1. UGT1A and UGT2B Genetic Variation Alters Nicotine and Nitrosamine Glucuronidation in European and African American Smokers
- Author
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Wassenaar, Catherine A, Conti, David V, Das, Soma, Chen, Peixian, Cook, Edwin H, Ratain, Mark J, Benowitz, Neal L, and Tyndale, Rachel F
- Subjects
Biomedical and Clinical Sciences ,Tobacco ,Cancer ,Tobacco Smoke and Health ,Genetics ,Adult ,Black or African American ,Aged ,Genetic Variation ,Genotyping Techniques ,Glucuronosyltransferase ,Humans ,Middle Aged ,Nicotine ,Nitrosamines ,Smoking ,White People ,Medical and Health Sciences ,Epidemiology ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundIdentifying sources of variation in the nicotine and nitrosamine metabolic inactivation pathways is important to understanding the relationship between smoking and cancer risk. Numerous UGT1A and UGT2B enzymes are implicated in nicotine and nitrosamine metabolism in vitro; however, little is known about their roles in vivo.MethodsWithin UGT1A1, UGT1A4, UGT1A9, UGT2B7, UGT2B10, and UGT2B17, 47 variants were genotyped, including UGT2B10*2 and UGT2B17*2. The association between variation in these UGTs and glucuronidation activity within European and African American current smokers (n = 128), quantified as urinary ratios of the glucuronide over unconjugated compound for nicotine, cotinine, trans-3'-hydroxycotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was investigated in regression models assuming a dominant effect of variant alleles.ResultsCorrecting for multiple testing, three UGT2B10 variants were associated with cotinine glucuronidation, rs2331559 and rs11726322 in European Americans and rs835309 in African Americans (P ≤ 0.0002). Additional variants predominantly in UGT2B10 were nominally associated with nicotine (P = 0.008-0.04) and cotinine (P =
- Published
- 2015