Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis

BackgroundEpidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. Methods and findingsWe performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 x 10(-8)) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), beta-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 x 10(-4)). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry. ConclusionsIn this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications. Author summary Why was this study done? Angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and thiazide diuretics are commonly prescribed antihypertensive medications.Some epidemiological studies have suggested that long-term use of these medications can increase cancer risk, though findings have been conflicting.Germline genetic variation in genes encoding drug targets can be used to proxy the effect of long-term modulation of these targets on disease endpoints (drug-target mendelian randomization). What did the researchers do and find? We used drug-target mendelian randomization to examine the association of genetically proxied inhibition of the drug targets of ACE inhibitors, beta blockers, and thiazide diuretics with risk of 4 of the most common adult cancers (breast, colorectal, lung, and prostate) in up to 289,612 cancer cases and 291,224 controls.We found evidence that genetically proxied inhibition of the drug target for ACE inhibitors was associated with an increased risk of colorectal cancer.There was little evidence that genetically proxied inhibition of the drug target for ACE inhibitors was associated with risk of the other cancers examined or evidence for an association of genetically proxied inhibition of drug targets for beta blockers and thiazide diuretics with risk of all 4 cancers examined. What do these findings mean? These findings provide support for a link between long-term inhibition of the drug target for ACE inhibitors and colorectal cancer risk, highlighting the need to evaluate the safety profiles of these medications in clinical trials with adequate follow-up length.Prior to confirmation of an effect of ACE inhibitor use on colorectal cancer risk in clinical trials, these findings should not alter clinical practice for ACE inhibitor prescribing