rs2230199 — C3 R102G

C3 R102G — Complement Activation and Macular Degeneration Risk

The C3 gene encodes complement component 3, the central protein of the complement cascade, an ancient immune surveillance system that clears pathogens and cellular debris. The R102G variant (rs2230199)¹¹ R102G variant (rs2230199)
also known as the C3F/C3S polymorphism substitutes arginine for glycine at position 102, creating the "fast" (C3F, glycine) electrophoretic variant versus the common "slow" (C3S, arginine) form. This amino acid change has functional consequences for complement regulation and is strongly associated with age-related macular degeneration²² strongly associated with age-related macular degeneration
Yates et al. NEJM 2007 (AMD), the leading cause of vision loss in the elderly.

The Mechanism

C3 sits at the convergence point of all three complement activation pathways. When activated, C3 is cleaved into C3a (an inflammatory signaling molecule) and C3b (which tags surfaces for destruction). The R102G substitution occurs in the MG1 domain of C3, altering a critical salt bridge (Arg102-Glu1032)³³ altering a critical salt bridge (Arg102-Glu1032)
crystal structure studies that stabilizes the protein's inactive form. The glycine variant (G allele) creates a more reactive C3 protein with enhanced complement activation and reduced regulation by complement factor H.

In the eye, dysregulated complement activation drives drusen formation—yellow deposits of lipids, proteins, and complement fragments that accumulate between the retinal pigment epithelium and Bruch's membrane. Drusen contain C3 and C3 activation fragments⁴⁴ Drusen contain C3 and C3 activation fragments
Johnson et al. 2001, marking sites of chronic inflammation. The G102 variant amplifies this inflammatory cascade, accelerating drusen growth and progression to advanced AMD with vision loss.

The Evidence

The association between C3 R102G and AMD is robust and replicated⁵⁵ association between C3 R102G and AMD is robust and replicated
systematic review, Thakkinstian et al. 2011. A meta-analysis of 15 studies found heterozygotes (CG) have 1.44 times higher AMD risk (95% CI 1.33-1.56), while homozygotes (GG) have 1.88 times higher risk (95% CI 1.59-2.23) compared to CC genotypes. The largest GWAS to date⁶⁶ largest GWAS to date
Fritsche et al. Nature Genetics 2013 confirmed the association with an odds ratio of 1.42 (p = 1×10⁻⁴¹) in over 17,000 cases and 60,000 controls.

The variant shows strong ethnic variation⁷⁷ strong ethnic variation
Goto et al. 2011: the G risk allele reaches 20% frequency in Europeans but is essentially absent (<1%) in Japanese and Chinese populations, where different C3 variants drive AMD susceptibility. In European-ancestry populations, R102G explains approximately 17-22% of AMD attributable risk, independent of other major risk genes like CFH Y402H.

Functional studies demonstrate that the G102 variant exhibits differential binding to complement receptors on monocytes⁸⁸ differential binding to complement receptors on monocytes
Botto et al. 1992 and affects C3 protein stability in physiological salt concentrations⁹⁹ C3 protein stability in physiological salt concentrations
Perkins et al. 2015. The variant has also been linked to other complement-mediated diseases including IgA nephropathy and membranoproliferative glomerulonephritis type II, underscoring its functional impact on immune regulation.

Practical Implications

If you carry one or two G alleles, you face moderately to significantly increased risk for AMD, particularly after age 60. The disease manifests as blurred or distorted central vision, difficulty reading, and dark or empty areas in the visual field. Early detection through regular dilated eye exams is critical—progression can be slowed¹⁰¹⁰ progression can be slowed
AREDS2 study with nutritional supplementation (zinc, copper, vitamins C and E, lutein, zeaxanthin) for intermediate or advanced AMD in one eye.

Smoking dramatically amplifies AMD risk across all genotypes and should be avoided entirely. Some evidence suggests omega-3 fatty acids may be protective, though results are mixed. For advanced wet AMD, anti-VEGF injections can preserve vision. Emerging complement-targeted therapies (C3 inhibitors like pegcetacoplan) show promise for geographic atrophy, though results are complex.

The complementopathy extends beyond the eye: carriers of high-risk C3 variants may benefit from monitoring kidney function¹¹¹¹ carriers of high-risk C3 variants may benefit from monitoring kidney function
association with glomerular diseases, as the complement system also regulates renal inflammation. Consider discussing family history and early screening with an ophthalmologist, especially if you have multiple AMD risk factors.

Interactions

C3 R102G interacts with other complement pathway variants to modify AMD risk. The most important interaction is with CFH Y402H (rs1061170), the strongest genetic risk factor for AMD. Individuals carrying risk alleles at both loci face compounded risk—the two genes operate in the same biological pathway but represent distinct mechanistic failures (CFH regulates complement, while C3 executes it). Studies show no statistical interaction between the two variants, meaning their effects are independent and additive.

C3 R102G is in strong linkage disequilibrium with another C3 variant, P314L (rs1047286), making it difficult to separate their individual effects. However, conditional analyses suggest R102G is the primary functional variant. Other complement genes (CFB, CFI, C2) also influence AMD risk but show no evidence of statistical interaction with C3 R102G.

Environmental factors modify genetic risk: smoking has the strongest effect, with smokers who carry the GG genotype facing dramatically elevated AMD risk. High dietary intake of omega-3 fatty acids¹²¹² High dietary intake of omega-3 fatty acids
SanGiovanni et al. 2008 may partially offset genetic risk, though this remains under investigation. The interplay between complement genetics and lipid metabolism in drusen formation suggests dietary fats influence disease expression in genetically susceptible individuals.