# Mechanistic insights into asthma pathogenesis through the integration of asthma genes, risk exposures, and metabolomics

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $820,705

## Abstract

PROJECT SUMMARY
Asthma continues to represent a major global public health problem resulting in significant disability and
resource utilization. Most asthma is diagnosed before the age of six years and is preceded by episodes of
troublesome lung symptoms – wheezing, in the years after birth. Asthma is a complex disease with both
genetic and environmental exposures contributing to its development: ORMDL3 and FADS are well-replicated
asthma genes while vitamin D2-5 and n-3 polyunsaturated fats (PUFAs)6 have recently been identified as
important prenatal risk factors for asthma. Despite the identification of these risk factors, a complete
mechanistic understanding of how these exposures and genes operate together to impact asthma
development remains unknown. Metabolomic profiling has the distinct advantage of being a marker that
reflects the cumulative sum of past and current environmental and genetic exposures leading to the disease.
Our preliminary metabolomics work has successfully identified associations between prenatal exposures
(Vitamin D, n-3 PUFAs), asthma genes (ORMDL3 and FADS), and metabolites, thereby providing a direct
mechanistic connection of how these risk variants may operate together to influence disease development.
The overarching hypothesis of this proposal is that the sphingolipid and eicosanoid pathways are important in
asthma pathogenesis and may enlighten the mechanisms through which asthma genes (e.g. ORMDL3, FADS)
and prenatal early life exposures (vitamin D and n-3 PUFAs) operate to cause or prevent asthma. For this
proposal, we will capitalize on two randomized clinical trials with analogous study design and follow-up
strategies – Vitamin D Antenatal Asthma Reduction Trial (VDAART) and Copenhagen Studies on Asthma in
Childhood (COPSAC2010). Together these studies showed that prenatal vitamin D and n-3 PUFAs in
supplementation reduce the risk of persistent wheeze/asthma in the first 3 years of life by 23% (p<0.01) and
32%6 (p=0.035) respectively. In this proposal we will: 1) Assess the effect of the maternal metabolome and
prenatal exposures on the child metabolome; 2) Study the relationship between metabolites in the sphingolipid
pathway, the ORMDL3 risk variant, and prenatal vitamin D supplementation on asthma risk; 3) Study the
relationship between pro- and anti-inflammatory eicosanoids, genetic variants in FADS, and prenatal n-3 PUFA
supplementation on asthma risk. Findings from this important study will have great public health importance in
elucidating mechanisms involved in the development of asthma in children and could lead to preventive
strategies against asthma in childhood.

## Key facts

- **NIH application ID:** 9921474
- **Project number:** 5R01HL141826-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** JESSICA A LASKY-SU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $820,705
- **Award type:** 5
- **Project period:** 2018-05-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921474

## Citation

> US National Institutes of Health, RePORTER application 9921474, Mechanistic insights into asthma pathogenesis through the integration of asthma genes, risk exposures, and metabolomics (5R01HL141826-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9921474. Licensed CC0.

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