Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Genome-wide Gene-by-smoking Interaction Study of Chronic Obstructive Pulmonary Disease

Risk for Chronic Obstructive Pulmonary Disease (COPD) is determined by both cigarette smoking and genetic susceptibility, but little is known about gene-by-smoking interactions. We performed a genome-wide association analysis of 179,689 controls and 21,077 COPD cases from UK Biobank subjects of European ancestry recruited from 2006 to 2010, considering genetic main effects and gene-by-smoking interaction effects simultaneously (2-degree-of-freedom test) as well as interaction effects alone (1-degree-of-freedom interaction test). We sought to replicate significant results in the COPDGene study and SpiroMeta Consortium. We considered two smoking variables: (1) ever/never and (2) current/non-current. In the 1-degree-of-freedom interaction test, we identified one genome-wide significant locus on 15q25.1 (CHRNB4) for ever- and current-smoking and identified PI*Z allele (rs28929474) of SERPINA1 for ever-smoking and 3q26.2 (MECOM) for current-smoking in an analysis of previously reported COPD loci. In the 2-degree-of-freedom test, most of the significant signals were also significant for genetic marginal effects, aside from 16q22.1 (SMPD3) and 19q13.2 (EGLN2). The significant effects at 15q25.1 and 19q13.2 loci, both previously described in prior genome-wide association studies of COPD or smoking, were replicated in the COPDGene and SpiroMeta. We identified interaction effects at previously reported COPD loci, however, we failed to identify novel susceptibility loci.

Flavor and Nicotine Effects on E-cigarette Appeal in Young Adults: Moderation by Reason for Vaping

Objectives: Effective regulations that reduce nicotine vaping among young adult dual (combustible and e-cigarette) users may differ depending on whether e-cigarettes are used for helping with smoking cessation. This laboratory experiment examined flavor and nicotine effects on e-cigarette product appeal among young adult dual users, stratified by reported use of e-cigarettes to quit smoking. Methods: Dual users aged 18-35 years that did (N = 31) or did not (N = 22) report vaping for the purpose of quitting smoking puffed e-cigarette solutions varied by a flavor (fruit, menthol, tobacco) and nicotine (nicotine-containing [6 mg/mL], nicotine-free) with-in-participant design. After puffing each solution, participants rated appeal. Results: In main effect analyses, non-tobacco (vs tobacco) flavors increased appeal and nicotine-containing (vs nicotine free) solutions reduced appeal similarly in dual users who did and did not vape to quit smoking. Interaction analyses found non-significant trend evidence that fruit and menthol flavors suppressed nicotine's appeal-reducing effects more powerfully in those that did not vape to quit smoking (flavor × nicotine × vape to quit smoking, ps = .05-.06). Conclusions: Non-tobacco flavors might increase e-cigarette product appeal in young adult dual users overall and disproportionately suppress nicotine's appeal-reducing effects in those that vape for purposes other than assisting with smoking cessation.

The influence of human leukocyte antigen-DRB1*15:01 and its interaction with smoking in MS development is dependent on DQA1*01:01 status

Background: HLA-DRB1*15:01, absence of HLA-A*02:01, and smoking interact to increase multiple sclerosis (MS) risk. Objective: To analyze whether MS-associated human leukocyte antigen (HLA) alleles, apart from DRB1*15:01 and absence of A*02:01, interact with smoking in MS development, and to explore whether the established HLA-smoking interaction is affected by the DQA1*01:01 allele, which confers a protective effect only in the presence of DRB1*15:01. Methods: In two Swedish population-based case–control studies (5838 cases, 5412 controls), subjects with different genotypes and smoking habits were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals employing logistic regression. Interaction on the additive scale between different genotypes and smoking was evaluated. Results: The DRB1*08:01 allele interacted with smoking to increase MS risk. The interaction between DRB1*15:01 and both the absence of A*02:01 and smoking was confined to DQA1*01:01 negative subjects, whereas no interactions occurred among DQA1*01:01 positive subjects. Conclusion: Multifaceted interactions take place between different class II alleles and smoking in MS development. The influence of DRB1*15:01 and its interaction with the absence of A*02:01 and smoking is dependent on DQA1*01:01 status which may be due to differences in the responding T-cell repertoires.