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

Today’s topic is a genotype-phenotype association study is which genome-wide (whole-exome sequencing; WES; i.e. coding region of genome only) was performed, and the (somewhat unusual) trait that was chosen to be studied is “preference of smoking menthol cigarettes..!!” Although overall rates of smoking have declined dramatically over the last 50 years, the use of mentholated cigarettes has not and has increased in some groups. Menthol is a flavoring additive commonly used in cigarettes and tobacco products; it is thought to reduce the harshness of cigarette smoke due to its soothing and anesthetic properties. Menthol cigarettes currently account for about 30% of the cigarette market in the U.S.


Interestingly, the prevalence of menthol cigarette smoking is especially high among young adults and in African Americans: more than 80% of African-American smokers use menthol cigarettes compared to 24% of Caucasian and 32% of Hispanic smokers; whether this disparity has a genetic basis, or is attributable solely to social or cultural factors, is not known. Menthol is known to interact with transient receptor potential (TRP) cation channels, including TRPM8 and TRPA1. Variations in the bitter-taste receptor gene TAS2R38 also appear to have a modest effect on smoking and on menthol cigarette use, but no comprehensive analysis of the role of variation in these and other genes in menthol cigarette smoking has been carried out.


To determine whether inherited variations in the protein-coding regions of the genome (i.e. exome) contribute to menthol cigarette smoking, authors [see attached article] performed a WES association study, in a multiethnic population-based sample (N=561 individuals) from Dallas, TX. Findings were replicated in an independent cohort (N=741) of African Americans from Washington, DC. Authors identified a haplotype (group of genes, usually contiguous along the same chromosome, inherited together from a single parent) of MRGPRX4 (MAS-related G-protein coupled recentor family member-X4); the variant encoded N245S (asparagine—>serine at amino-acid 245) plus T43TA>G (nucleotide change A>G, causing no amino-acid change; i.e. threonine at amino-acid 43 stays the same; a synonymous mutation).


This haplotype was associated with a 5- to 8-fold increase in the odds of menthol cigarette preference; this haplotype appears to be present solely in persons of African ancestry. Functional studies indicated that the G protein-coupled receptor variant, encoded by MRGPRX4, results in decreased agonistic action (stimulation) in both arrestin-based and G protein-based assays, and menthol alters that agonism. These findings indicate that genetic factors do exist, in predisposing vulnerable populations to mentholated cigarette smoking. The gene-environment interactions in this case represent a genetic haplotype associated with “preference to smoke menthol cigarettes“.     🙂






PLoS Genet   Feb 2o19; 15: e1007916

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