The Role of Pharmacogenetics in Smoking

El‐Boraie, Ahmed; Tyndale, Rachel F.

doi:10.1002/cpt.2345

Cited by 17 publications

(17 citation statements)

References 31 publications

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“…As reported, smoking and nutrition are associated with the activity variation of CYPs [ 77 , 78 ]. It was shown that smokers had higher CYP2D6, CYP2E1, and CYP2B6 levels compared with nonsmokers [ 69 , 79 ].…”

Section: Individual Variation Of Cyp-mediated Drug Metabolismmentioning

confidence: 99%

Cytochrome P450 Enzymes and Drug Metabolism in Humans

Zhao

Ma²,

et al. 2021

IJMS

384

147

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Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1–3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action. Structures of CYPs have recently provided new insights into both understanding the mechanisms of drug metabolism and exploiting CYPs as drug targets. Genetic polymorphisms and epigenetic changes in CYP genes and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. In this review, we summarize and highlight the structural knowledge about CYPs and the major CYPs in drug metabolism. Additionally, genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response are also reviewed, to reveal the multifarious and important roles of CYP-mediated metabolism and elimination in drug therapy.

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Section: Individual Variation Of Cyp-mediated Drug Metabolismmentioning

confidence: 99%

Cytochrome P450 Enzymes and Drug Metabolism in Humans

Zhao

Ma²,

et al. 2021

IJMS

384

147

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“…We studied the associations of rare coding variants in the human genome, captured via exome sequencing, with six major smoking phenotypes and a range of secondary phenotypes including diseases in which smoking has been well established as a major risk factor. We also selectively explored the rare variant associations with genes whose associations with smoking via common variants has been realized since the candidate gene era 26 , well replicated by GWAS [15][16][17]27 and the mechanisms through which they influence smoking behavior are understood 28,29 . Since we had information on common variants genome-wide for the study participants, we also conducted ancestryspecific and cross-ancestry GWAS meta-analyses for the six smoking phenotypes to validate known loci and to identify novel loci.…”

Section: Mainmentioning

confidence: 99%

Rare coding variants inCHRNB2reduce the likelihood of smoking

Rajagopal

Watanabe

Mbatchou

et al. 2022

Preprint

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Human genetic studies of smoking behavior have been so far largely limited to common variations. Studying rare coding variants has potential to identify new drug targets and refine our understanding of the mechanisms of known targets. We performed an exome-wide association study (ExWAS) of smoking phenotypes in up to 749,459 individuals across multiple ancestries and discovered a protective association signal in CHRNB2 that encodes the β2 subunit of α4β2 nicotine acetylcholine receptor (nAChR). Rare predicted loss-of-function (pLOF) and likely deleterious missense variants in CHRNB2 in aggregate were associated with a 35% decreased odds for smoking more than 10 cigarettes per day (OR=0.65, CI=0.56-0.76, P=1.9e-8). An independent common variant association in the protective direction (rs2072659; OR=0.96; CI=0.94-0.98; P=5.3e-6) was also evident, suggesting an allelic series. The protective effects of both rare and common variants were detectable to some extent on phenotypes downstream of smoking including lung function, emphysema, chronic obstructive pulmonary disease (COPD) and lung cancer. α4β2 is the predominant nAChR in human brain and is one of the targets of varenicline, a partial nAChR agonist/antagonist used to aid smoking cessation. Our findings in humans align with decades-old experimental observations in mice that β2 loss abolishes nicotine mediated neuronal responses and attenuates nicotine self-administration. Our genetic discovery will inspire future drug designs targeting CHRNB2 in the brain for the treatment of nicotine addiction.

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“…There is now considerable preclinical, clinical, and human genetics evidence implicating nAChRs located in the central nervous system (CNS) in regulating the abuse liability of nicotine-containing tobacco products [ 12 , 38 , 39 ] ( Fig. 1 ).…”

Section: Human Genetics-based Discovery Of Novel Targets For Smoking ...mentioning

confidence: 99%