Assessing SNP-SNP Interactions among DNA Repair, Modification and Metabolism Related Pathway Genes in Breast Cancer Susceptibility

Abstract

Genome-wide association studies (GWASs) have identified low-penetrance common variants (i.e., single nucleotide polymorphisms, SNPs) associated with breast cancer susceptibility. Although GWASs are primarily focused on single-locus effects, gene-gene interactions (i.e., epistasis) are also assumed to contribute to the genetic risks for complex diseases including breast cancer. While it has been hypothesized that moderately ranked (P value based) weak single-locus effects in GWASs could potentially harbor valuable information for evaluating epistasis, we lack systematic efforts to investigate SNPs showing consistent associations with weak statistical significance across independent discovery and replication stages. The objectives of this study were i) to select SNPs showing single-locus effects with weak statistical significance for breast cancer in a GWAS and/or candidate-gene studies; ii) to replicate these SNPs in an independent set of breast cancer cases and controls; and iii) to explore their potential SNP-SNP interactions contributing to breast cancer susceptibility. A total of 17 SNPs related to DNA repair, modification and metabolism pathway genes were selected since these pathways offer a priori knowledge for potential epistatic interactions and an overall role in breast carcinogenesis. The study design included predominantly Caucasian women (2,795 cases and 4,505 controls) from Alberta, Canada. We observed two two-way SNP-SNP interactions (APEX1-rs1130409 and RPAP1-rs2297381; MLH1-rs1799977 and MDM2-rs769412) in logistic regression that conferred elevated risks for breast cancer (P interaction<7.3×10−3). Logic regression identified an interaction involving four SNPs (MBD2-rs4041245, MLH1-rs1799977, MDM2-rs769412, BRCA2-rs1799943) (P permutation = 2.4×10−3). SNPs involved in SNP-SNP interactions also showed single-locus effects with weak statistical significance, while BRCA2-rs1799943 showed stronger statistical significance (P correlation/trend = 3.2×10−4) than the others. These single-locus effects were independent of body mass index. Our results provide a framework for evaluating SNPs showing statistically weak but reproducible single-locus effects for epistatic effects contributing to disease susceptibility.

Combined Effects of Six Cytokine Gene Polymorphisms and SNP-SNP Interactions on Hepatocellular Carcinoma Risk in Southern Guangxi, China

“…We found that SNP-SNP interactions between SNPs that did not exert individual effects on HCC risk were associated with HCC occurrence. Previous studies investigated SNP-SNP interactions during the development of breast cancer (Sapkota et al, 2013) and colorectal cancer (Goodman et al, 2006). These reports support our findings regarding the effects of SNP-SNP interactions on HCC risk.…”

“…Numerous studies have investigated the relations between cytokine polymorphisms and HCC risk; however, their results are controversial (Shin et al, 2003;Hirankarn et al, 2006;Slattery et al, 2007). Two studies have consistently noted that IL-1β-511 polymorphisms are significant risk factors for HCC progression in the Thai population and in Japanese patients (Tanaka et al, 2003;Hirankarn et al, 2006).…”

“…IL-10 is the most studied anti-inflammatory cytokine involved in cancer research. The promoter region is highly polymorphic and is associated with gastric cancer and HCC (Shin et al, 2003;Pan et al, 2013). IL-6 is a multifunctional cytokine that serves pro-and anti-inflammatory functions.…”

Polymorphisms in base excision repair genes: Breast cancer risk and individual radiosensitivity

“…In general, SNPs may contribute to the genetic risk for BC, although their effect is usually only slightly statistically significant. In some studies, SNP-SNP interactions have been examined to evaluate epistatic effects contributing to BC [47] . SNPs in different DNA repair pathways, or in other pathways related to DNA metabolism, were selected, and specific SNP pairs showed a statistical association with BC risk.…”

Polymorphisms in X-Ray Repair Cross-Complementing Group 1 Gene: Haplotypes, Breast Cancer Risk and Individual Radiosensitivity

“…Specific SNP pairs, selected within genes in DNA repair pathways or in other DNA metabolism pathways, showed a statistical association with BC risk [26]. Significant trends in BC risk were also observed in association with an increasing number of risk alleles in different DNA repair genes [27].…”