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Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts

Abstract

Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797–22,562 persons, aged 18–104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 × 10−8), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 × 10−11; LDL, P = 2.6 × 10−10), TMEM57 (TC, P = 5.4 × 10−10), CTCF-PRMT8 region (HDL, P = 8.3 × 10−16), DNAH11 (LDL, P = 6.1 × 10−9), FADS3-FADS2 (TC, P = 1.5 × 10−10; LDL, P = 4.4 × 10−13) and MADD-FOLH1 region (HDL, P = 6 × 10−11). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.

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Acknowledgements

Above all, we thank study participants for making this work possible. We thank H.-Y. Shen and M. Allen for ENGAGE project management and M. Krestyaninova for IT-system setup.

The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme 'Quality of Life and Management of the Living Resources' of 5th Framework Programme (no. QLG2-CT-2002-01254). The Finnish Heart Association (M.P., L.P.) is gratefully acknowledged for its financial support. L.P. and J.K. have been supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics.

NFBC genotyping was supported on NHLBI grant 5R01HL087679-02 through the STAMPEED program.

EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947).

For the MICROS study in South Tyrol, we thank the primary care practitioners R. Stocker, S. Waldner, T. Pizzecco, J. Plangger, U. Marcadent and the personnel of the Hospital of Silandro (Department of Laboratory Medicine) for their participation and collaboration in the research project. In South Tyrol, the study was supported by the Ministry of Health of the Autonomous Province of Bolzano and the South Tyrolean Sparkasse Foundation.

NTR/NESDA was supported by “Genetic basis of anxiety and depression” program (NWO 904-61-090); Twin-family database for behavior genomics studies (NWO 480-04-004); Center for Medical Systems Biology (NWO Genomics); Spinozapremie (SPI 56-464-14192); Centre for Neurogenomics and Cognitive Research (CNCR-VU); Genome-wide analyses of European twin and population cohorts (EU/QLRT-2001-01254); Geestkracht program of ZonMW (10-000-1002); and matching funds from universities and mental health care institutes involved in NESDA (GGZ Buitenamstel-Geestgronden, Rivierduinen, University Medical Center Groningen, GGZ Lentis, GGZ Friesland, GGZ Drenthe). Major funding for this project is from the Genetic Association Information Network of the Foundation for the US National Institutes of Health, a public-private partnership between the NIH and Pfizer, Affymetrix and Abbott Laboratories.

The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFN) and by the “Genomics of Lipid-associated Disorders – GOLD” of the “Austrian Genome Research Programme GEN-AU”. The KORA research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. We gratefully acknowledge the contribution of P. Lichtner, G. Eckstein and T. Strom and all other members of the Helmholtz Zentrum München genotyping staff in generating and analyzing the SNP dataset. We thank all members of field staffs who were involved in the planning and conduct of the MONICA/KORA Augsburg studies. Finally, we express our appreciation to all study participants.

Genome-wide genotyping of the Rotterdam Study was supported by NWO (175.010.2005.011). The Vis study in the Croatian island of Vis was supported through the grants from the Medical Research Council UK to H.C., A.W. and I.R.; and Ministry of Science, Education and Sport of the Republic of Croatia to I.R. (number 108-1080315-0302). The ERF study was supported by grants from The Netherlands Organisation for Scientific Research, Erasmus MC and the Centre for Medical Systems Biology (CMSB). We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. The Northern Swedish Population Health Study was funded by the Swedish Medical Research Council and the European Commission through the EUROSPAN project. We are greatly indebted to the participants in the study. The ORCADES study was supported by the Scottish Executive Health Department, the Royal Society and the Wellcome Trust Clinical Research Facility. We would like to acknowledge the data collection team in Orkney, the clerical team in Edinburgh and the people of Orkney.

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The study was designed by L.P., C.M.v.D., Y.S.A. and S.R. Genotype and phenotype information were collected by D.B., I.M.H., C.P., B.W.J.H.P., I.R., T.S., N.G.M., N.L.P., K.O.K., J.K., A.H., N.B.F., M.-R.J., U.G., H.C., J.F.W., Å.J., F.M., C.H., V.V., I.J., P.P.P., A.W., N.H., I.P., A.A.H., M.F., G.W., J.-J.H., E.J.C.d.G., G.W.M., J.W., P.M., M.P., K.S., A.I., E.J.G.S., A.G.U., J.C.M.W., B.A.O., P.E., A.R., C.S., C.G., T.M., F.K., A.D., H.-E.W., J.H.S., M.I.M., C.M.v.D. and L.P. Statistical analysis was performed by Y.S.A., S.R., I.L., A.C.J.W.J., J.-J.H. and J.S. The manuscript was written by Y.S.A., S.R., A.C.J.W.J., C.M.v.D. and L.P. All authors reviewed the manuscript.

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Correspondence to Leena Peltonen.

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the ENGAGE Consortium. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 41, 47–55 (2009). https://doi.org/10.1038/ng.269

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