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

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

Genetic association and characterization of FSTL5 in isolated clubfoot

ACKNOWLEDGEMENTS: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The authors thank the staff and participants of the ARIC study for their important contributions. Funding for GENEVA was provided by National Human Genome Research Institute grant U01HG004402 (E.Boerwinkle). We thank H. Hobbs and J. Cohen for contributing control samples for replication genotyping, Nadav Ahituv for sharing RNA-seq data for both bat and mouse embryonic limb buds, Tommy Hyatt for designing the custom genotyping assay, and members of the UT Southwestern Transgenic Core facility, including John Ritter, Mylinh Nguyen, and Robert Hammer. Publicly available mouse embryonic expression analysis results were provided online at https://oncoscape.v3.sttrcancer.org/atlas.gs.washington.edu.mouse.rna/landing (24). The authors acknowledge the contributions and support of the Center for Excellence in Clubfoot Research at Scottish Rite for Children, including Shawne Faulks and Kristhen Atala. Fstl5 mutant rats were produced by the NIH Mutant Rat Resource at UT Southwestern Medical Center (R24RR03232601, R24OD011108, R01HD036022, and (5R01HD053889). This study was supported by funding from the Scottish Rite for Children Research Fund (J.J.R.), Shriners Hospital for Children (J.T.H), and the National Institutes of Health award R01HD043342 (J.T.H.).Peer reviewedPostprin

Genetic Variation in the TAS2R38 Bitter Taste Receptor and Smoking Behaviors

Common TAS2R38 taste receptor gene variants specify the ability to taste phenylthiocarbamide (PTC), 6-n-propylthiouracil (PROP) and structurally related compounds. Tobacco smoke contains a complex mixture of chemical substances of varying structure and functionality, some of which activate different taste receptors. Accordingly, it has been suggested that non-taster individuals may be more likely to smoke because of their inability to taste bitter compounds present in tobacco smoke, but results to date have been conflicting. We studied three cohorts: 237 European-Americans from the state of Georgia, 1,353 European-Americans and 2,363 African-Americans from the Dallas Heart Study (DHS), and 4,973 African-Americans from the Dallas Biobank. Tobacco use data was collected and TAS2R38 polymorphisms were genotyped for all participants, and PTC taste sensitivity was assessed in the Georgia population. In the Georgia group, PTC tasters were less common among those who smoke: 71.5% of smokers were PTC tasters while 82.5% of non-smokers were PTC tasters (P = 0.03). The frequency of the TAS2R38 PAV taster haplotype showed a trend toward being lower in smokers (38.4%) than in non-smokers (43.1%), although this was not statistically significant (P = 0.31). In the DHS European-Americans, the taster haplotype was less common in smokers (37.0% vs. 44.0% in non-smokers, P = 0.003), and conversely the frequency of the non-taster haplotype was more common in smokers (58.7% vs. 51.5% in non-smokers, P = 0.002). No difference in the frequency of these haplotypes was observed in African Americans in either the Dallas Heart Study or the Dallas Biobank. We conclude that TAS2R38 haplotypes are associated with smoking status in European-Americans but not in African-American populations. PTC taster status may play a role in protecting individuals from cigarette smoking in specific populations

Telomere length and genetic variant associations with interstitial lung disease progression and survival

Leukocyte telomere length (LTL), MUC5B rs35705950 and TOLLIP rs5743890 have been associated with idiopathic pulmonary fibrosis (IPF).In this observational cohort study, we assessed the associations between these genomic markers and outcomes of survival and rate of disease progression in patients with interstitial pneumonia with autoimmune features (IPAF, n=250) and connective tissue disease-associated interstitial lung disease (CTD-ILD, n=248). IPF (n=499) was used as a comparator.The LTL of IPAF and CTD-ILD patients (mean age-adjusted log-transformed T/S of -0.05±0.29 and -0.04±0.25, respectively) is longer than that of IPF patients (-0.17±0.32). For IPAF patients, LTL <10th percentile is associated with faster lung function decline compared to LTL ≥10th percentile (-6.43% per year versus -0.86% per year; p<0.0001) and worse transplant-free survival (hazard ratio 2.97, 95% CI 1.70-5.20; p=0.00014). The MUC5B rs35705950 minor allele frequency (MAF) is greater for IPAF patients (23.2, 95% CI 18.8-28.2; p<0.0001) than controls and is associated with worse transplant-free IPAF survival (hazard ratio 1.92, 95% CI 1.18-3.13; p=0.0091). Rheumatoid arthritis (RA)-associated ILD (RA-ILD) has a shorter LTL than non-RA CTD-ILD (-0.14±0.27 versus -0.01±0.23; p=0.00055) and higher MUC5B MAF (34.6, 95% CI 24.4-46.3 versus 14.1, 95% CI 9.8-20.0; p=0.00025). Neither LTL nor MUC5B are associated with transplant-free CTD-ILD survival.LTL and MUC5B MAF have different associations with lung function progression and survival for IPAF and CTD-ILD

Genetic Variation in the <i>TAS2R38</i> Bitter Taste Receptor and Smoking Behaviors

<div><p>Common <i>TAS2R38</i> taste receptor gene variants specify the ability to taste phenylthiocarbamide (PTC), 6-n-propylthiouracil (PROP) and structurally related compounds. Tobacco smoke contains a complex mixture of chemical substances of varying structure and functionality, some of which activate different taste receptors. Accordingly, it has been suggested that non-taster individuals may be more likely to smoke because of their inability to taste bitter compounds present in tobacco smoke, but results to date have been conflicting. We studied three cohorts: 237 European-Americans from the state of Georgia, 1,353 European-Americans and 2,363 African-Americans from the Dallas Heart Study (DHS), and 4,973 African-Americans from the Dallas Biobank. Tobacco use data was collected and <i>TAS2R38</i> polymorphisms were genotyped for all participants, and PTC taste sensitivity was assessed in the Georgia population. In the Georgia group, PTC tasters were less common among those who smoke: 71.5% of smokers were PTC tasters while 82.5% of non-smokers were PTC tasters (P = 0.03). The frequency of the <i>TAS2R38</i> PAV taster haplotype showed a trend toward being lower in smokers (38.4%) than in non-smokers (43.1%), although this was not statistically significant (P = 0.31). In the DHS European-Americans, the taster haplotype was less common in smokers (37.0% vs. 44.0% in non-smokers, P = 0.003), and conversely the frequency of the non-taster haplotype was more common in smokers (58.7% vs. 51.5% in non-smokers, P = 0.002). No difference in the frequency of these haplotypes was observed in African Americans in either the Dallas Heart Study or the Dallas Biobank. We conclude that <i>TAS2R38</i> haplotypes are associated with smoking status in European-Americans but not in African-American populations. PTC taster status may play a role in protecting individuals from cigarette smoking in specific populations.</p></div

Distribution of <i>TAS2R38</i> haplotypes between smokers and non-smokers in the DHS population.

<p>Distribution of <i>TAS2R38</i> haplotypes between smokers and non-smokers in the DHS population.</p