rs1831282 — CFH

Intronic CFH variant at chromosome 1q31.3 associated with AMD risk; the C allele (common globally) tags a complement-dysregulation haplotype, while the rare A allele (GRCh38 reference) is protective

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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.

Genotype Interpretations

What each possible genotype means for this variant.

AA Protective Genotype Beneficial

Two copies of the rare protective A allele — lowest CFH-haplotype AMD risk at this locus

You carry two copies of the A allele at rs1831282 — the rarer, GRCh38 reference allele and the protective version at this CFH locus. About 16% of people globally share this genotype, with higher rates (~18%) in European populations. The A allele tags the complement-protective CFH haplotype, associated with better-regulated complement activity at retinal surfaces. GWAS evidence records an OR of ~2.4-2.6 per C allele copy for AMD, meaning AA homozygotes carry substantially lower risk from this particular CFH variant than CC carriers.

AMD is a polygenic disease — your low risk at this locus should be interpreted alongside your results for the CFH Y402H variant (rs1061170), the ARMS2 locus (rs10490924), and other AMD risk factors including smoking, body weight, and diet.

AC Intermediate Complement Risk Intermediate

One C risk allele and one protective A allele — moderately elevated AMD risk from this CFH haplotype

The additive inheritance pattern at rs1831282 means heterozygotes experience intermediate CFH haplotype dysregulation at the retinal pigment epithelium. One protective A-allele chromosome still contributes CFH function from the protective haplotype, partially compensating for the C-allele chromosome's reduced complement regulation. The net result is a modest but meaningful increase in lifetime AMD risk, predominantly manifesting as greater vulnerability to drusen accumulation and geographic atrophy after age 60 when the cumulative retinal oxidative burden increases.

In East Asian populations, the C allele is present in ~94% of individuals, making heterozygous AC individuals in those populations among the least common genotype. In Europeans, approximately 49% of individuals carry the AC genotype.

CC Higher Complement Risk High Risk

Two copies of the C risk allele — elevated AMD risk through CFH complement-dysregulation haplotype; proactive monitoring warranted

The CC genotype at rs1831282 places both chromosomal copies within the complement-risk CFH haplotype. Without any protective A-allele haplotype contribution, complement regulation at the retinal pigment epithelium and Bruch's membrane is more impaired than in AA or AC carriers. This leaves the retina more vulnerable to complement-driven inflammatory damage as oxidized lipid debris, drusen precursors, and other sub-retinal stressors accumulate from middle age onward.

The extreme C allele frequency in East Asian populations (~94%) may help explain the high AMD burden observed in aging Asian populations despite lower rates of the Y402H variant (rs1061170), which is rare in Asians. In these populations, noncoding CFH variants like rs1831282 that sit within the same complement-risk haplotype block carry the primary CFH AMD risk signal.

Emerging complement-targeted therapies for AMD — including C3 inhibitors and C5 inhibitors — may be particularly relevant for individuals with CFH-driven complement dysregulation. Heesterbeek et al. 2020 found that CFH genetic variants predict complement activation levels across AMD disease stages, supporting genotype-informed patient selection for complement inhibitor trials. If you develop geographic atrophy (dry AMD), discuss your complement genetic profile with your retinal specialist when evaluating eligibility for complement inhibitor therapies.