We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
Association of Genetically Enhanced Lipoprotein Lipase-Mediated Lipolysis and Low-Density Lipoprotein Cholesterol-Lowering Alleles With Risk of Coronary Disease and Type 2 Diabetes.Version 2. JAMA Cardiol. 2018 Oct 1;3(10):957-966. doi: 10.1001/jamacardio.2018.2866. JAMA Cardiol. 2018. PMID: 30326043 Free PMC article. Clinical Trial.
Multiple associated variants increase the heritability explained for plasma lipids and coronary artery disease.Circ Cardiovasc Genet. 2014 Oct;7(5):583-7. doi: 10.1161/CIRCGENETICS.113.000420. Epub 2014 Aug 28. Circ Cardiovasc Genet. 2014. PMID: 25170055 Free PMC article.
Genetic analysis of emerging risk factors in coronary artery disease.Atherosclerosis. 2016 Nov;254:35-41. doi: 10.1016/j.atherosclerosis.2016.09.008. Epub 2016 Sep 13. Atherosclerosis. 2016. PMID: 27684604
Genetics of lipid traits and relationship to coronary artery disease.Curr Cardiol Rep. 2013 Sep;15(9):396. doi: 10.1007/s11886-013-0396-9. Curr Cardiol Rep. 2013. PMID: 23881580 Free PMC article. Review.
Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density lipoprotein heterogeneity.Am J Cardiol. 2002 Oct 17;90(8A):30i-47i. doi: 10.1016/s0002-9149(02)02749-2. Am J Cardiol. 2002. PMID: 12419479 Review.
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