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Replication and extension of association of choline acetyltransferase with nicotine dependence in European and African American smokers.

ABSTRACT: Choline acetyltransferase is critical in the synthesis of acetylcholine and regulation of cholinergic neuron functions. We recently reported association of the encoding gene ChAT with both smoking cessation and nicotine dependence (ND) in two independent European American (EA) samples; however, in the replication sample, only limited SNPs partially covering the gene were examined. In this study, we examined the association of 14 SNPs, which cover the entire gene, with ND, assessed by smoking quantity (SQ), heaviness of smoking index (HSI), and Fagerström Test for ND (FTND), in 2,037 subjects from 602 families of African American (AA) or EA origin. Individual SNP-based association analysis revealed that five SNPs showed nominal association with at least one ND measure in one of the samples (P = 0.022-0.042); none remained significant after correction for multiple testing. Haplotype-based association analysis revealed that haplotypes G-G-A-C, formed by rs1880676-rs3810950-rs10082479-rs8178990 (P = 0.005-0.0178), and G-G-T-C-G-C, formed by rs1880676-rs3810950-rs10082479-rs8178990-rs3793790-rs12266458 (P = 0.00247-0.00468), displayed significant association with all three ND measures in the AA sample, as did haplotype T-C-G-A-T, formed by rs12266458-rs11101191-rs8178991-rs4838544-rs4838547 (P = 0.00741-0.0103), in the EA sample. All these detected haplotype-based associations remained significant after correction for all major haplotypes for a given SNP combination. Together, our findings, in conjunction with the previous report of the association, warrant further investigation of ChAT in ND.

SUBMITTER: Wei J

PROVIDER: S-EPMC5574174 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Replication and extension of association of choline acetyltransferase with nicotine dependence in European and African American smokers.

Wei Jinxue J Ma Jennie Z JZ Payne Thomas J TJ Cui Wenyan W Ray Riju R Mitra Nandita N Lerman Caryn C Li Ming D MD

Human genetics 20100410 6

Choline acetyltransferase is critical in the synthesis of acetylcholine and regulation of cholinergic neuron functions. We recently reported association of the encoding gene ChAT with both smoking cessation and nicotine dependence (ND) in two independent European American (EA) samples; however, in the replication sample, only limited SNPs partially covering the gene were examined. In this study, we examined the association of 14 SNPs, which cover the entire gene, with ND, assessed by smoking qua ...[more]

PMID: 20383528

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Project description: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 = <0.001-0.02) glucuronidation in both ethnicities in addition to UGT2B10*2 in European Americans (P = 0.01, P < 0.001). UGT2B17*2 (P = 0.03) in European Americans and UGT2B7 variants (P = 0.02-0.04) in African Americans were nominally associated with 3HC glucuronidation. UGT1A (P = 0.007-0.01), UGT2B10 (P = 0.02), and UGT2B7 (P = 0.02-0.03) variants in African Americans were nominally associated with NNAL glucuronidation.ConclusionsFindings from this initial in vivo study support a role for multiple UGTs in the glucuronidation of tobacco-related compounds in vivo, in particular UGT2B10 and cotinine glucuronidation.ImpactFindings also provide insight into ethnic differences in glucuronidation activity, which could be contributing to ethnic disparities in the risk for smoking-related cancers. Cancer Epidemiol Biomarkers Prev; 24(1); 94-104. ©2014 AACR.

Dataset Information

Replication and extension of association of choline acetyltransferase with nicotine dependence in European and African American smokers.

Publications

Replication and extension of association of choline acetyltransferase with nicotine dependence in European and African American smokers.

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