LAUSR

Introduction: Despite numerous efforts to understand the molecular mechanisms underlying cardiovascular disease, it remains the leading cause of death worldwide. Circulating proteins are frequently used as clinical biomarkers and may serve as effective drug targets. Hypothesis: Identifying genetic variants associated with circulating protein concentrations (pQTLs) and combining them with genome-wide association study (GWAS) results may bridge a knowledge gap of unexplained heritability, identify potentially causal proteins, and highlight promising therapeutic targets. Methods: We measured concentrations of 436 plasma proteins among 484 Framingham participants using OLINK cardiovascular disease and inflammation panels. For each protein, we conducted a GWAS using 1000G imputed genotypes (imputation quality >20%). Then we performed two sample Mendelian randomization using cis-pQTLs (SNPs within 1Mb of transcriptional start site of the protein coding gene) as instrumental variables and 11 public cardiovascular trait GWAS (coronary artery disease (CAD), HDL cholesterol, LDL cholesterol, triglycerides (TG), body mass index (BMI), obesity, fasting blood glucose, type 2 diabetes, systolic blood pressure, diastolic blood pressure, and Hypertension) as outcomes. Results: At Bonferroni-corrected P<0.05, we identified 5281 cis-pQTLs for 76 proteins. Mendelian randomization identified 13 putatively causal proteins for seven cardiovascular traits: FGF-5, IL-6RA, LPL , and TFPI for CAD; CAPG, IGG_FCrrec, LPL, and TFPI for HDL; KIM1, LPL, and TNFB for TG, ENTPD6 for BMI; FGF-5, TFPI, UMOD, IGFBP3, PXN, and NUCB2 for blood pressure traits. Conclusions: At Bonferroni-corrected P<0.05, we identified 5281 cis-pQTLs for 76 proteins. Mendelian randomization identified 13 putatively causal proteins for seven cardiovascular traits: FGF-5, IL-6RA, LPL , and TFPI for CAD; CAPG, IGG_FCrrec, LPL, and TFPI for HDL; KIM1, LPL, and TNFB for TG, ENTPD6 for BMI; FGF-5, TFPI, UMOD, IGFBP3, PXN, and NUCB2 for blood pressure traits.