Joint Analysis of SNP-SNP-Environment Interactions for Chronic Dialysis by an Improved Branch and Bound Algorithm

In previous studies, both single-nucleotide polymorphism (SNP)-SNP or gene-gene (G × G) interactions and SNP-environmental factor (G × E) interactions were reported to partially account for "missing" heritability. However, (G × G) × E interactions were less commonly addressed. The purpose of this study was to develop a novel strategy to evaluate possible (G × G) × E interactions in D-loop-based chronic dialysis association. Using values from our previously published data set (704 controls and 193 cases) of 77 D-loop SNPs and 7 environmental factors (coronary heart disease, hypertension, diabetes mellitus, triglyceride, cholesterol, blood thiol, and TBARS levels), we compared the performances of G, G × G, G × E, and (G × G) × E. We found that the interactions of four individual SNPs previously associated with a significantly high risk of chronic dialysis [odds ratio (OR) = 1.56-4.93] with environmental factors (G × E) increased the risk of chronic dialysis (maximum OR = 35.43). We then used an improved branch and bound algorithm to identify combinations of two to four SNPs that were most highly associated with chronic dialysis (OR = 9.27-34.39). When the interactions of the two- and three-SNP combinations with environmental factors were evaluated, we found that the (G × G) × E effects increased the risk of chronic dialysis (maximum OR = 8.32-57.54 and OR = 12.52-57.81, respectively; adjusted OR = 8.67-81.81 and OR = 12.29-81.95, respectively). Taken together, the (G × G) × E interactions identified chronic dialysis-associated SNPs that would not have been found using G × G or G × E interactions, suggesting that (G × G) × E interactions may be helpful to solve the problems of missing heritability in association studies.