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Author Notes:

KS, Kstefans@decode.is

HH, hilma.holm.decode.is

A.H., S.G., G. Thorleifsson, U.T., D.F.G., H.H., and K.S. conceived and designed the study. D.F.G. developed statistical tools. E.H. and G.M. contributed to bioinformatic analysis. A.S., A.M., A.J., and H.K. performed experiments. A.H., G. Thorleifsson, D.F.G., A.O., and G.S. performed statistical analysis. T.R., I.J., I.O., G.I.E., O.S., M.S.D., D.K., F.A., D.W.S., L.K., A.A.Q., A.I.L., R.S.P., S.S.H., I.J.G., V.S., and G. Thorgeirsson contributed to data acquisition. A.H., S.G., G. Thorleifsson, P.S., I.O., G. Thorgeirsson, U.T., D.F.G., H.H., and K.S. analyzed and interpreted the data. All authors reviewed and approved the manuscript. K.S. supervised the study.

The authors thank all the individuals who participated in this study and whose contribution made this work possible. We also thank our valued colleagues who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data.

The authors declare competing financial interests: details are available in the online version of the paper.

Subjects:

Research Funding:

Funding was provided by deCODE Genetics/Amgen and at Emory by NIH grants UL1RR025008 from the Clinical and Translational Science Award program, R01HL089650-02, and Emory Neuroscience NINDS Core Facilities grant P30NS055077.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • SEQUENCING IDENTIFIES RARE
  • LOW-FREQUENCY
  • GENETIC-VARIANTS
  • HEART-DISEASE
  • RISK
  • ASSOCIATION
  • MUTATIONS
  • PLASMA

Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease

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Journal Title:

NATURE GENETICS

Volume:

Volume 48, Number 6

Publisher:

, Pages 634-+

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 × 10 -28), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 × 10 -8), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.
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