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

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  • Kozlitina, J.
    • Other Affiliation: University of Texas Southwestern Medical Center
  • Risso, D.
    • Other Affiliation: National Institutes of Health
  • Lansu, K.
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Olsen, R.H.J.
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Sainz, E.
    • Other Affiliation: National Institutes of Health
  • Luiselli, D.
    • Other Affiliation: University of Bologna
  • Barik, A.
    • Other Affiliation: National Institutes of Health
  • Frigerio-Domingues, C.
    • Other Affiliation: National Institutes of Health
  • Pagani, L.
    • Other Affiliation: University of Tartu
  • Wooding, S.
    • Other Affiliation: University of California, Merced
  • Kirchner, T.
    • Other Affiliation: New York University
  • Niaura, R.
    • Other Affiliation: New York University
  • Roth, B.
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Drayna, D.
    • Other Affiliation: National Institutes of Health
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.
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  • Article
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  • In Copyright
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  • Public Domain Mark 1.0
Journal title
  • PLoS Genetics
Journal volume
  • 15
Journal issue
  • 2
Language
  • English
ISSN
  • 1553-7390
Publisher
  • Public Library of Science

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