G894T and 4a/b polymorphisms of NOS3 gene are not associated with cancer risk: a meta-analysis.

Shafiul Haque,Arif Hussain,Aditya K Panda,Mohtashim Lohani,Saif Khan,Naseem Akhter,Raju K Mandal

doi:10.7314/apjcp.2015.16.7.2929

Shafiul Haque, Arif Hussain + Show 5 more

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https://doi.org/10.7314/apjcp.2015.16.7.2929

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Abstract

Endothelial nitric oxide synthase (eNOS or NOS3) produces nitric oxide and genetic polymorphisms of NOS3 gene play significant roles in various processes of carcinogenesis. The results from published studies on the association between NOS3 G894T and NOS3 intron 4 (4a/b) polymorphisms and cancer risk are conflicting and inconclusive. However, i n order to assess this relationship more precisely, a meta-analysis was performed with PubMed (Medline), EMBASE and Google web searches until February 2014 to select all published case- control and cohort studies. Genotype distribution data were collected to calculate the pooled odd ratios (ORs) and 95% confidence intervals (CIs) to evaluate the strength of association. A total of 10,546 cancer cases and 10,550 controls were included from twenty four case-control studies for the NOS3 G894T polymorphism. The results indicated no significant association with cancer risk as observed in allelic (T vs G: OR=1.024, 95%CI=0.954 to 1.099, p=0.508), homozygous (TT vs GG: OR=1.137, 95%CI=0.944 to 1.370, p=0.176), heterozygous (GT vs GG: OR=0.993, 95%CI=0.932 to 1.059, p=0.835), recessive (TT vs GG+GT: OR=1.100, 95%CI=0.936 to 1.293, p=0.249) and dominant (TT+GT vs GG: OR=1.012, 95%CI=0.927 to 1.105, p=0.789) genetic models. Similarly, a total of 3,449 cancer cases and 3,691 controls were recruited from fourteen case-control studies for NOS3 4a/b polymorphism. Pooled results indicated no significant association under allelic (A vs B: OR=0.981, 95%CI=0.725 to 1.329, p=0.902), homozygous (AA vs BB: OR=1.166, 95%CI=0.524 to 2.593, p=0.707), heterozygous (BA vs BB: OR=1.129, 95%CI=0.896 to 1.422, p=0.305), dominant (AA+BA vs BB: OR=1.046, 95%CI=0.779 to 1.405, p=0.763) and recessive (AA vs BB+BA: OR=1.196, 95%CI=0.587 to 2.439, p=0.622) genetic contrast models. This meta-analysis suggests that G894T and 4a/b polymorphisms of NOS3 gene are not associated with increased or decreased risk of overall cancer.

Highlights

Cancer is an ever dreadful disease and shown major impact on human health problem linked with very high morbidity and mortality across the globe (Jemal et al, 2011)
The free radical nitric oxide (NO) is a pleiotropic molecule primarily synthesized during the conversion of L-arginine to L-citrulline by endothelial nitric oxide synthase, which is known as nitric oxide synthase 3 (NOS3) or constitutive NOS (Forstermann et al, 1998)
Till date many polymorphisms have been reported in NOS3 gene, among them G894T polymorphism, which is located in exon 7 of the NOS3 gene and leads to the amino acid substitution from Glu298Asp that alters susceptibility to cleavage, and reduced enzyme activity and basal NO production in NOS3 894T (298Asp) allele carriers compared with the GG homozygotes (Wang et al, 1997; Veldman et al, 2002)

Summary

Introduction

Cancer is an ever dreadful disease and shown major impact on human health problem linked with very high morbidity and mortality across the globe (Jemal et al, 2011). Till date many polymorphisms have been reported in NOS3 gene, among them G894T polymorphism (rs1799983), which is located in exon 7 of the NOS3 gene and leads to the amino acid substitution from Glu298Asp that alters susceptibility to cleavage, and reduced enzyme activity and basal NO production in NOS3 894T (298Asp) allele carriers compared with the GG homozygotes (Wang et al, 1997; Veldman et al, 2002). Burton et al suggested that larger sample sizes are good to study the genetic associations with complex diseases (Burton et al, 2009) These findings prompted us to perform this meta-analysis to pool all pertinent published studies to evaluate the more precise association and understanding the role NOS3 G894T and NOS3 4a/b polymorphisms in cancer development. A meta-analysis is an important statistical tool because it uses quantitative approach to pool the data from individual studies where individual sample sizes are small with low statistical power, and delivers robust conclusion (Cohn and Becker, 2002; Mandal et al, 2013)

Materials and Methods

Study design

Discussion