Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration

Area of Science:

• Ophthalmology
• Genetics
• Immunology

Background:

• Growing evidence links inflammation to age-related macular degeneration (AMD) pathogenesis.
• Case-control studies suggest a strong association between the complement factor H (CFH) gene and AMD.

Purpose of the Study:

• To evaluate the association between the CFH gene and AMD in a general population.
• To investigate how smoking, serum inflammatory markers, and C-reactive protein (CRP) gene variations modify this association.

Main Methods:

• A population-based, prospective cohort study in Rotterdam, Netherlands, involving 5681 individuals aged 55+.
• Analysis of the CFH Y402H polymorphism, smoking status, erythrocyte sedimentation rate, serum CRP levels, and CRP gene haplotypes.
• AMD severity was graded using international classification; prevalent and incident cases were assessed over a mean follow-up of 8 years.

Main Results:

• The CFH Y402H polymorphism was present in 36.2% of alleles.
• An allele-dose effect was observed: homozygous individuals had significantly higher odds ratios for AMD stages 2, 3, and 4 (late AMD).
• Cumulative risk of late AMD by age 95 was 48.3% for homozygotes vs. 21.9% for non-carriers.
• Elevated inflammatory markers (ESR, CRP) and smoking dramatically increased AMD risk in CFH Y402H homozygotes.
• CRP haplotypes associated with high CRP levels significantly amplified the effect of CFH Y402H (P<.01).

Conclusions:

• The CFH Y402H polymorphism is a significant risk factor for AMD, accounting for a substantial proportion of cases.
• Environmental factors (smoking) and genetic factors (CRP haplotypes) that stimulate the complement cascade can particularly increase AMD risk in carriers.