Targeted sequencing identifies genetic polymorphisms of flavin‐containing monooxygenase genes contributing to susceptibility of nicotine dependence in European American and African American

Abstract

BackgroundSmoking is a leading cause of preventable death. Early studies based on samples of twins have linked the lifetime smoking practices to genetic predisposition. The flavin‐containing monooxygenase (FMO) protein family consists of a group of enzymes that metabolize drugs and xenobiotics. Both FMO1 and FMO3 were potentially susceptible genes for nicotine metabolism process.MethodsIn this study, we investigated the potential of FMO genes to confer risk of nicotine dependence via deep targeted sequencing in 2,820 study subjects comprising 1,583 nicotine dependents and 1,237 controls from European American and African American. Specifically, we focused on the two genomic segments including FMO1,FMO3, and pseudo gene FMO6P, and aimed to investigate the potential association between FMO genes and nicotine dependence. Both common and low‐frequency/rare variants were analyzed using different algorithms. The potential functional significance of SNPs with association signal was investigated with relevant bioinformatics tools.ResultsWe identified different clusters of significant common variants in European (with most significant SNP rs6674596, p = .0004, OR = 0.67, MAF_EA = 0.14, FMO1) and African Americans (with the most significant SNP rs6608453, p = .001, OR = 0.64, MAF_AA = 0.1, FMO6P). No significant signals were identified through haplotype‐based analyses. Gene network investigation indicated that both FMO1 and FMO3 have a strong relation with a variety of genes belonging to CYP gene families (with combined score greater than 0.9). Most of the significant variants identified were SNPs located within intron regions or with unknown functional significance, indicating a need for future work to understand the underlying functional significance of these signals.ConclusionsOur findings indicated significant association between FMO genes and nicotine dependence. Replications of our findings in other ethnic groups were needed in the future. Most of the significant variants identified were SNPs located within intronic regions or with unknown functional significance, indicating a need for future work to understand the underlying functional significance of these signals.

Neurogenetic determinants and mechanisms of addiction to nicotine and smoked tobacco

“…In addition to replicating the association of two CHRNB2 SNPs, a significant association of rare SNPs at CHRNA4 was also reported. More recently, a targeted sequencing study focused on the flavin‐containing monooxygenase (FMO) protein family that is involved in nicotine metabolism (Zhang et al ., ). The authors replicated prior findings showing the association between smoking dependence and some common FMO gene variants, but did not detect signals for novel rare variants.…”

Evaluation of relationship between SPON1 gene and genetic susceptibility of postmenopausal osteoporosis

“…In future studies, functional analyses on SNP rs2697825 could offer information on its role in the regulation of SPON1 gene expression. In addition, several previous genetic studies of complex disorders have shown that rare variants could also contribute significantly to the risk of diseases [21][22][23]. Therefore, to investigate the genetic architecture of SPON1, a sequencing-based study with all potential DNA variants genotyped was necessary.…”

The Role of Pharmacogenetics in Smoking

“…The 1, 2, and 3 flavin‐containing monooxygenase (FMO) subtypes metabolize nicotine to its nicotine N′‐oxide metabolite, typically accounting for 4–7% of nicotine’s clearance 7 . FMOs are expressed both in the liver and in the brain 23 . Significant associations with smoking behaviors are predominately from candidate gene assessments, and not GWASs, where common FMO variants have been associated with nicotine dependence and cigarette consumption 23 ( Table 1 ).…”

“…FMOs are expressed both in the liver and in the brain 23 . Significant associations with smoking behaviors are predominately from candidate gene assessments, and not GWASs, where common FMO variants have been associated with nicotine dependence and cigarette consumption 23 ( Table 1 ). Furthermore, the effect of FMO on the NMR and nicotine pharmacokinetics is minimal, further supporting the specificity of the NMR as a CYP2A6 activity measure 24 …”