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

Julia Kozlitina, Davide Risso, Katherine Lansu, Reid Hans Johnson Olsen, Eduardo Sainz, Donata Luiselli, Arnab Barik, Carlos Frigerio-Domingues, Luca Pagani, Stephen Wooding, Thomas Kirchner, Ray Niaura, Bryan Roth, Dennis Drayna

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere1007916
JournalPLoS genetics
Issue number2
StatePublished - Feb 2019

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research


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