부산대학교 도서관

Introduction: Lipoprotein(a) (Lp(a)) is a risk factor for atherosclerosis but its physiological function remains obscure. Furthermore, the potential introduction of LPA targeting therapies into clinical practice warrants an assessment of non-lipid effects of LPA.Objective: We conducted an electronic health record (EHR)-based phenome-wide association study (PheWAS) in the electronic MEdical Records and GEnomics (eMERGE) Network to determine associations of LPA variants and a range of human phenotypes.Methods: High-density genotype data linked to the EHR were available in 60,995 non-Hispanic whites (mean age 60±24 years, 52% females). A set of cases and controls was defined for each phenotype using the PheWAS R package; 13,707 diagnosis codes were converted to 1,814 phenocodes. We tested 10 LPA variants (associated with plasma Lp(a) levels, minor allele frequency (MAF) ≥0.1%, INFO score >0.7, CADD score >1) with 895 EHR-derived binary phenotypes (≥300 cases per trait) using logistic regression assuming an additive genetic model. All models were adjusted for age, sex, and the first two principal components.Results: Two variants associated with increased Lp(a) levels, rs10455872 (MAF 6.7%) and rs3798220 (MAF 1.9%), were associated with coronary atherosclerosis and hyperlipidemia at a phenome-wide significance level (P<0.05/(10 variants х 895 traits)); rs10455872 was also associated with increased odds of the following traits: aortic valve disease, systolic heart failure, atherosclerosis of carotid and lower extremity arteries, and abdominal aortic aneurysm (Table). rs41272112 (MAF 0.6%), associated with lower Lp(a) levels, was associated with degenerative spinal cord disorders.Conclusions: A large-scale PheWAS demonstrated that variants in LPA are associated with atherosclerosis and related traits and identified a neurological association warranting additional study.