Background: Hypertension is associated with increasing risk of renal cancer in observational studies, but there is insufficient evidence on whether hypertension is a causal factor for renal cancer. Methods: We analysed data from 313,520 individuals of White British ancestry aged 40-69 years at baseline from the UK Biobank prospective cohort. We used polygenic risk scores (PRS) for SBP and DBP, respectively, in Mendelian randomisation analyses to assess the causal effect of blood pressure on renal cancer. Our primary outcome is renal-parenchyma cancer, and we used bladder cancer as a negative control. We conducted additional sensitivity analyses, using individual SNPs from the PRS as instruments, to ensure the MR results are robust. Results: Among the study population, 1159 participants developed renal-parenchyma cancer over the median of 12.5 years of follow-up. Every 5 mmHg increase in measured SBP and DBP was significantly associated with increased risk for renal-parenchyma cancer (HR: 1.04; 95% CI: 1.02-1.05; p < 0.001 and HR: 1.07; 95% CI: 1.03-1.10; p < 0.001 respectively). Consistent with observational association analyses, we observed statistically significant associations between each 5 mmHg genetically elevated BP and risk of renal-parenchyma cancer, with DBP (HR: 1.17; 95% CI: 1.07-1.27; p < 0.001) having a stronger association than SBP (HR: 1.09; 95% CI: 1.02-1.17; p = 0.009). These significant associations were maintained in sensitivity analyses. We observed a null association of genetically predicted blood pressure with bladder cancer. Conclusions: These findings provide evidence that elevated BP is causally associated with renal-parenchyma cancer. Key words: systolic, diastolic, blood pressure, hypertension, renal, parenchyma, cancer, Mendelian randomisation, polygenic risk score, UK Biobank.

The authors have declared no competing interest.

The UK Biobank study was supported by the Wellcome Trust, Medical Research Council, Department of Health, Scottish government, and Northwest Regional Development Agency. It has also received funding from the Welsh Assembly government and British Heart Foundation. The analyses here were funded by the Cancer Research UK (grant no C16077/A29186), and supported by the Nuffield Department of Population Health, Oxford University.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

This research has been conducted using the UK Biobank Resource under Application Number 33952. Requests to access the data should be made via application directly to the UK Biobank, https://www.ukbiobank.ac.uk

https://github.com/xiaonanl1996/MRforRenal