Description of the Lab/Research Project
The major aim of my research is to determine whether specific gene-environment interactions are determinants of primary open angle glaucoma (POAG) in two large, well-established, aging cohorts (the Nurses Health Study and the Health Professionals Follow-up Study). A wealth of prospectively obtained environmental data and biomarker specimens are amassed in these cohorts. From these cohorts we have performed a myriad of cohort studies to assess the relation between environmental exposures and incident POAG. We have also formed a prospective nested case-control sample drawn from our cohorts to evaluate the relation between candidate gene-environment interactions and POAG.
Currently we are assessing the relation between nitric oxide synthase 3 (NOS3) gene variants and POAG. We have genotyped members of our case control sample for two functional single nucleotide polymorphisms (SNPs) and 3 tagging SNPs in NOS3. A gene association analysis is in progress. Subsequently we will assess the interaction between the NOS3 haplotypes and postmenopausal hormone use (PMH) in POAG. Previously we showed that among post-menopausal women older than 65 years old, older age of menopause was associated with a reduced risk of POAG.1 Specifically, we will explore if PMH use among postmenopausal women with selected NOS3 genotypes is associated with an additive or multiplicative inverse risk of POAG in nested case control analyses. Finally, we will assess the interaction between the NOS3 haplotypes and alcohol intake in POAG. Previously we showed that moderate to high consumption of alcohol was associated with inverse risk of POAG that was not statistically significant.2 Specifically, we will explore if high alcohol consumption among subjects with selected NOS3 genotypes is associated with an additive or multiplicative inverse risk of POAG in nested case-control analyses.
1. Pasquale LR, Rosner BA, Hankinson SE, Kang JH. Attributes of female reproductive aging and their relation to primary open angle glaucoma: a prospective study. J of Glaucoma 2007;16:598-605.
2. Kang JH, Willett WC, Rosner BA, Hankinson SE, Pasquale LR. Prospective study of alcohol consumption and the risk of primary open-angle glaucoma. Ophthalmic Epidemiology. 2007;14(3):141-
Permanent vision loss from POAG is a condition of public health significance. Current evidence suggests that POAG is a polygenetic disease modified by environmental influences. We hypothesize that the identification and characterization of POAG susceptibility genes via a genome-wide association study (GWAS) will reveal significant environmental determinants that influence the disease process, as well as a better understanding of how gene-environment and gene-gene interactions contribute to this complex disease. For this study we have formulated a case-control study population from three cohorts: the Nurses Health Study (NHS); Health Professionals Follow-up Study (HPFS); and Massachusetts Eye and Ear Infirmary (MEEI). The cohort consists of 1200 cases and 1200 controls with DNA. Members of the NHS and HPFS also have repeated environmental exposure data over a 16 to 24 year period. We will perform a single-stage GWAS and carry out the appropriate statistical analyses to find genetic markers with the strongest association with POAG. For the cuurent application, we will submit data on a myriad of environmental exposures (from members of NHS and HPFS) that could modify genetic predisposition for POAG to a central data repository. Thus this work will generate a valuable collection of genotype, phenotype and environment exposure data, allowing scientists to test numerous hypotheses regarding how genes and enviroment relate to incident POAG. We will collaborate with Dr. Michael Hauser at Duke University who is planning an admixture study to identify genetic loci associated with POAG among African Americans. We will seek to find concordance between genetic markers identified in his study and those identified in our stage I scan. Fine gene mapping and assessment of gene-gene and gene-environemnt interactions will be deferred until genetic markers associated with POAG are confirmed in a replication WGAS. Discovery of the various combinations of gene and environment interactions involved in POAG could lead to genotype-specific primary prevention strategies for this disease.