Abstract P389: Sex-Specific Genetic Interrogation of Cardiovascular Disease Drug Targets

Abstract

Investigating sex-specific effects of genetically-proxied drug target inhibition on cardiovascular disease (CVD) liability may improve the understanding of CVD pathophysiology and therapeutic intervention, to enhance the formulation of sex-specific treatment in clinical practice. We aimed to investigate sex-specific associations between genetic variation at CVD drug targets and CVD risk factors in the UK Biobank for anti-hypertensive, lipid-lowering and anti-inflammatory drug targets. Firstly, we conducted genome-wide association studies (GWAS) for systolic blood pressure (SBP), C-reactive protein (CRP), low density lipoprotein (LDL)-cholesterol for 488,226 women and men in the UK Biobank. We then performed genetic colocalization analyses to identify shared or differential genetic loci for CVD risk factors in males and females. Our findings highlight that females and males share potentially causal variants for SBP at the ADRB1, CACNA1D, CACNB2, CACNB3 and SLC12A3 drug targets, for LDL-cholesterol at PCSK9, HMGCR, and for CRP at IL6R . Notably, we highlight heterogeneous effects of SBP in men and women at ACE, CACNA1S, CACNA1C . This is the first comprehensive genetic interrogation of sex-specific effects on drug targets, suggesting physiological differences in hypertension-mediated CVD between men and women and potential differential response to anti-hypertensive medication. Whether this has viable clinical implications is yet to be formally tested in further sex-specific analyses in genetic association studies and clinical trials.