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Rs1495741 as a tag single nucleotide polymorphism of N-acetyltransferase 2 acetylator phenotype associates bladder cancer risk and interacts with smoking: A systematic review and meta-analysis.

ABSTRACT: Rs1495741 has been identified to infer N-acetyltransferase 2 (NAT2) acetylator phenotype, and to decrease the risk of bladder cancer. However, a number of studies conducted in various regions showed controversial results. To quantify the association between rs1495741 and the risk of bladder cancer and to estimate the interaction effect of this genetic variant with smoking, we performed a systematic literature review and meta-analysis involving 14,815 cases and 58,282 controls from 29 studies. Our results indicates rs1495741 significantly associated with bladder cancer risk (OR?=?0.85, 95% CI?=?0.82-0.89, test for heterogeneity P?=?0.36, I?=?7.0%). And we verified this association in populations from Europe, America, and Asia. Further, our stratified meta-analysis showed rs1495741's role is typically evident only in ever smokers, which suggests its interaction with smoking. This study may provide new insight into gene-environment study on bladder cancer.

SUBMITTER: Ma C

PROVIDER: S-EPMC4979814 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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rs1495741 as a tag single nucleotide polymorphism of N-acetyltransferase 2 acetylator phenotype associates bladder cancer risk and interacts with smoking: A systematic review and meta-analysis.

Ma Chong C Gu Liyan L Yang Mingyuan M Zhang Zhensheng Z Zeng Shuxiong S Song Ruixiang R Xu Chuanliang C Sun Yinghao Y

Medicine 20160801 31

Rs1495741 has been identified to infer N-acetyltransferase 2 (NAT2) acetylator phenotype, and to decrease the risk of bladder cancer. However, a number of studies conducted in various regions showed controversial results. To quantify the association between rs1495741 and the risk of bladder cancer and to estimate the interaction effect of this genetic variant with smoking, we performed a systematic literature review and meta-analysis involving 14,815 cases and 58,282 controls from 29 studies. Ou ...[more]

PMID: 27495060

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Project description:The arylamine N-acetyltransferase 2 (NAT2) slow acetylation phenotype is an established risk factor for urinary bladder cancer. We reported earlier on this risk association using NAT2 phenotypic categories inferred from NAT2 haplotypes based on seven single nucleotide polymorphisms (SNPs) in a study in Spain. In a subsequent genome-wide scan, we have identified a single common tag SNP (rs1495741) located in the 3' end of NAT2 that is also associated with bladder cancer risk. The aim of this report is to evaluate the agreement between the common tag SNP and the 7-SNP NAT2 inferred phenotype. The agreement between the 7-SNP NAT2 inferred phenotype and the tag SNP, rs1495741, was initially assessed in 2174 individuals from the Spanish Bladder Cancer Study (SBCS), and confirmed in a subset of individuals from the Main and Vermont component the New England Bladder Cancer Study (NEBCS). We also investigated the association of rs1495741 genotypes with NAT2 catalytic activity in cryopreserved hepatocytes from 154 individuals of European background. We observed very strong agreement between rs1495741 and the 7-SNP inferred NAT2 phenotype: sensitivity and specificity for the NAT2 slow phenotype was 99 and 95%, respectively. Our findings were replicated in an independent population from the NEBCS. Estimates for the association between NAT2 slow phenotype and bladder cancer risk in the SBCS and its interaction with cigarette smoking were comparable for the 7-SNP inferred NAT2 phenotype and rs1495741. In addition, rs1495741 genotypes were strongly related to NAT2 activity measured in hepatocytes (P<0.0001). A novel NAT2 tag SNP (rs1495741) predicts with high accuracy the 7-SNP inferred NAT2 phenotype, and thus can be used as a sole marker in pharmacogenetic or epidemiological studies of populations of European background. These findings illustrate the utility of tag SNPs, often used in genome-wide association studies (GWAS), to identify novel phenotypic markers. Further studies are required to determine the functional implications of rs1495741 and the structure and evolution of the haplotype on which it resides.

Project description:IntroductionInterstitial Cystitis (IC) is a chronic condition diagnosed based on the presence of symptoms, such as suprapubic/ pelvic pain, pressure or discomfort in association with urgency and increased urinary frequency. Confusable diseases must be excluded. However, there is no objective test or marker to establish the presence of the disease. Diagnosis and patient management is often difficult, given the poor understanding of IC pathogenesis and its unknown etiology and genetics. As an attempt to find biomarkers related to IC, we assessed the association between 20 selected single nucleotide polymorphism (SNPs) with IC and pain severity.ObjectivesTo assess the presence of SNPs in IC patients' blood samples and correlate them with the disease and chronic pain condition.MethodsA case-control study was conducted. We selected 34 female patients with IC diagnosed according to NIDDK criteria and 23 patients in the control group (previously healthy women with only stress urinary incontinence). IC patients were allocated into two groups according to reported chronic pain severity. We selected the following SNPs for analysis: rs1800871, rs1800872, rs1800896, rs1800471, rs1800629, rs361525, rs1800497, rs6311, rs6277, rs6276, rs6313, rs2835859, rs11127292, rs2243248, rs6887695, rs3212227, rs1799971, rs12579350, rs3813034, and rs6746030. Genotyping was performed by real-time PCR (q-PCR).ResultsThe polymorphic allele of SNP rs11127292 exhibited a higher frequency in subjects with IC than in controls (p:0.01). The polymorphic allele of SNP rs6311 was more frequent in patients with severe pain (p:0.03). The frequency of the wild-type allele of SNP rs1799971 was higher in patients with mild to moderate pain (p:0.04).ConclusionThe results indicated differences in SNP frequency among subjects, suggesting that SNPs could serve either as a marker of IC or as a marker of pain severity in IC patients. The study showed promising results regarding IC and polymorphism associations. These associations have not been previously reported.

Dataset Information

Rs1495741 as a tag single nucleotide polymorphism of N-acetyltransferase 2 acetylator phenotype associates bladder cancer risk and interacts with smoking: A systematic review and meta-analysis.

Publications

rs1495741 as a tag single nucleotide polymorphism of N-acetyltransferase 2 acetylator phenotype associates bladder cancer risk and interacts with smoking: A systematic review and meta-analysis.

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