Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis.
<h4>Background</h4>Epidemiological 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 targe...
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Public Library of Science (PLoS)
2022-02-01
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| author | James Yarmolinsky Virginia Díez-Obrero Tom G Richardson Marie Pigeyre Jennifer Sjaarda Guillaume Paré Venexia M Walker Emma E Vincent Vanessa Y Tan Mireia Obón-Santacana Demetrius Albanes Jochen Hampe Andrea Gsur Heather Hampel Rish K Pai Mark Jenkins Steven Gallinger Graham Casey Wei Zheng Christopher I Amos International Lung Cancer Consortium PRACTICAL consortium MEGASTROKE consortium George Davey Smith Richard M Martin Victor Moreno |
| author_facet | James Yarmolinsky Virginia Díez-Obrero Tom G Richardson Marie Pigeyre Jennifer Sjaarda Guillaume Paré Venexia M Walker Emma E Vincent Vanessa Y Tan Mireia Obón-Santacana Demetrius Albanes Jochen Hampe Andrea Gsur Heather Hampel Rish K Pai Mark Jenkins Steven Gallinger Graham Casey Wei Zheng Christopher I Amos International Lung Cancer Consortium PRACTICAL consortium MEGASTROKE consortium George Davey Smith Richard M Martin Victor Moreno |
| author_sort | James Yarmolinsky |
| collection | DOAJ |
| description | <h4>Background</h4>Epidemiological 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.<h4>Methods and findings</h4>We 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 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), β-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 × 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.<h4>Conclusions</h4>In 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. |
| format | Article |
| id | doaj-art-34b1a0c7008a49a584262cd8aef7a5ec |
| institution | OA Journals |
| issn | 1549-1277 1549-1676 |
| language | English |
| publishDate | 2022-02-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Medicine |
| spelling | doaj-art-34b1a0c7008a49a584262cd8aef7a5ec2025-08-20T02:23:28ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762022-02-01192e100389710.1371/journal.pmed.1003897Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis.James YarmolinskyVirginia Díez-ObreroTom G RichardsonMarie PigeyreJennifer SjaardaGuillaume ParéVenexia M WalkerEmma E VincentVanessa Y TanMireia Obón-SantacanaDemetrius AlbanesJochen HampeAndrea GsurHeather HampelRish K PaiMark JenkinsSteven GallingerGraham CaseyWei ZhengChristopher I AmosInternational Lung Cancer ConsortiumPRACTICAL consortiumMEGASTROKE consortiumGeorge Davey SmithRichard M MartinVictor Moreno<h4>Background</h4>Epidemiological 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.<h4>Methods and findings</h4>We 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 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), β-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 × 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.<h4>Conclusions</h4>In 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.https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1003897&type=printable |
| spellingShingle | James Yarmolinsky Virginia Díez-Obrero Tom G Richardson Marie Pigeyre Jennifer Sjaarda Guillaume Paré Venexia M Walker Emma E Vincent Vanessa Y Tan Mireia Obón-Santacana Demetrius Albanes Jochen Hampe Andrea Gsur Heather Hampel Rish K Pai Mark Jenkins Steven Gallinger Graham Casey Wei Zheng Christopher I Amos International Lung Cancer Consortium PRACTICAL consortium MEGASTROKE consortium George Davey Smith Richard M Martin Victor Moreno Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis. PLoS Medicine |
| title | Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis. |
| title_full | Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis. |
| title_fullStr | Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis. |
| title_full_unstemmed | Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis. |
| title_short | Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis. |
| title_sort | genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers a mendelian randomization analysis |
| url | https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1003897&type=printable |
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