Current NIH-funded Projects Included in the 'Mass. Eye and Ear Program in Genetics and Epidemiology'

Grant Number: 5R01EY014458-05
Principal Investigator: Margaret DeAngelis, Ph.D.

We propose to recruit pairs of siblings for a molecular genetic search for genes having a role in the development of neovascular age-related macular degeneration (AMD). Two types of sibling pairs will be recruited, extremely discordant sibpairs and extremely concordant sibpairs. Extremely discordant sibpairs will be composed of one member, the index sib, with neovascular AMD, and the second member with few or no aging signs of the macula at the age at which the index sibling developed neovascular AMD. Extremely concordant sibpairs will be composed of two siblings with neovascular AMD. Leukocyte DNA will be purified from blood samples collected from these siblings. The sibpairs will form the basis for a genome-wide linkage study to search for chromosomal regions where the extremely discordant pairs, on average, share fewer alleles than expected by chance alone, and where the extremely concordant sibpairs, on average, share more alleles than expected. Chromosomal regions having these properties are likely to harbor AMD genes. In addition, candidate genes that may have a role in susceptibility to AMD, such as ABCA4 and apoE, will be analyzed by evaluating DNA sequence variations in those genes and looking for a correlation between any alleles and neovascular AMD. To our knowledge, a molecular genetics approach to finding genes for neovascular AMD based on extremely discordant and extremely concordant sibpairs has not been previously carried out by any other group of investigators. If successful, our work should provide substantial progress toward identifying the genetic causes of neovascular AMD, one of the leading causes of legal blindness among the elderly.

Grant Number: 5R01EY015473-04
Project Title: Gene-Environment Interactions in Glaucoma
Principle investigator: Lou Pasquale, M.D.

We propose to investigate whether selected gene-environment interactions are risk factors for primary open angle glaucoma (POAG) in two prospectively followed cohorts of men and women. First, we will determine whether several variants of the endothelial nitric oxide synthase gene (NOS3) are associated with POAG using a nested case-control cohort drawn from our study population. Then, in separate cohort analyses we will study hormone replacement therapy and alcohol consumption in relation to POAG using stratified and multivariate techniques after controlling for important confounders. Finally, we will return to our case-control cohort to ascertain how the interaction between selected NOS3 polymorphisms and our environment exposure alters the risk of developing POAG. The Nurses' Health Study (NHS) began in 1976 among 121,700 women ranging in age from 30 to 55. Approximately 89,000 participants completed a validated semi quantitative food frequency questionnaire (FFQ) in 1980 and every 2-4 years since. The Health Professionals Follow-up Study (HPFS) began in 1986 among 52,000 men ranging in age from 45-75, all of whom completed a FFQ at baseline and every 4 years thereafter. Both groups have been sent a questionnaire biennially to update exposure information and report major illness including POAG. Information has been collected repeatedly on postmenopausal hormone use, alcohol consumption and other related covariates. We have 69,099 DNA samples from NHS participants and 33,545 DNA samples from HPFS participants in storage. In the proposed study we will confirm reports of POAG by contacting the participant's eye care provider, and obtaining pertinent information from the medical record. A self-report of POAG, will be confirmed by systematic record review documenting reproducible visual field loss consistent with glaucomatous optic neuropathy. We anticipate identifying 1246 POAG cases, 909 of which will have DNA samples available for analysis. Overall, the prospective design, large size of the cohorts, the high follow-up rates, repeated assessment of exposures known to alter NOS3 gene activity, and carefully confirmed POAG definition provide a unique opportunity to evaluate several hypotheses of public health importance. The discovery of gene-environment interactions that serve as determinants of POAG could lead to genotype-specific primary prevention strategies for this complex disease.

Grant Number: 5R01EY015872-03
Project Title: Genetic Etiologies of Primary Open Angle Glaucoma
Principle investigator: Janey L. Wiggs, M.D., Ph.D.

Primary open angle glaucoma (POAG) is a significant cause of blindness worldwide. Compelling evidence supports the hypothesis that specific genes influence susceptibility to the disease. We have previously completed a genome wide screen and follow-up studies that have identified two POAG candidate loci with high likelihood of containing POAG susceptibility genes on chromosomes 14 and 15. The major objective of this proposal is to identify the POAG susceptibility gene(s) located within the defined genetic region on chromosome 14 and determine the relationships between specific genetic defects and clinical phenotype. In addition to providing insight into disease related molecular pathology, this information will be the basis of new treatment and diagnostic modalities. To accomplish this overall goal, the size of the minimal genetic interval on chromosome 14 will be reduced by performing linkage analyses on new multiplex families affected with POAG, as well as identifying areas of linkage disequillibrium within the minimal genetic interval using family-based SNP association studies. Known genes and novel gene fragments within the refined minimal genetic interval will be identified using the annotated human genome sequence and will be prioritized for screening using function and expression information from a variety of sources. Identified DNA sequence variants will be examined for biological significance by case/control analyses using a large cohort of POAG cases and age-matched controls. Haplotypes associated with candidate genes will be analyzed using a case/control approach to identify potential regulatory changes that could be missed by sequencing alone. Specific genetic defects will be correlated with clinical phenotype by investigating familial aggregation of clinical parameters and looking for evidence of gene/gene interactions and how these interactions may influence phenotype.

Grant Number: 5R01EY009847-16
Project Title: Linkage Study of Juvenile Glaucoma
Principle Investigator: Janey L. Wiggs, M.D., Ph.D.

The general hypothesis of this research program is that biological mechanisms responsible for different forms of inherited glaucoma represent different processes that culminate in optic nerve degeneration. Elucidating each mechanism will produce a composite picture of the complex pathophysiology of this disease. The primary objective of this proposal is to characterize genetic defects responsible for inherited glaucoma, and to determine the relationships between specific mutations and clinical phenotype. In addition to providing insight into disease related molecular pathology, this information will be the basis of new treatment and diagnostic modalities. Identifying genes and gene projects that contribute to the disease process will be the first step toward the development of novel treatment based on specific disease mechanisms. The correlation of gene defects with clinical phenotypes will provide the fundamental knowledge needed to devise DNA-based diagnostic and prognostic tests. Screening different populations of glaucoma patients will illustrate the range of phenotypic expression of mutant genes and will indicate mutations that may contribute to the pathogenesis of more complex forms of the disease. During the previous grant cycle, a genome wide scan for juvenile open angle glaucoma (JOAG) was completed identifying two new JOAG loci, the genetic interval of the 7q36 PDS locus has been reduced to 5cM, and a second locus for pigment dispersion syndrome has been identified, the genetic interval for the RIEG2 locus has been reduced to 7cM and candidate genes have been identified and screened, and genotype/phenotype studies have been completed on patients with abnormalities in the TIGR/Myocilin gene, the CYP1B1 gene and the RIEG1 gene (PITX2). During the next grant period, we plan to achieve the following specific aims: 1) Refine the newly identified loci for juvenile open angle glaucoma (JOAG) and identify and screen candidate genes. 2) Screen candidate genes located in the pigment dispersion (PDS) regions located on 7q35 and 18q22. 3) Screen candidate genes located in the RIEG2 region on chromosome 13q14. 4) Correlate mutations in genes known to cause glaucoma with clinical phenotypes.

Mass. Eye and Ear site Principle Investigator: Ivana Kim, M.D.
Age-Related Eye Disease Study 2 (AREDS2)
Purpose | Background | Description | Patient Eligibility | Patient Recruitment Status | Current Status of Study | Results | Publications | Clinical Centers | NEI Representative | Resource Centers

To study the effects of high supplemental doses of dietary xanthophylls (lutein and zeaxanthin)and omega-3 long-chain polyunsaturated fatty acids (LCPUFAs)(DHA and EPA)on the development of advanced AMD.
To study the effects of these supplements on cataract and moderate vision loss.
To study the effects of eliminating beta-carotene from the original AREDS formulation on the development and progression of AMD.
To study the effects of reducing zinc in the original AREDS formulation on the development and progression of AMD.
To contribute data for validation of the photographic AMD scales developed from the Age-Related Eye Disease Study.

Complete details (including investigator list) at:

Current projects without NIH funding:

Risk factors of Fungal Keratitis
Kathryn Colby, M.D.

This study is being conducted in the Cornea clinic of Massachusetts Eye and Ear.

Current projects planned:
Genetic risk factors for diabetic retinopathy
Lucia Sobrin, M.D.

This study will be in coloration with investigators leading the Jackson Heart Study in Jackson Mississippi.