Background: The association between trace elements and bladder cancer risk is not well understood. Individuals are typically exposed to a mixture of multiple elements simultaneously, such as through water pollution or diet. While previous studies have explored associations between individual elements and bladder cancer, there has been limited work in exploring the overall or joint effect of these elements. Methods: We leveraged the New England Bladder Cancer Study, a population-based matched case-control study, to estimate associations between a mixture of 12 trace elements and bladder cancer. Toenail clipping samples were collected and analyzed for 12 trace elements from 979 cases and 1232 controls. Using quantile-based g-computation, we assessed associations between the overall elements mixture and bladder cancer risk. Results: After adjustment for matching factors (i.e., age, sex, and state) and other potential confounders (e.g., smoking habits and high-risk occupation), we estimated an inverse association between the overall mixture of trace elements and bladder cancer (odds ratio: 0.78, 95% confidence interval: 0.66, 0.93). Results were relatively unchanged after adjustment for smoking, high-risk occupation, and diet. We examined indirect evidence for reverse causation in explaining this inverse relationship for arsenic and found evidence that bladder cancer diagnosis may lead to changes in short-term behavior, which affects concentrations of arsenic and possibly other elements in toenail samples.
Maria E. Kamenetsky, Stella Koutros, Maya Spaur et al.· Environmental Epidemiology· 0 citations
Bladder cancer is the ninth most common cancer worldwide, caused by genetic and environmental risk factors. Here, we report the findings of a multi-population meta-analysis of genome-wide association studies, including 32,470 individuals with and 1,753,462 without bladder cancer. We identify 70 independent risk loci, of which 43 are novel. Using a 70-marker polygenic risk score (HR = 1.63 per standard deviation), we increase the area under the curve from 0.71 (baseline risk model) to 0.75. Integrative analyses reveal the enrichment of the associated variants within accessible chromatin regions, and of the prioritized genes within pathways for xenobiotic metabolism and smoking behavior. Specifically, we show that the 15q25.1 variant rs71581744-ACCCC/A co-localizes with tissue-specific CHRNA3 expression, modulates mRNA stability, and associates with risk of muscle-invasive bladder cancer among current smokers. Together, these findings substantially expand the known genetic architecture of bladder cancer risk and highlight the germline regulation of smoking behavior as a mechanism driving bladder cancer susceptibility. This study integrates genetic data from diverse populations to identify 70 loci linked to bladder cancer risk, including 43 novel, and uses experimental approaches to uncover how inherited variation influences this risk in the context of smoking.
L. Prokunina-Olsson, O. Flórez-Vargas, Michael G. Levin et al.· Nature Communications· 0 citations
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