Inverse Association of Hormone Replacement Therapy and Oral Contraceptive Use With Age Related Macular Degeneration and Synergy With ARMS2 Promoter Polymorphisms

Abstract

Purpose: : Previous studies have observed associations between factors pertaining to reproductive history and age related macular degeneration (AMD). The objective of this study was to investigate whether female reproductive history and hormone replacement therapy (HRT) influence risk for AMD either directly or by interaction with genetic factors.

Methods: : 799 female participants (560 with AMD and 239 without AMD) comprising a mixture of related and unrelated individuals were examined. Adjustments for age at exam and smoking status were performed using generalized estimating equations. Individuals with AMD grades (gr) 1-2 were coded as "unaffected" and 3-5 were coded as "affected" in initial analyses. To investigate whether the association differed in early AMD (gr 3), geographic atrophy (gr 4) or neovascular AMD (gr 5) we followed-up significant (p<0.05) associations by stratifying affected individuals by AMD grade. We examined interactions with AMD genetic risk factors: complement factor H (CFH), CFH-related proteins(CFH- R1, R3, and R4), complement factor B (CFB), age-related macular degeneration 2 gene (ARMS2), and apolipoprotein E (APOE).

Results: : When considering all AMD cases, significant inverse associations were observed for AMD and HRT (OR=0.65, 95%CI 0.48-0.90, p=0.008) and birth control pill use (BCP) (OR=0.60, 95%CI 0.36-0.10, p=0.048). When analyses were stratified by AMD grade for both HTR and BCP, the inverse association remained significant (HRT OR=0.45, 95%CI 0.30-0.66, p<0.0001; BCP OR=0.55, 95%CI 0.32-0.96, p=0.036) only in the comparison of neovascular AMD vs. unaffected controls. Two strong, synergistic, interactions were observed for HRT and ARMS2 promoter markers rs10490923 (p=0.007) and rs17623531 (p=0.019).

Conclusions: : Associations of HRT and BCP with AMD have inconsistently replicated in the past. Our findings suggest a protective relationship between exogenous estrogen use and neovascular AMD consistent with reports by Snow et al (2002) and Fraser-Bell et al (2006). This inverse association is significant only in carriers of the minor alleles at the two ARMS2 promoter polymorphisms suggesting a synergistic protective effect. These findingshighlight the genetic and environmental complexity of the etiologic architecture of AMD.

Keywords: genetics • gene modifiers • candidate gene analysis