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Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans

A Corrigendum to this article was published on 01 November 2008

This article has been updated

Abstract

Blood concentrations of lipoproteins and lipids are heritable1 risk factors for cardiovascular disease2,3. Using genome-wide association data from three studies (n = 8,816 that included 2,758 individuals from the Diabetes Genetics Initiative specific to the current paper as well as 1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables reported in a companion paper in this issue4) and targeted replication association analyses in up to 18,554 independent participants, we show that common SNPs at 18 loci are reproducibly associated with concentrations of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and/or triglycerides. Six of these loci are new (P < 5 × 10−8 for each new locus). Of the six newly identified chromosomal regions, two were associated with LDL cholesterol (1p13 near CELSR2, PSRC1 and SORT1 and 19p13 near CILP2 and PBX4), one with HDL cholesterol (1q42 in GALNT2) and five with triglycerides (7q11 near TBL2 and MLXIPL, 8q24 near TRIB1, 1q42 in GALNT2, 19p13 near CILP2 and PBX4 and 1p31 near ANGPTL3). At 1p13, the LDL-associated SNP was also strongly correlated with CELSR2, PSRC1, and SORT1 transcript levels in human liver, and a proxy for this SNP was recently shown to affect risk for coronary artery disease5. Understanding the molecular, cellular and clinical consequences of the newly identified loci may inform therapy and clinical care.

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  • 29 October 2008

    NOTE: In the version of this article initially published, the institutional affiliation for Dolores Corella was not complete. Her affiliation is with the Department of Preventive Medicine, School of Medicine, University of Valencia and CIBER Fisiopatología de la Obesidad y Nutrition, ISCIII, Valencia, 46010, Spain. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We acknowledge R. Saxena, P.I. de Bakker, V. Lyssenko, M. Daly, J. Hirschhorn, S. Gabriel, H. Chen, T. Hughes, the entire Diabetes Genetics Initiative study team, and the Botnia Study team for their roles in sample collection, phenotyping, design and conduct of the DGI study. We thank our colleagues from the FUSION study and the SardiNIA study for sharing data before publication. We thank J. Carlson for the isolation and preparation of the DNA samples from the Cardiovascular Cohort of the Malmö Diet and Cancer Study. We thank M. Svenson and L. Rosberg for technical assistance in Malmö and the Region Scania Competence Centrum 2 genotyping facility for help with genotyping in the NORDIL sample. We thank D. Ausiello and K. Chien for support and E. Lander for comments on the manuscript.

S.K. is supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award, a charitable gift from the Fannie E. Rippel Foundation, the Donovan Family Foundation,and a career development award from the United States National Institutes of Health (NIH). C.N.-C. is supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award, a career development award from the US NIH and a Burroughs Wellcome Fund Career Award for Medical Scientists. D.M.A. is a Burroughs Wellcome Fund Clinical Scholar in Translational Research and a Distinguished Clinical Scholar of the Doris Duke Charitable Foundation. V.S. is supported by the Sigrid Juselius Foundation. L.G. is supported by the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, The Folkhalsan Research Foundation and Clinical Research Institute HUCH Ltd. His work in Malmö, Sweden was also funded by a Linné grant from the Swedish Medical Research Council. M.O.-M. is supported by the Diabetes programme at the Lund University, the Novo Nordic Foundation and the Linne grant from the Swedish Research Council. M.O.-M. and O.M. are supported by the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Medical Faculty of Lund University, Malmö University Hospital, the Albert Påhlsson Research Foundation and the Crafoord Foundation. O.M. is supported by the Swedish Medical Society, the Ernhold Lundströms Research Foundation, the Mossfelt Foundation, the King Gustav V and Queen Victoria Foundation and the Region Skane. J.M.O. is supported by the United States Department of Agriculture, the National Heart, Lung, and Blood Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases. G.B. is supported by grants from The Swedish Medical Research Council, the Region Skane, the Ernhold Lundstrom Reseach Foundation and the European Council (InterAct study). B.H. is supported by the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Region Skane, the Ernhold Lundstrom Research Foundation and the Malmö University Hospital Foundation. M.-R.T. is supported by the Sigrid Juselius Foundation, the Clinical Research Institute HUCH Ltd. and the Finnish Heart Foundation. G.M.C. is a fellow of the Jane Coffin Childs Memorial Fund for Medical Research. M.J.R. is supported by a grant from the US NIH. The University of Washington School of Pharmacy Human Liver Bank is supported in part by a US NIH grant. Liver expression studies were supported in part by the University of Washington School of Pharmacy Drug Metabolism, Transporter and Pharmocogenetics Research program (funded by unrestricted gifts from Abbott, Allergan, Amgen, Bend Research, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Roche and Pfizer).

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Authors

Contributions

S.K., O.M. and M.O.-M. designed the study. C.G. and A.S. performed genotyping and laboratory work. N.P.B. and M.O.-M. supervised the laboratory work. L.G., N.P.B. and D.M.A. designed and conducted the DGI genome-wide association study. M.-R.T. conducted the lipoprotein and lipid phenotype measurements in the DGI samples. G.B., B.H., and O.M. collected and phenotyped the Malmo Diet and Cancer Study sample. A.S.H., E.V., P.J., V.S. and L.P. collected and phenotyped the FINRISK97 sample. B.W., T.H. and O.M. collected and phenotyped the NORDIL sample. E.S.T., D.C. and J.M.O. conducted the replication study in the Singaporean sample. M.J.R. and G.M.C. conducted the liver expression studies. S.K., M.J.R., G.M.C., C.R., B.F.V. and M.O.-M. conducted the analyses. S.K. wrote the first draft of the paper. O.M., M.J.R., G.M.C., J.M.O., G.B., M.-R.T., C.N.-C., V.S., L.P., L.G., D.M.A. and M.O.-M. revised the manuscript for important intellectual content.

Corresponding authors

Correspondence to Sekar Kathiresan or Marju Orho-Melander.

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Kathiresan, S., Melander, O., Guiducci, C. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 40, 189–197 (2008). https://doi.org/10.1038/ng.75

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