Publication Date



Open access

Degree Type


Degree Name

Doctor of Philosophy (PHD)


Molecular Cell and Developmental Biology (Medicine)

Date of Defense


First Committee Member

Vinata B. Lokeshwar

Second Committee Member

Richard K. Lee

Third Committee Member

John R. Gilbert

Fourth Committee Member

Margaret A. Pericak-Vance


The purpose of the study was to assess single nucleotide polymorphisms (SNPs) in NOS2 A, ESR1, ESR2 and MMP-2 genes that may affect the risk for age-related macular degeneration (AMD) and may interact with environmental factors such as estrogen exposure and smoking, thereby modifying their effect on AMD. AMD is an ocular degenerative disease with known genetic and environmental factors. However, the disease risk genes identified so far account only for part of the genetic attributable risk and the role of new disease risk genes remain to be evaluated. For non-genetic risk factors, the most extensively analyzed are smoking and estrogen exposure. Smoking increases the risk for development of AMD and estrogen exposure has a protective effect. Both of these factors have been linked to oxidative pathway activation and extracellular matrix homeostasis (ECM) through interactions with the NOS2A and metallomatrix proteinase (MMP) genes, respectively. In addition, estrogen exerts its activity through the estrogen receptors ER alpha and ER beta. We examined a Caucasian cohort of AMD cases and controls. Nine hundred and ninety-eight individuals (males and females) for the NOS2A gene and 777 females for both the ESR1/2 and MMP-2 genes were assessed. We genotyped TagSNPs within these selected candidate gene regions using HapMap phase II or III. Multivariable logistic regression or generalized estimating equation (GEE) models containing SNP genotypes, age, sex, environmental factor and genotype/environmental interaction were constructed. In addition, because we previously reported interactions between the ARMS2 locus and estrogen exposure and smoking, we also analyzed interactions within ARMS2 locus. We found that SNPs in NOS2A are associated with increased risk for AMD and might modulate the smoking effect on AMD. The synergistic interaction between NOS2A and smoking is independent of the ARMS2 locus. No SNP in the MMP-2 gene was significantly associated with increased risk for AMD. We also detected no significant interactions with estrogen exposure or with the ARMS2 locus. SNPs within the ESR1 gene are associated with an increased risk for developing AMD and the inverse association of AMD and HRT is dependent on SNP genotypes in ESR1 and ESR2 and independent of the ARMS2 locus.


Gene-gene And Gene-environmental Interactions; Genetics; AMD