The potential effect and pathway of valsartan: genome-wide and phenome-wide association study from UK Biobank data

Valsartan, an angiotensin II receptor blocker, is widely used for hypertension and heart failure. While its cardiovascular benefits are established, its broader pharmacological effects remain incompletely characterized. This study aimed to identify genetic variants associated with valsartan use and to systematically explore its potential effects and adverse events across a wide range of phenotypes.

Using UK Biobank data, we selected participants of European ancestry prescribed valsartan as cases, compared with controls not prescribed any ARBs. A genome-wide association study (GWAS) was conducted to identify suggestive genetic variants associated with valsartan use. These variants were then used as instruments in a phenome-wide association study (PheWAS) to screen for associated traits. Mendelian randomization analyses, including inverse-variance weighted and pleiotropy-robust methods, were employed to assess potential causal relationships.

The GWAS identified 19 suggestive single nucleotide polymorphisms ( P  < 1 × 10 -5 ) near genes, including PREP , GCLC , and ZNF133 . The PheWAS analysis revealed associations with 14 phenotypes, including lower levels of total cholesterol ( β = -0.59) and low-density lipoprotein cholesterol (LDL-C) ( β = -0.56), and increased risk of cough (odds ratio = 1.67). Mendelian randomization provided genetic evidence consistent with potential causal effects of valsartan in lowering LDL-C ( β = -2.34 × 10 -3 ) and reducing the risk of transient cerebral ischemic attack.

Our genetic-based study suggests valsartan use may be associated with lowered LDL-C and reduced risks of certain ischemic cardiovascular events. These findings generate novel hypotheses regarding the drug's pleiotropic effects and potential applications beyond hypertension management, which warrant further clinical investigation.