Purpose: Identification of genetic factors for age-related macular degeneration (AMD) is of crucial importance in this common cause of blindness. Exudative AMD is rapidly progressive and usually associated with severe prognosis. Our purpose was to investigate this association on locus 10q26 in a case-control study including French patients specifically affected with exudative AMD.
Methods: Polymorphisms rs4146894:G>A of Pleckstrin Homology Domain-containing Protein Family A member 1 (PLEKHA1) gene, rs10490924:G>T at LOC387715, and rs11200638:G>A of HTRA1 (HTRA serine peptidase 1) gene were analyzed in AMD cases (n=118, age=72.3+/-3.8 years old) and healthy controls (n=116, age=72.0+/-3.8 years old).
Results: PLEKHA1 polymorphism was associated with AMD. The A allele frequency was 0.67 in cases versus 0.41 in controls, (p=0.0001). After age and sex adjustment, the odds ratio for risk of AMD was 9.1 (4.0-20.9, 95% CI, p=0.0001) for the AA genotype and 2.6 (1.3-5.5, 95% CI, p=0.04) for the AG genotype, conditional on HTRA1. Association was even stronger and independent with HTRA1. The A allele frequency was 0.51 in cases versus 0.22 in controls, (p=0.0001). The odds ratio was 15.5 (5.5-43.9, 95% CI, p=0.0001) for the AA genotype and 3.4 (1.9-6.1, 95% CI, p=0.0001) for the AG genotype. No further information was obtained from LOC387715 due to virtually complete linkage disequilibrium with HTRA1 polymorphism in cases (D'=1.0) and controls (D'=0.98). Although a role for PLEKHA1 could not be totally excluded, there was a four times higher AMD risk was associated with haplotype "A-T-A" involving "PLEKHA1-LOC387715-HTRA1" risk alleles.
Conclusions: Compared to PLEKHA1, HTRA1/LOC387715 genetic variations were independently and strongly associated with exudative AMD in the French population. Chromosome-10 genetic variants appear as potentially useful risk markers for early detection of AMD.