TY - JOUR

T1 - A genome-wide association study of nausea incidence in varenicline-treated cigarette smokers

AU - Chenoweth, Meghan J

AU - Lerman, Caryn

AU - Knight, Jo

AU - Tyndale, Rachel F

N1 - This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Nicotine and Tobacco Research following peer review. The definitive publisher-authenticated version Meghan J Chenoweth, PhD, Caryn Lerman, PhD, Jo Knight, PhD, Rachel F Tyndale, PhD, A genome-wide association study of nausea incidence in varenicline-treated cigarette smokers, Nicotine & Tobacco Research, 2021; 23, 10, 1805-1809 ntab044, https://doi.org/10.1093/ntr/ntab044 is available online at: https://academic.oup.com/ntr/article/23/10/1805/6170363

PY - 2021/10/31

Y1 - 2021/10/31

N2 - INTRODUCTION: Varenicline is the most efficacious smoking cessation treatment, however long-term cessation rates tend to be <25%. Nausea, the most common side effect of varenicline, observed in ~28% of individuals treated, peaks early following treatment initiation and reduces cessation success. Genetic variation influences treatment response, however genetic contributors to individual differences in side effects are less understood.METHODS: We conducted a genome-wide association study of nausea incidence at one week following the initiation of varenicline treatment (corresponding to the target quit date) in 189 cigarette smokers of European ancestry (NCT01314001). Additive genetic models examining the likelihood of experiencing any versus no nausea controlled for population substructure, age, and sex. Variants with minor allele frequencies (MAF) ≥ 10% were considered.RESULTS: Fifty-seven (30.2%) out of 189 participants reported nausea. The top variant associated with nausea was rs1568209 (OR=2.61 for A vs. G allele; 95% CI=1.65,4.15; P=2.1e-7; MAF=48.7%), mapping to the SLCO3A1 drug transporter gene on chromosome 15. In the same trial, rs1568209 was not associated with nausea in either the nicotine patch (P=0.56; n=181) or placebo (P=0.59; n=174) arms. In varenicline-treated smokers, the incidence of nausea was higher in females (44.6%; n=74) versus males (20.9%; n=115) (P=0.001), however there was no evidence of a difference in the influence of rs1568209 on nausea between the sexes (P for sex*genotype interaction=0.36). Future studies in larger samples are required to test the robustness of this finding.CONCLUSIONS: Variation in SLCO3A1 may influence the risk for developing nausea in varenicline-treated smokers, which may alter adherence and cessation.IMPLICATIONS: Varenicline-associated nausea reduces adherence and limits cessation success. Previous candidate gene association studies showed genetic factors influence nausea on varenicline. This pilot genome-wide investigation of nausea, the most common side effect associated with varenicline treatment and an importance cause of treatment discontinuation, suggests the potential involvement of common variation in the SLCO3A1 drug transporter gene.

AB - INTRODUCTION: Varenicline is the most efficacious smoking cessation treatment, however long-term cessation rates tend to be <25%. Nausea, the most common side effect of varenicline, observed in ~28% of individuals treated, peaks early following treatment initiation and reduces cessation success. Genetic variation influences treatment response, however genetic contributors to individual differences in side effects are less understood.METHODS: We conducted a genome-wide association study of nausea incidence at one week following the initiation of varenicline treatment (corresponding to the target quit date) in 189 cigarette smokers of European ancestry (NCT01314001). Additive genetic models examining the likelihood of experiencing any versus no nausea controlled for population substructure, age, and sex. Variants with minor allele frequencies (MAF) ≥ 10% were considered.RESULTS: Fifty-seven (30.2%) out of 189 participants reported nausea. The top variant associated with nausea was rs1568209 (OR=2.61 for A vs. G allele; 95% CI=1.65,4.15; P=2.1e-7; MAF=48.7%), mapping to the SLCO3A1 drug transporter gene on chromosome 15. In the same trial, rs1568209 was not associated with nausea in either the nicotine patch (P=0.56; n=181) or placebo (P=0.59; n=174) arms. In varenicline-treated smokers, the incidence of nausea was higher in females (44.6%; n=74) versus males (20.9%; n=115) (P=0.001), however there was no evidence of a difference in the influence of rs1568209 on nausea between the sexes (P for sex*genotype interaction=0.36). Future studies in larger samples are required to test the robustness of this finding.CONCLUSIONS: Variation in SLCO3A1 may influence the risk for developing nausea in varenicline-treated smokers, which may alter adherence and cessation.IMPLICATIONS: Varenicline-associated nausea reduces adherence and limits cessation success. Previous candidate gene association studies showed genetic factors influence nausea on varenicline. This pilot genome-wide investigation of nausea, the most common side effect associated with varenicline treatment and an importance cause of treatment discontinuation, suggests the potential involvement of common variation in the SLCO3A1 drug transporter gene.

KW - Nicotine patches

KW - Smoking cessation

KW - Genes

KW - Genome

KW - Genotype

KW - Membrane transport

KW - Proteins

KW - Nausea

KW - Genetics

KW - Varenicline

KW - Cigarettes

KW - Genome-wide association study

KW - Smokers

U2 - 10.1093/ntr/ntab044

DO - 10.1093/ntr/ntab044

M3 - Journal article

C2 - 33713409

VL - 23

SP - 1805

EP - 1809

JO - Nicotine and Tobacco Research

JF - Nicotine and Tobacco Research

SN - 1462-2203

IS - 10

ER -