Potential role of gene-environment interactions in ion transport mechanisms in the etiology of renal cell cancer

• Published in: Scientific reports 2016-09, Vol.6 (1), p.34262, Article 34262
• Main Authors: Deckers, Ivette A. G., van den Brandt, Piet A., van Engeland, Manon, van Schooten, Frederik J., Godschalk, Roger W. L., Keszei, András P., Hogervorst, Janneke G. F., Schouten, Leo J.
• Format: Article
• Language: English
• Subjects: 45/22; 692/699/1585/1588/1351; 692/699/67/2324; Cancer; Diet; Dietary intake; Environmental factors; Etiology; Fluid intake; Genetic effects; Genotype & phenotype; Genotype-environment interactions; Humanities and Social Sciences; Hypertension; Ion transport; Kidney cancer; Kidneys; multidisciplinary; Potassium; Renal cell carcinoma; Science; Science (multidisciplinary); Single-nucleotide polymorphism; Sodium; Statistical analysis; Toenail
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep34262

We investigated the ion transport mechanism (ITM) in renal cell cancer (RCC) etiology using gene-environment interactions between candidate single nucleotide polymorphisms (SNPs) and associated environmental factors, including dietary intakes of sodium, potassium and fluid, hypertension and diuretic medication. A literature-based selection of 13 SNPs in ten ITM genes were successfully genotyped in toenail DNA of 3,048 subcohort members and 419 RCC cases from the Netherlands Cohort Study. Diet and lifestyle were measured with baseline questionnaires. Cox regression analyses were conducted for main effects and gene-environment interactions. ADD1 _rs4961 was significantly associated with RCC risk, showing a Hazard Ratio (HR) of 1.24 (95% confidence intervals (CI): 1.01–1.53) for the GT + TT ( versus GG) genotype. Four of 65 tested gene-environment interactions were statistically significant. Three of these interactions clustered in SLC9A3 _rs4957061, including the ones with fluid and potassium intake, and diuretic medication. For fluid intake, the RCC risk was significantly lower for high versus low intake in participants with the CC genotype (HR(95% CI): 0.47(0.26–0.86)), but not for the CT + TT genotype ( P -interaction = 0.002). None of the main genetic effects and gene-environment interactions remained significant after adjustment for multiple testing. Data do not support the general hypothesis that the ITM is a disease mechanism in RCC etiology.