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No association between variant N-acetyltransferase genes, cigarette smoking and Prostate Cancer susceptibility among men of African descent.

ABSTRACT: OBJECTIVE: We evaluated the individual and combination effects of NAT1, NAT2 and tobacco smoking in a case-control study of 219 incident prostate cancer (PCa) cases and 555 disease-free men. METHODS: Allelic discriminations for 15 NAT1 and NAT2 loci were detected in germ-line DNA samples using TaqMan polymerase chain reaction (PCR) assays. Single gene, gene-gene and gene-smoking interactions were analyzed using logistic regression models and multi-factor dimensionality reduction (MDR) adjusted for age and subpopulation stratification. MDR involves a rigorous algorithm that has ample statistical power to assess and visualize gene-gene and gene-environment interactions using relatively small samples sizes (i.e., 200 cases and 200 controls). RESULTS: Despite the relatively high prevalence of NAT1*10/*10 (40.1%), NAT2 slow (30.6%), and NAT2 very slow acetylator genotypes (10.1%) among our study participants, these putative risk factors did not individually or jointly increase PCa risk among all subjects or a subset analysis restricted to tobacco smokers. CONCLUSION: Our data do not support the use of N-acetyltransferase genetic susceptibilities as PCa risk factors among men of African descent; however, subsequent studies in larger sample populations are needed to confirm this finding.

SUBMITTER: Kidd LC

PROVIDER: S-EPMC3122269 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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No association between variant N-acetyltransferase genes, cigarette smoking and Prostate Cancer susceptibility among men of African descent.

Kidd La Creis Renee LC Vancleave Tiva T TT Doll Mark A MA Srivastava Daya S DS Thacker Brandon B Komolafe Oyeyemi O Pihur Vasyl V Brock Guy N GN Hein David W DW

Biomarkers in cancer 20110201 3

OBJECTIVE: We evaluated the individual and combination effects of NAT1, NAT2 and tobacco smoking in a case-control study of 219 incident prostate cancer (PCa) cases and 555 disease-free men. METHODS: Allelic discriminations for 15 NAT1 and NAT2 loci were detected in germ-line DNA samples using TaqMan polymerase chain reaction (PCR) assays. Single gene, gene-gene and gene-smoking interactions were analyzed using logistic regression models and multi-factor dimensionality reduction (MDR) adjusted f ...[more]

PMID: 21709725

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Project description:BACKGROUND:Polymorphisms in glutathione S-transferase (GST) genes may influence response to oxidative stress and modify prostate cancer (PCA) susceptibility. These enzymes generally detoxify endogenous and exogenous agents, but also participate in the activation and inactivation of oxidative metabolites that may contribute to PCA development. Genetic variations within selected GST genes may influence PCA risk following exposure to carcinogen compounds found in cigarette smoke and decreased the ability to detoxify them. Thus, we evaluated the effects of polymorphic GSTs (M1, T1, and P1) alone and combined with cigarette smoking on PCA susceptibility. METHODS:In order to evaluate the effects of GST polymorphisms in relation to PCA risk, we used TaqMan allelic discrimination assays along with a multi-faceted statistical strategy involving conventional and advanced statistical methodologies (e.g., Multifactor Dimensionality Reduction and Interaction Graphs). Genetic profiles collected from 873 men of African-descent (208 cases and 665 controls) were utilized to systematically evaluate the single and joint modifying effects of GSTM1 and GSTT1 gene deletions, GSTP1 105 Val and cigarette smoking on PCA risk. RESULTS:We observed a moderately significant association between risk among men possessing at least one variant GSTP1 105 Val allele (OR = 1.56; 95%CI = 0.95-2.58; p = 0.049), which was confirmed by MDR permutation testing (p = 0.001). We did not observe any significant single gene effects among GSTM1 (OR = 1.08; 95%CI = 0.65-1.82; p = 0.718) and GSTT1 (OR = 1.15; 95%CI = 0.66-2.02; p = 0.622) on PCA risk among all subjects. Although the GSTM1-GSTP1 pairwise combination was selected as the best two factor LR and MDR models (p = 0.01), assessment of the hierarchical entropy graph suggested that the observed synergistic effect was primarily driven by the GSTP1 Val marker. Notably, the GSTM1-GSTP1 axis did not provide additional information gain when compared to either loci alone based on a hierarchical entropy algorithm and graph. Smoking status did not significantly modify the relationship between the GST SNPs and PCA. CONCLUSION:A moderately significant association was observed between PCA risk and men possessing at least one variant GSTP1 105 Val allele (p = 0.049) among men of African descent. We also observed a 2.1-fold increase in PCA risk associated with men possessing the GSTP1 (Val/Val) and GSTM1 (*1/*1 + *1/*0) alleles. MDR analysis validated these findings; detecting GSTP1 105 Val (p = 0.001) as the best single factor for predicting PCA risk. Our findings emphasize the importance of utilizing a combination of traditional and advanced statistical tools to identify and validate single gene and multi-locus interactions in relation to cancer susceptibility.

Dataset Information

No association between variant N-acetyltransferase genes, cigarette smoking and Prostate Cancer susceptibility among men of African descent.

Publications

No association between variant N-acetyltransferase genes, cigarette smoking and Prostate Cancer susceptibility among men of African descent.

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