# Differential impact of smoking on the transcriptome and epigenome in Crohn's disease and ulcerative colitis"

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $167,500

## Abstract

Project Summary
Crohn’s disease (CD) and ulcerative colitis (UC) affect over 2 million individuals in the United States and are
associated with considerable morbidity. They develop due to a dysregulated immune response to a dysbiotic
microbiome on a background of genetic susceptibility. Environmental factors play an important role in these
diseases. However, the mechanisms of influence of environmental determinants is poorly understood, and
consequently, insights into disease prevention cannot be inferred. Smoking is the only consistently replicated
environmental determinant of IBD. It intriguingly exerts an unexplained divergent effect on CD and UC. Former
and current smoking are both associated with an increased risk and greater progression of CD. In contrast,
current smoking confers protection against UC and is associated with a milder disease course while former
smoking triggers relapses and is associated with a two-fold increase in disease risk. The exact component
within the complex exposures comprising cigarette smoke as well as the mechanisms for this divergent effect
have not been established. Defining the determinants of this divergent effect will shed fundamental insights on
the different biologic pathways (and consequently, differing natural history and progression) in CD and UC.
Further, identifying mechanisms for the protective influence of cigarette smoke on UC activity may offer
insights into novel therapeutic pathways that can be harnessed for treatment. In this propose, we present an
overarching hypothesis that the effect of smoking on disease risk and progression is through its differential
impact on the mucosal transcriptome and epigenome in CD and UC. We also hypothesize that this effect
differs between current and former smoking. In the first two aims, we will quantify exposure to cigarette smoke
by measuring serum cotinine, and examine its biologic impact on the transcriptome and epigenome through
RNAseq from ileal and colonic biopsies, and DNA methylation profiles from peripheral blood. By performing
pairwise comparisons, we will be able to define the differential biologic impact of smoking by disease-type,
smoking history, and disease-location. In the third aim, we will define the contribution of genotype to these
biologic effects by performing a novel gene-smoking interaction analysis on three, large well-characterized
cohorts to identify variants on whole exome sequencing that modify effect of smoking on transcriptional and
epigenetic profiles in CD or UC. The insights obtained from this innovative and exploratory proposal leveraging
the strengths of large international genotyped cohorts, expertise in gene-environment interaction analysis, and
comprehensive tissue immune-profiling will lay an important foundation for more robust study on the biologic
effects of the environment and their translation to disease prevention in CD and UC.

## Key facts

- **NIH application ID:** 10263320
- **Project number:** 5R21DK127227-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Ashwin N Ananthakrishnan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $167,500
- **Award type:** 5
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10263320

## Citation

> US National Institutes of Health, RePORTER application 10263320, Differential impact of smoking on the transcriptome and epigenome in Crohn's disease and ulcerative colitis" (5R21DK127227-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10263320. Licensed CC0.

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