The Cumulative Effect of Gene-Gene and Gene-Environment Interactions on the Risk of Prostate Cancer in Chinese Men.

Ming Liu,Ze Yang,Ling Zhu,Siying Liang,Liang Sun,Chenguang Zheng,Lei Tang,Jianye Wang,Yaoguang Zhang,Xiaoquan Zhu,Xin Wang,Yong Xu,Xin Chen,Xiaohong Shi,Dong Wei,Kuo Yang,Fan Yang,Chengxiao Zhao

doi:10.3390/ijerph13020162

Abstract

Prostate cancer (PCa) is a multifactorial disease involving complex genetic and environmental factors interactions. Gene-gene and gene-environment interactions associated with PCa in Chinese men are less studied. We explored the association between 36 SNPs and PCa in 574 subjects from northern China. Body mass index (BMI), smoking, and alcohol consumption were determined through self-administered questionnaires in 134 PCa patients. Then gene-gene and gene-environment interactions among the PCa-associated SNPs were analyzed using the generalized multifactor dimensionality reduction (GMDR) and logistic regression methods. Allelic and genotypic association analyses showed that six variants were associated with PCa and the cumulative effect suggested men who carried any combination of 1, 2, or ≥3 risk genotypes had a gradually increased PCa risk (odds ratios (ORs) = 1.79–4.41). GMDR analysis identified the best gene-gene interaction model with scores of 10 for both the cross-validation consistency and sign tests. For gene-environment interactions, rs6983561 CC and rs16901966 GG in individuals with a BMI ≥ 28 had ORs of 7.66 (p = 0.032) and 5.33 (p = 0.046), respectively. rs7679673 CC + CA and rs12653946 TT in individuals that smoked had ORs of 2.77 (p = 0.007) and 3.11 (p = 0.024), respectively. rs7679673 CC in individuals that consumed alcohol had an OR of 4.37 (p = 0.041). These results suggest that polymorphisms, either individually or by interacting with other genes or environmental factors, contribute to an increased risk of PCa.

Highlights

Prostate cancer (PCa) is a complex multifactorial disease
Based on allelic and genotypic association analyses, we explored the gene-gene interactions among six confirmed PCa risk variants and their cumulative effect on the risk of PCa in a case-control study
Our results showed that rs6983561 and rs16901966, that exhibit a high degree of linkage disequilibrium at 8q24, interacted with Body mass index (BMI) ě 28 and contributed to a higher risk of PCa (ORs = 7.66, 5.33, respectively)

Summary

Introduction

A twin study suggested that genetic factors may explain 42% of the etiological risk of PCa [1]. Identified over 70 PCa susceptibility variants, providing evidence of genetic susceptibility in the development of PCa. identified over 70 PCa susceptibility variants, providing evidence of genetic susceptibility in the development of PCa These polymorphic loci were common variants, mostly with low penetrance [2]. The odds ratios (ORs) of these PCa-associated single nucleotide polymorphisms (SNPs) were modest (1.02–1.66) and no one locus contributed highly to the risk of PCa [3]. Gene-gene interactions play a role in potential mechanisms of the missing heritability in human genetics, and research has identified the phenomenon in PCa. For example, Tao et al identified

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