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Biological, clinical and population relevance of 95 loci for blood lipids

Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 × 10−8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes—GALNT2, PPP1R3B and TTC39B—with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

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Figure 1: Effects of altered Galnt2, Ppp1r3b or Ttc39b expression in mouse liver on plasma lipid levels.

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Acknowledgements

We wish to dedicate this paper to the memory of Dr Leena Peltonen, who passed away on 11 March 2010. A full listing of acknowledgements is provided in Supplementary Information.

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Authors and Affiliations

Authors

Contributions

T.M.T., K.M., A.V.S., A.C.E., I.M.S., M.K. and J.P.P. carried out the primary data analyses and/or experimental work. All other authors contributed to additional analyses. L.A.C., M.S.S., P.M.R., D.J.R., C.M.v.D., L.P., G.R.A., M.B. and S.K. conceived, designed, and supervised the study. K.M. wrote the manuscript.

Corresponding author

Correspondence to Sekar Kathiresan.

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Competing interests

Competing interests: D.M.W., K.S. and V.M. are full-time employees of GlaxoSmithKline. M.S.S. has received research funding from GlaxoSmithKline. P.V. and G.W. received grant money from GlaxoSmithKline to fund the CoLaus study. G.T., K.S., U.T. and H.H. are full-time employees of deCODE genetics. The other authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Methods, References, Supplementary Figures 1-3 with legends, Supplementary Tables 1-19 and a full list of Acknowledgments. (PDF 2944 kb)

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Teslovich, T., Musunuru, K., Smith, A. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010). https://doi.org/10.1038/nature09270

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