# Gene-Environment Interactions in Glaucoma

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $546,195

## Abstract

Primary open-angle glaucoma (POAG) is the leading cause of chronic optic neuropathy and a major source of
ocular morbidity worldwide. Understanding preclinical events, early phase disease and disease heterogeneity
represent key objectives in early disease detection, prevention and treatment of POAG. In this study, we
propose 4 specific aims. 1) We will perform both targeted and untargeted metabolome-wide association
studies (MWAS) for POAG using pre-clinical serum from a large case-control group (500 cases and 500
controls) nested within ongoing prospective studies of the Nurses' Health Study (NHS), NHS2, and Health
Professionals Follow-up Study (HPFS) to advance our understanding of the biochemical events that precede
POAG diagnosis (blood was collected ~ 10 years prior to disease diagnosis). Prior studies suggest that nitric
oxide metabolites represent genetically informed markers and will form the basis for targeted profiling. 2) While
considerable discoveries have been made of POAG genes, more work is needed to leverage genome-wide
information to inform POAG etiology. Thus, we will create a genome-wide genetic correlation matrix between
POAG and complex traits previously linked to POAG, using data from the NEIGHBORHOOD (National Eye
Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database; 3800 POAG
cases) consortium and publicly available summary genome-wide association study data. An assessment of the
shared heritability between POAG and these traits as well as the relation between the genetic risk scores for
these traits and POAG will lead to new etiologic insights. 3) New-onset POAG is clinically heterogeneous with
variable visual field (VF) loss patterns that may reflect different etiologies. We will apply archetype analysis,
which objectively quantifies a patient's VF loss pattern to 16 existing clinically validated archetypes (ATs), 9 of
which are glaucomatous in nature. Each POAG case (n=1250 from NHS, NHS2 and HPFS) and10 matched
controls will be assigned 16 weighted coefficients that add up to 1, with each value representing how
consistent his / her VF loss pattern is with each glaucomatous AT. We will evaluate the differential relation
between established POAG risk factors and the values on the 16 ATs, to identify unique risk factors for
homogeneous incident POAG subtypes. 4) A carbohydrate-restricted diet may meet the energy requirement in
the non-myelinated retinal ganglion cell axon segment of the optic nerve and reduce risk of POAG. We will
conduct a prospective evaluation of this exposure in relation to POAG and POAG subtypes in the 3 cohorts
(n=2100 cases). By integrating MWAS, genomics with prospective environmental exposure data and AT
analysis, this proposal addresses a number of important knowledge gaps—in particular, it will shed light on
how genetic and pre-diagnostic risk factors influence POAG and POAG heterogeneity. Linking specific
exposures with POAG subtypes will provide important mec...

## Key facts

- **NIH application ID:** 9933925
- **Project number:** 5R01EY015473-16
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Louis Robert Pasquale
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $546,195
- **Award type:** 5
- **Project period:** 2005-04-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933925

## Citation

> US National Institutes of Health, RePORTER application 9933925, Gene-Environment Interactions in Glaucoma (5R01EY015473-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933925. Licensed CC0.

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