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PLoS Genet. 2019 Feb 15;15(2):e1007916. doi: 10.1371/journal.pgen.1007916. eCollection 2019 Feb.

An African-specific haplotype in MRGPRX4 is associated with menthol cigarette smoking.

Author information

1
McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
2
National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, United States of America.
3
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.
4
Department of Biological, Geological, and Environmental Sciences, University of Bologna, Bologna, Italy.
5
National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, Maryland, United States of America.
6
Estonian Biocentre, Institute of Genomics, University of Tartu, Estonia.
7
School of Public Health, University of California, Merced, California, United States of America.
8
Schroeder Institute for Tobacco Research, Washington, District of Columbia, United States of America.

Abstract

In the U.S., more than 80% of African-American smokers use mentholated cigarettes, compared to less than 30% of Caucasian smokers. The reasons for these differences are not well understood. To determine if genetic variation contributes to mentholated cigarette smoking, we performed an exome-wide association analysis in a multiethnic population-based sample from Dallas, TX (N = 561). Findings were replicated in an independent cohort of African Americans from Washington, DC (N = 741). We identified a haplotype of MRGPRX4 (composed of rs7102322[G], encoding N245S, and rs61733596[G], T43T), that was associated with a 5-to-8 fold increase in the odds of menthol cigarette smoking. The variants are present solely in persons of African ancestry. Functional studies indicated that the variant G protein-coupled receptor encoded by MRGPRX4 displays reduced agonism in both arrestin-based and G protein-based assays, and alteration of agonism by menthol. These data indicate that genetic variation in MRGPRX4 contributes to inter-individual and inter-ethnic differences in the preference for mentholated cigarettes, and that the existence of genetic factors predisposing vulnerable populations to mentholated cigarette smoking can inform tobacco control and public health policies.

PMID:
30768591
PMCID:
PMC6377114
DOI:
10.1371/journal.pgen.1007916
[Indexed for MEDLINE]
Free PMC Article

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