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Significant association of the neurexin-1 gene (NRXN1) with nicotine dependence in European- and African-American smokers.

ABSTRACT: The neurexin-1 gene (NRXN1) has been shown to play a fundamental role in synaptogenesis and synaptic maintenance, as well as Ca(2+) channel and NMDA receptor recruitment. A recent study reported that NRXN1 is associated with nicotine dependence (ND); this, together with the intriguing physiological functions of the gene, motivated us to investigate the involvement of NRXN1 with ND in independent samples. In this study, we analyzed 21 single nucleotide polymorphisms (SNPs) within NRXN1 for association with ND, which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerström test for ND (FTND). Individual SNP and haplotype association tests were carried out in a sample consisting of 2037 individuals from 602 nuclear families of African-American (AA) or European-American (EA) origin. Individual SNP analysis revealed significant associations of rs2193225 with SQ, HSI and FTND (P = 0.00014-0.0010) in the EA sample and with SQ (P = 0.0019) in the pooled sample under the dominant model and rs6721498 with SQ, HSI and FTND in the AA (P = 0.000090-0.0000086) and pooled (P = 0.0010-0.00099) samples under the additive model, following correction for multiple testing. Haplotype analysis revealed six major haplotypes in the AA sample (minimum P-value = 0.000079), one major haplotype in the EA sample (P = 0.0062) and five major haplotypes in the pooled sample (minimum P-value = 0.00083), which showed significant association with all three ND measures; all of these contained one specific allele from one of the two aforementioned SNPs. Based on our findings that NRXN1 has significant association with ND in two independent samples, recent findings that NRXN1 plays an important role in synaptic development, and the previous report of association, we conclude that this gene represents a strong candidate for involvement in the etiology of ND.

SUBMITTER: Nussbaum J

PROVIDER: S-EPMC2902291 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Significant association of the neurexin-1 gene (NRXN1) with nicotine dependence in European- and African-American smokers.

Nussbaum Justin J Xu Qing Q Payne Thomas J TJ Ma Jennie Z JZ Huang Weihua W Gelernter Joel J Li Ming D MD

Human molecular genetics 20080211 11

The neurexin-1 gene (NRXN1) has been shown to play a fundamental role in synaptogenesis and synaptic maintenance, as well as Ca(2+) channel and NMDA receptor recruitment. A recent study reported that NRXN1 is associated with nicotine dependence (ND); this, together with the intriguing physiological functions of the gene, motivated us to investigate the involvement of NRXN1 with ND in independent samples. In this study, we analyzed 21 single nucleotide polymorphisms (SNPs) within NRXN1 for associ ...[more]

PMID: 18270208

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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

Significant association of the neurexin-1 gene (NRXN1) with nicotine dependence in European- and African-American smokers.

Publications

Significant association of the neurexin-1 gene (NRXN1) with nicotine dependence in European- and African-American smokers.

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