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Olle Melander

Principal investigator

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Exome-wide association study of plasma lipids in >300,000 individuals

Author

  • Dajiang J Liu
  • Gina M. Peloso
  • Haojie Yu
  • Adam S. Butterworth
  • Anubha Mahajan
  • Danish Saleheen
  • Paul Franks
  • Frida Renström
  • Tibor V Varga
  • Leif Groop
  • Olle Melander
  • Marju Orho-Melander

Summary, in English

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-densitylipoprotein 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 TGrich 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.

Department/s

  • Genetic and Molecular Epidemiology
  • Genomics, Diabetes and Endocrinology
  • Cardiovascular Research - Hypertension
  • Diabetes - Cardiovascular Disease
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health

Publishing year

2017

Language

English

Pages

1758-1766

Publication/Series

Nature Genetics

Volume

49

Issue

12

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Medical Genetics

Status

Published

Research group

  • Genetic and Molecular Epidemiology
  • Genomics, Diabetes and Endocrinology
  • Cardiovascular Research - Hypertension
  • Diabetes - Cardiovascular Disease

ISBN/ISSN/Other

  • ISSN: 1546-1718