Interaction Between SNPs in the ESR1 and ESR2 Genes and Estrogen Exposure in Age-Related Macular Degeneration

Abstract

Purpose: : SNPs in ESR1 and ESR2 have been associated with decreased estradiol levels and increased risk of age-related macular degeneration (AMD). Estrogen exposure is a protective factor for AMD, with a reported interaction with ARMS 2 genotypes. The purpose of the study was to assess association of AMD with SNPs in ESR1 and ESR2 and their interactions with estrogen exposure and ARMS2 genotypes.

Methods: : We genotyped 770 Caucasian non-Hispanic females (520 AMD cases and 257 controls) for 30 tagSNPs in the ESR1 and ESR2 genes using the Sequenom MASSArray. Association between AMD, ESR1 and ESR2 SNPs, and estrogen exposure (Oral Contraceptive usage [OC] or Hormonal Replacement Therapy [HRT]) was examined using generalized estimating equations adjusting for ARMS2 genotype, age and cigarette smoking.

Results: : HRT and OC use remain strongly inversely associated with neovascular AMD in this sample (HRT: OR=0.5, 95% CI [0.31,0.81], p<0.01; OC: OR=0.41, 95% CI [0.24,0.68], p<0.01). When testing main effects of each tagSNP, only rs3020410 in ESR1 was significantly associated with increased risk of AMD (p=0.03). There were no significant interactions detected with OC and ESR1 or ESR2 SNPs. Significant SNP/HRT interactions were detected for six ESR1 and three ESR2 tagSNPs. Of these SNPs, only rs827423 and rs2234693 are in strong linkage disequilibrium (r²=0.76). Stratified analysis for ESR1 demonstrated that the inverse association of AMD and HRT is found only in carriers of at least one copy of the minor allele at rs3020375, rs9341052, rs2813543, rs2234693, and rs827423 and in carriers of two copies of the major allele at rs2813544. Stratified analysis was significant in carriers of two copies of the major allele at rs154455 and rs3020449 in ESR2. No significant three-way interactions between tagSNPs, HRT, and ARMS2 SNPs were detected.

Conclusions: : Our data suggest that SNPs within the ESR1 gene are associated with a decreased risk of developing AMD. In addition, the inverse association of AMD and HRT is dependent on SNP genotypesin ESR1 and ESR2. Of the tagSNPs that interact with HRT, rs2234693 has a putative functional effect, reportedly altering ESR1 mRNA levels by eliminating transcription factor binding sites. This suggests a potential mechanism by which the SNP might eliminate the protective effect of HRT use.

Keywords: age-related macular degeneration • genetics • clinical (human) or epidemiologic studies: risk factor assessment