HSD3B and Gene-Gene Interactions in a Pathway-Based Analysis of Genetic Susceptibility to Bladder Cancer

Abstract

Bladder cancer is the 4th most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case–control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene–gene interactions using Multifactor Dimensionality Reduction (MDR) and Statistical Epistasis Network analysis. The 3′UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31–2.62). This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06–12.63). The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40–3.25) than females (OR 1.56 95%CI 0.83–2.95), (SNP-gender interaction P = 0.048). We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003). The fact that bladder cancer incidence is 3–4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.

A Screening-Testing Approach for Detecting Gene-Environment Interactions Using Sequential Penalized and Unpenalized Multiple Logistic Regression

“…The overwhelming majority (~ 98%) of the subjects were of Caucasian origin. Given the large proportion of Caucasian subjects, population structure should not be an issue for this data set, as confirmed in Andrew et al 19 We interviewed a total of 857 patients with bladder cancer, which was 85% of the cases confirmed to be eligible for the study, and 1191 controls without cancer. Informed consent was obtained from each participant and all procedures and study materials were approved by the Committee for the Protection of Human Subjects at Dartmouth College.…”

Approaching “Phantom Heritability” in Psychiatry by Hypothesis-Driven Gene–Gene Interactions

“…In this sense, this line of research could even help in the development and improvement of techniques (machine learning methods, for example) to be applied in GWAS analyses of gene–gene interactions. Some approaches have recently been implemented with this objective in cancer biology and cardiology (Andrew et al, 2012; Ma et al, 2012). Interrelationships of computational statistics and modern molecular biology could help narrow the gap between “missing” and “phantom” heritabilities in psychiatric genetics.…”

A network approach to prioritizing susceptibility genes for genome‐wide association studies

“…We measured the strength of the interaction between any pair of SNPs in terms of information gain (IG) (Andrew et al, ; Fan et al, ; Hu et al, , 2013b; Moore & Hu, ; Pan et al, ). This metric quantifies the amount of the disease status that the epistatic effect of the corresponding genotype pair represents.…”

“…We measured the strength of the interaction between any pair of SNPs in terms of information gain (IG) (Andrew et al, 2012;Fan et al, 2011;Hu et al, 2013bHu et al, , 2013b F I G U R E 1 The implementation of TURF + SURF. A and R denote the set of SNPs (i.e., attributes) and individuals, respectively.…”