# Analysis of a missense SNP in the aryl hydrocarbon receptor repressor gene that may disproportionately increase lung cancer risk in Black Americans

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $64,284

## Abstract

The parent grant studies a single nucleotide polymorphism (SNP) in the aryl hydrocarbon receptor repressor
(AHRR) gene that may influence the lung cancer risk of Black/African American (B/AA) subjects. AHRR is a
negative regulator of detoxification responses involved in the metabolism and elimination of tobacco smoke
carcinogens. B/AA men have the highest rate of lung cancer death compared to all other groups, with a 12%
higher lung cancer incidence rate and a 15% higher lung cancer death rate than White/European (W/E) men.
Elevated AHRR expression has been implicated in lung cancer risk; thus, a SNP that improves AHRR function
would likely increase lung cancer risk. We have identified a missense SNP, rs35008248, in AHRR exon 4 that,
while rare in W/E subjects, is present one third of B/AA subjects. The SNP was not included in most previously
used arrays. Preliminary data from GWAS explorer suggests an association with smoking in B/AA males
(p=3.87E-3) and with smoking-related cancers in B/AA subjects (p=0.04927). B/AA individuals comprise only a
small fraction of the subjects (<4%); power to determine the role of SNPs in this group has been limited. AHRR
is a negative regulator of the aryl hydrocarbon receptor (AHR). Upon tobacco smoke exposure, AHR binds to
polycyclic aromatic hydrocarbons, dimerizes with ARNT and the dimer binds to xenobiotic response elements
(XREs), switching on detoxification genes. In a negative regulatory loop, AHR/ARNT turns on AHRR, which also
binds to ARNT, competing with AHR/ARNT for XRE sites, dampening the detoxification response. The reference
allele of rs35008248 (T) encodes a leucine at position 114, while the alternate allele (C) encodes a turn-inducing
proline. Combined annotation-dependent depletion (CADD) suggests the SNP might affect AHRR function. In
the co-crystal structure of the AHRR/ARNT heterodimer, leucine 114 borders a loop entwining ARNT. We
hypothesize that a proline at position 114 constrains AHRR loop conformation, thereby stabilizing AHRR/ARNT
interaction, increasing the repressive effect of AHRR/ARNT heterodimers, interfering with the detoxification
response, and increasing lung cancer risk of B/AA smokers, 34% of whom carry the minor allele. Here we
will test for associations between genetic variation at AHRR and lung cancer outcomes using existing large-scale
genetic data in B/AA individuals (Aim 1), use CRISPR-based genome editing to engineer the minor allele into
the genome of our unique immortalized human alveolar epithelial cell lines and assess its effects on the response
to tobacco smoke in vitro (Aim 2), and test whether the amino acid at position 114 affects the kinetics of the
interaction between AHRR and ARNT (Aim 3).Together, the specific aims of this pilot project will provide insight
into the role of a potential functional SNP in AHRR that is common in B/AA subjects and that could help explain
their increased lung cancer risk. The Diversity Supplement will give Diego Velarde trai...

## Key facts

- **NIH application ID:** 11064650
- **Project number:** 3R21CA290319-01S1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** ITE A OFFRINGA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $64,284
- **Award type:** 3
- **Project period:** 2024-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11064650

## Citation

> US National Institutes of Health, RePORTER application 11064650, Analysis of a missense SNP in the aryl hydrocarbon receptor repressor gene that may disproportionately increase lung cancer risk in Black Americans (3R21CA290319-01S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11064650. Licensed CC0.

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