Researchers have discovered a genetic variant exclusively in individuals of African descent that they say significantly increases preference for smoking menthol cigarettes.
Across two cohorts, African Americans with the variant of the MRGPRX4 gene were five to eight times more likely to smoke menthol cigarettes compared to those without it, Dennis Drayna, MD, PhD, of the National Institute on Deafness and Other Communication Disorders (NIDCD), and colleagues reported in PLOS Genetics.
In a multiethnic group, the odds of menthol preference was significant in the 8% of African Americans with the allele (OR 8.5, 10.4% vs 1.3%). And a confirmatory analysis confined to African Americans, where allele frequency was 5%, showed a similar increased likelihood (OR 6.3, 7.0% vs 1.3%).
“We expected to find genes that related to taste receptors, since menthol is a flavor additive,” Drayna said in a press statement. “Instead, we discovered a different kind of signaling molecule that appears to be involved in menthol preference.”
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.
“This study sheds light on the molecular mechanisms of how menthol interacts with the body,” NIDCD Acting Deputy Director Andrew Griffith, MD, PhD, said in a statement. “These results can help inform public health strategies to lower the rates of harmful cigarette smoking among groups particularly vulnerable to using menthol cigarettes.”
Nearly 20 million Americans regularly smoke menthol cigarettes, with close to 9 in 10 African-American smokers choosing menthol over non-menthol cigarettes. About 30% of non-Hispanic white smokers in the U.S. choose menthols.
Menthol cigarettes are also popular among very young smokers. Late last year, FDA Commissioner Scott Gottlieb, MD, announced that the agency would seek to ban menthol from combustible cigarettes in an effort to reduce youth tobacco use.
Menthol-flavored cigarettes are generally perceived as being less harsh, and there is also some evidence that they may be harder to quit, than other cigarettes.
The new findings, conducted by investigators from the NIH’s NIDCD and academic centers across the U.S. and Europe, used cigarette smoker data from the multiethnic, population-based Dallas Heart Study and the Dallas Biobank.
The findings were then replicated in an independent cohort of 741 African Americans enrolled in the Washington D.C. Tobacco Quitline.
The research suggests that around 8% of African Americans may have the gene variant; none of the European, Asian, or Native Americans included in the analyses had it.
“Cell-based assays of MRGPRX4 receptor function identified menthol as a novel negative modulator for this receptor, acting to reduce the responsiveness of this G-protein-coupled receptor to its only known agonist at the [wild type] and African-specific coding variant further,” the researchers wrote.
Given that the variant is relatively uncommon among African Americans, the researchers noted that it “alone cannot account for all of the difference in menthol cigarette smoking prevalence between African American and other ethnic groups.”
Menthol exerts its effects through transient receptor potential (TRP) channels TRPM8, and to a lesser extent TRPA1. The researchers noted that TRPM8 is also known to mediate menthol-induced analgesia, and studies have shown that even low levels of menthol in tobacco can activate TRPM8.
“Although our study was underpowered to detect variants with small effects, we found no evidence of association between variants at the TRPM8 and TRPA1 loci and menthol use, suggesting that variation in these menthol receptors is not a major contributor to the differential use of menthol cigarettes among African Americans,” Drayna and colleagues wrote.
The finding that “ancestry-specific variants in genes involved in nociception contribute to both inter-individual and inter-ethnic differences in menthol cigarette smoking” could have significant implications for public health, the researchers concluded.
“The existence of population-specific genetic variants presents a new risk factor for menthol cigarette use, and suggests that the existence of this risk factor can inform health policies and tobacco regulatory actions designed to reduce health disparities in the United States,” they wrote.
Funding for this research was provided by the NIH intramural research program, the FDA, and the NIDCD.