H, and in East Asian populations where Y402H is rare, non-coding CFH variants like rs1831282 may carry the primary CFH risk signal. ARMS2 variants (rs10490924) operate through a distinct oxidative-stress pathway and compound with CFH risk alleles to give the highest AMD risk combinations documented.