Inverse association of female hormone replacement therapy with age-related macular degeneration and interactions with ARMS2 polymorphisms.
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.
Edwards
Digna R Velez
DR
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.
Gallins
Paul
P
Polk
Monica
M
Ayala-Haedo
Juan
J
Schwartz
Stephen G
SG
Kovach
Jaclyn L
JL
Spencer
Kylee
K
Wang
Gaofeng
G
Agarwal
Anita
A
Postel
Eric A
EA
Haines
Jonathan L
JL
Pericak-Vance
Margaret
M
Scott
William K
WK
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
C514392:ARMS2 protein, human; D003276:Contraceptives, Oral; D004967:Estrogens; D011506:Proteins