A1 Refereed original research article in a scientific journal
Polygenic Hyperlipidemias and Coronary Artery Disease Risk
Authors: Ripatti P, Ramo JT, Mars NJ, Fu Y, Lin JK, Soderlund S, Benner C, Surakka I, Kiiskinen T, Havulinna AS, Palta P, Freimer NB, Widen E, Salomaa V, Tukiainen T, Pirinen M, Palotie A, Taskinen MR, Ripatti S; and on behalf of FinnGen
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Publication year: 2020
Journal: Circulation: Genomic and Precision Medicine
Journal name in source: CIRCULATION-GENOMIC AND PRECISION MEDICINE
Journal acronym: CIRC-GENOM PRECIS ME
Volume: 13
Issue: 2
First page : 59
Last page: 65
Number of pages: 7
ISSN: 2574-8300
eISSN: 2574-8300
DOI: https://doi.org/10.1161/CIRCGEN.119.002725
Web address : https://www.ahajournals.org/doi/10.1161/CIRCGEN.119.002725
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/52298031
Background:Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk.Methods:We derived polygenic risk scores (PRSs) with approximate to 6M variants separately for LDL-C and TG with weights from a UK Biobank-based genome-wide association study with approximate to 324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen).Results:In FINRISK, median LDL-C was 3.39 (95% CI, 3.38-3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82-2.94) to 3.78 (95% CI, 3.71-3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18-1.20) mmol/L, ranging from 0.97 (95% CI, 0.94-1.00) to 1.55 (95% CI, 1.48-1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24-1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19-1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16-1.38] for LDL-C and 1.24 [95% CI, 1.13-1.36] for TG PRS).Conclusions:The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.
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