title: Inverse association of female hormone replacement therapy with age-related macular degeneration and interactions with ARMS2 polymorphisms.
abstract: Purpose. To investigate whether female reproductive history and hormone replacement therapy (HRT) or birth control pills (BCPs) influence risk for age-related macular degeneration (AMD) and whether genetic factors interact with HRT to modulate AMD risk. Methods. Related and unrelated female participants (n = 799) were examined and data were analyzed with generalized estimating equations with adjustment for age and smoking. Individuals with AMD grades 1 to 2 were considered to be unaffected (n = 239) and those with grades 3 to 5 were considered affected (n = 560). Results. When comparing all cases with controls, significant inverse associations were observed for HRT (odds ratio [OR] = 0.65, 95% CI 0.48-0.90, P = 0.008) and BCPs (OR = 0.60, 95% CI 0.36-0.10, P = 0.048). When analyses were stratified by AMD severity (early versus geographic atrophy versus neovascular), 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 when comparing neovascular AMD with the control. All pair-wise HRT-genotype and BCP-genotype interactions were examined, to determine whether HRT or BCP modifies the effect of established genetic risk factors. The strongest interactions were observed for HRT x ARMS2 coding SNP (R73H) rs10490923 (P = 0.007) and HRT x ARMS2 intronic SNP rs17623531 (P = 0.019). Conclusions. These findings provide the first evidence suggesting that ARMS2 interacts with HRT to modulate AMD risk and are consistent with previous reports demonstrating a protective relationship between exogenous estrogen use and neovascular AMD. These results highlight the genetic and environmental complexity of the etiologic architecture of AMD; however, further replication is necessary to validate them.
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Digna R Velez
authors.initials: DR
authors.lastname: Edwards
authors.forename: Paul
authors.initials: P
authors.lastname: Gallins
authors.forename: Monica
authors.initials: M
authors.lastname: Polk
authors.forename: Juan
authors.initials: J
authors.lastname: Ayala-Haedo
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Schwartz
authors.forename: Jaclyn L
authors.initials: JL
authors.lastname: Kovach
authors.forename: Kylee
authors.initials: K
authors.lastname: Spencer
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Wang
authors.forename: Anita
authors.initials: A
authors.lastname: Agarwal
authors.forename: Eric A
authors.initials: EA
authors.lastname: Postel
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Margaret
authors.initials: M
authors.lastname: Pericak-Vance
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
mesh_terms: D000368:Aged; D003276:Contraceptives, Oral; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000517:prevention & control*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D017584:Reproductive History; D011795:Surveys and Questionnaires
chemical_list: C514392:ARMS2 protein, human; D003276:Contraceptives, Oral; D004967:Estrogens; D011506:Proteins