rs551397 — CFH

Intronic CFH variant that tags the AMD-risk haplotype; the C allele tracks complement dysregulation and elevated AMD susceptibility, while the T allele is protective

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CFH's Haplotype Architecture — How rs551397 Tags Complement-Mediated AMD Risk

The complement factor H gene (CFH) spans nearly 100 kilobases on chromosome 1q31.3 and encodes the central brake on the alternative complement pathway. When Factor H is working normally, it binds C3b11 C3b
the activated form of complement component C3 and prevents it from triggering an amplifying cascade that damages host tissue. When CFH variants shift this balance, the eye's Bruch's membrane22 Bruch's membrane
the thin extracellular matrix between the retinal pigment epithelium and the choroidal blood supply becomes a target for low-grade, chronic complement attack — the cellular substrate of age-related macular degeneration (AMD).

rs551397 is an intronic variant located in the CFH gene at chromosome 1 position 196,672,942 (GRCh38). It does not alter any amino acid, but it marks a haplotype block that has been associated with AMD across multiple Asian and European populations. The C allele tracks the risk haplotype; the T allele tracks the protective haplotype.

The Mechanism

CFH contains 20 short consensus repeat (SCR) domains that mediate its binding to C3b, heparin, and C-reactive protein — molecules concentrated at sites of tissue damage. rs551397 is in intron 1 (c.59-36 position in transcript NM_000186.4) and has no known direct functional effect on protein sequence or splicing. Its disease association arises primarily through linkage disequilibrium33 linkage disequilibrium
the tendency for certain allele combinations to be inherited together because they rarely get separated by recombination with functionally important nearby variants, particularly rs800292 (CFH Val62Ile).

The Evidence

The AMD association for rs551397 has been replicated across multiple populations. In a Chinese case-control study of 163 AMD patients and 155 controls, Ng et al. 200844 Ng et al. 2008
Multiple gene polymorphisms in the complement factor H gene are associated with exudative age-related macular degeneration in Chinese. Invest Ophthalmol Vis Sci, 2008 found the TG haplotype across rs551397–rs800292 conferred an OR of 1.91 (95% CI 1.36–2.68, P=0.0001) for exudative AMD. A Korean study of 114 AMD patients and 240 controls (Kim et al. 201355 Kim et al. 2013
Ophthalmic Genetics, 2013) found individuals homozygous CC at rs551397 had OR=2.84, while C allele carriers had OR=1.67 for AMD.

The largest synthesis comes from a meta-analysis of 53 studies encompassing 53,774 AMD patients and 56,973 controls (Lu et al. 201866 Lu et al. 2018
Genet Test Mol Biomarkers, 2018), which found the rs551397 T allele was associated with reduced AMD risk at OR=0.53 (95% CI 0.45–0.61). This substantial effect size — a 47% reduction in AMD odds per T allele — is clinically meaningful and positions rs551397 as a useful risk-stratification marker even when the well-studied Y402H variant is already known.

Population frequency varies dramatically: the protective T allele is rare in Europeans (~20%) but common in Africans (~71%), mirroring the lower AMD prevalence observed in African populations.

Practical Actions

For CC carriers — approximately 36% of the global population and ~65% of people of European ancestry — the elevated AMD risk from this haplotype is modifiable through targeted nutritional interventions. Complement-reducing dietary strategies — particularly reducing ultra-processed food intake and systemic inflammation — are the clearest mechanistic lever. Annual dilated eye exams beginning in the mid-40s provide the earliest window for intervention.

Interactions

rs551397 is in moderate linkage disequilibrium with rs800292 (CFH Val62Ile).

Individuals carrying risk alleles at both rs551397 and rs1061170 should discuss their compound complement risk with an ophthalmologist, as the combined effect likely exceeds either variant alone. The protective H7 haplotype (involving CFB rs641153 and C2 rs547154) may partially counteract CFH risk alleles, but this requires separate testing.

Genotype Interpretations

What each possible genotype means for this variant.

TT Beneficial

Two protective T alleles — lowest CFH-haplotype AMD risk at this locus

You carry two copies of the protective T allele at rs551397. In the large meta-analysis of over 110,000 individuals (Lu et al. 2018), T allele carriers showed OR=0.53 for AMD, meaning TT individuals have substantially lower risk from this complement haplotype than CC carriers. About 16% of people globally are TT, with much higher rates in African populations (~50%) where AMD rates are correspondingly lower.

This result is reassuring at this locus, but AMD is a polygenic disease — your full complement risk profile includes rs1061170 (Y402H), rs800292, and ARMS2/HTRA1 variants that operate independently. A low-risk TT result here does not eliminate AMD risk entirely, but it removes one of the locus-specific contributions.

CT Intermediate

One protective T allele — moderately reduced AMD risk versus CC

The additive architecture of this locus means CT heterozygotes experience intermediate AMD risk: one copy of the protective T allele partially counteracts the risk-elevating C allele. The Lu et al. 2018 meta-analysis showed OR=0.53 per T allele in the heterozygote model, suggesting CT individuals have substantially lower risk than CC but higher risk than TT. Knowing your rs1061170 (Y402H) genotype is particularly important for CT individuals, since that coding variant has an independent and often larger effect on AMD risk and may shift the net balance considerably.

CC High Risk

Higher complement-mediated AMD risk — C allele on both chromosomes

The CC genotype at rs551397 marks the CFH risk haplotype that has been replicated in multiple Asian and European AMD case-control studies. In Korean patients (Kim et al. 2013, PMID 23289807), CC individuals had OR=2.84 for exudative AMD. A meta-analysis of 53 studies found the T allele (absent in CC individuals) associated with OR=0.53 (protective), implying that without any T alleles, risk is substantially elevated.

The CFH protein normally acts as a fluid-phase and surface regulator of the alternative complement pathway by binding C3b and accelerating the decay of the C3 convertase (C3bBb). Genetic variation that shifts this regulatory efficiency allows complement activation to proceed unchecked at the RPE-choroid interface, gradually depositing drusen and ultimately leading to geographic atrophy or choroidal neovascularization.

AMD has the highest population-attributable fraction of any complex disease for complement genetics: CFH variants collectively explain roughly 40-60% of AMD heritability in Europeans.