Application of Multi-SNP Approaches Bayesian LASSO and AUC-RF to Detect Main Effects of Inflammatory-Gene Variants Associated with Bladder Cancer Risk

Abstract

The relationship between inflammation and cancer is well established in several tumor types, including bladder cancer. We performed an association study between 886 inflammatory-gene variants and bladder cancer risk in 1,047 cases and 988 controls from the Spanish Bladder Cancer (SBC)/EPICURO Study. A preliminary exploration with the widely used univariate logistic regression approach did not identify any significant SNP after correcting for multiple testing. We further applied two more comprehensive methods to capture the complexity of bladder cancer genetic susceptibility: Bayesian Threshold LASSO (BTL), a regularized regression method, and AUC-Random Forest, a machine-learning algorithm. Both approaches explore the joint effect of markers. BTL analysis identified a signature of 37 SNPs in 34 genes showing an association with bladder cancer. AUC-RF detected an optimal predictive subset of 56 SNPs. 13 SNPs were identified by both methods in the total population. Using resources from the Texas Bladder Cancer study we were able to replicate 30% of the SNPs assessed. The associations between inflammatory SNPs and bladder cancer were reexamined among non-smokers to eliminate the effect of tobacco, one of the strongest and most prevalent environmental risk factor for this tumor. A 9 SNP-signature was detected by BTL. Here we report, for the first time, a set of SNP in inflammatory genes jointly associated with bladder cancer risk. These results highlight the importance of the complex structure of genetic susceptibility associated with cancer risk.

Inflammatory-Related Genetic Variants in Non–Muscle-Invasive Bladder Cancer Prognosis: A Multimarker Bayesian Assessment

“…Among them, JAK3-rs6523 and CD5-rs7104333 were already identified as associated with UBC risk (24). Only 2 SNPs were associated with TP using MMM.…”

“…Genes (n ¼ 251, Supplementary Table S1) were carefully selected according to current available evidence of their involvement in inflammatory processes, favoring those inflammatory genes showing association with cancer as described elsewhere (24). TagSNPs covering these genes were identified using SYSNP (26) and genotyped with the GoldenGate Illumina Genotyping Assay platform (27).…”

“…Those studies have had limited success, as they have applied simplistic models analyzing each SNP individually, therefore ignoring the complexity of the disease likely underlined by many genetic variants with relatively low effects (23). A recent study has shown the usefulness of multi-marker methods (MMM) able to handle large amount of SNPsç often exceeding the number of individuals, to assess associations between SNPs in inflammatory genes and UBC risk (24).…”

Variations in Immediate-early Genes Encoding c-Fos, c-Jun and IER5 Transcription Factors are Associated with Ischemic Stroke

“…Thus, it was demonstrated that minor allele of FOS rs7101 SNP is protective against bladder cancer, whereas minor allele of FOS rs1063169 SNP associates with an increased risk of bladder cancer [49]. Also, in the genome-wide association study in Koreans FOS rs1063169 SNP demonstrated marginal association with Crohn's disease and low LD with rs4899554 SNP, which is intergenic between TMED10 and FOS and is located in one of 140 Chrohn's disease risk loci identified in Caucasians [50].…”

Cloning and sequence analysis of the LOC339524 gene in Sprague-Dawley rats

“…The LOC339524 gene has the chromosomal locus 1p22.3 (Ota et al, 2004). This locus has a high frequency of deletions, amplifications, and translocations (Li et al, 2013), which are associated with tumors (Balakrishnanet al, 2006;Muranenet al, 2011;Johanssonet al, 2012;de Maturana et al, 2013;Li et al, 2013;Rinket al, 2013), alcohol dependence (Gizeret al, 2011), leprosy (Liu et al, 2013), and mandibular prognathism (Ikunoet al, 2014), suggesting that the LOC339524 gene might be involved in the occurrence of these diseases and that its function is extremely important. Both the LOC339524 gene sequence of the Sprague-Dawley (SD) rat and the function of the protein it encodes are still unknown.…”