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We investigated the relationship between germline single nucleotide polymorphisms (SNPs) in  Von Hippel-Lindau (VHL)  and  Hypoxia-inducible factor 1-alpha (HIF1A) , and their gene-environment and gene-gene interactions, and clear-cell RCC (ccRCC) risk. Furthermore, we assessed the relationship between  VHL  SNPs and  VHL  promoter methylation. Three  VHL  polymorphisms and one  HIF1A  polymorphism were genotyped in the Netherlands Cohort Study. In 1986, 120,852 participants aged 55–69 completed a self-administered questionnaire on diet and lifestyle and toenail clippings were collected. Toenail DNA was genotyped using the Sequenom MassARRAY platform. After 20.3 years, 3004 subcohort members and 406 RCC cases, of which 263 ccRCC cases, were eligible for multivariate case-cohort analyses. V HL _rs779805 was associated with RCC (Hazard Ratio (HR) 1.53; 95% Confidence Interval (CI) 1.07–2.17) and ccRCC risk (HR 1.88; 95% CI 1.25–2.81). No associations were found for other SNPs. Potential gene-environment interactions were found between alcohol consumption and selected SNPs. However, none remained statistically significant after multiple comparison correction. No gene-gene interactions were observed between  VHL  and  HIF1A .  VHL  promoter methylation was not associated with  VHL  SNPs.  VHL  SNPs may increase (cc)RCC susceptibility. No associations were found between gene-environment and gene-gene interactions and (cc)RCC risk and between  VHL  promoter methylation and  VHL  SNPs.

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Germline polymorphisms in the Von Hippel-Lindau and Hypoxia-inducible factor 1-alpha genes, gene-environment and gene-gene interactions and renal cell cancer