Janne Pott1,2, Jesper R Gådin3, Elizabeth Theusch4, Marcus E Kleber5,6, Graciela E Delgado5, Holger Kirsten1,2, Stefanie M Hauck7, Ralph Burkhardt2,8,9, Hubert Scharnagl10, Ronald M Krauss4,11, Markus Loeffler1,2, Winfried März5,10,12, Joachim Thiery2,8,13, Angela Silveira3, Ferdinand M Van't Hooft3, Markus Scholz1,2. 1. Institute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, Leipzig, Germany. 2. LIFE Research Center for Civilization Diseases, Medical Faculty, University of Leipzig, Leipzig, Germany. 3. Division of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Karolinska University Hospital Solna, Solna, Sweden. 4. Department of Pediatrics, University of California San Francisco, Oakland, CA, USA. 5. Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. 6. SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany. 7. Metabolomics and Proteomics Core and Research Unit Protein Science, Helmholtz Zentrum München, Neuherberg, Germany. 8. Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany. 9. Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany. 10. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. 11. Department of Medicine, University of California San Francisco, Oakland, CA, USA. 12. SYNLAB Academy, SYNALB Holding Deutschland GmbH, Mannheim, Germany. 13. Faculty of Medicine, Kiel University, Kiel, Germany.
Abstract
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in lipid metabolism, as it degrades low-density lipoprotein (LDL) receptors from hepatic cell membranes. So far, only variants of the PCSK9 gene locus were found to be associated with PCSK9 levels. Here we aimed to identify novel genetic loci that regulate PCSK9 levels and how they relate to other lipid traits. Additionally, we investigated to what extend the causal effect of PCSK9 on coronary artery disease (CAD) is mediated by low-density lipoprotein-cholesterol (LDL-C). METHODS AND RESULTS: We performed a genome-wide association study meta-analysis of PCSK9 levels in up to 12 721 samples of European ancestry. The estimated heritability was 10.3%, which increased to 12.6% using only samples from patients without statin treatment. We successfully replicated the known PCSK9 hit consisting of three independent signals. Interestingly, in a study of 300 African Americans, we confirmed the locus with a different PCSK9 variant. Beyond PCSK9, our meta-analysis detected three novel loci with genome-wide significance. Co-localization analysis with cis-eQTLs and lipid traits revealed biologically plausible candidate genes at two of them: APOB and TM6SF2. In a bivariate Mendelian Randomization analysis, we detected a strong effect of PCSK9 on LDL-C, but not vice versa. LDL-C mediated 63% of the total causal effect of PCSK9 on CAD. CONCLUSION: Our study identified novel genetic loci with plausible candidate genes affecting PCSK9 levels. Ethnic heterogeneity was observed at the PCSK9 locus itself. Although the causal effect of PCSK9 on CAD is mainly mediated by LDL-C, an independent direct effect also occurs.
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in lipid metabolism, as it degrades low-density lipoprotein (LDL) receptors from hepatic cell membranes. So far, only variants of the PCSK9 gene locus were found to be associated with PCSK9 levels. Here we aimed to identify novel genetic loci that regulate PCSK9 levels and how they relate to other lipid traits. Additionally, we investigated to what extend the causal effect of PCSK9 on coronary artery disease (CAD) is mediated by low-density lipoprotein-cholesterol (LDL-C). METHODS AND RESULTS: We performed a genome-wide association study meta-analysis of PCSK9 levels in up to 12 721 samples of European ancestry. The estimated heritability was 10.3%, which increased to 12.6% using only samples from patients without statin treatment. We successfully replicated the known PCSK9 hit consisting of three independent signals. Interestingly, in a study of 300 African Americans, we confirmed the locus with a different PCSK9 variant. Beyond PCSK9, our meta-analysis detected three novel loci with genome-wide significance. Co-localization analysis with cis-eQTLs and lipid traits revealed biologically plausible candidate genes at two of them: APOB and TM6SF2. In a bivariate Mendelian Randomization analysis, we detected a strong effect of PCSK9 on LDL-C, but not vice versa. LDL-C mediated 63% of the total causal effect of PCSK9 on CAD. CONCLUSION: Our study identified novel genetic loci with plausible candidate genes affecting PCSK9 levels. Ethnic heterogeneity was observed at the PCSK9 locus itself. Although the causal effect of PCSK9 on CAD is mainly mediated by LDL-C, an independent direct effect also occurs.
Authors: Marc S Sabatine; Robert P Giugliano; Stephen D Wiviott; Frederick J Raal; Dirk J Blom; Jennifer Robinson; Christie M Ballantyne; Ransi Somaratne; Jason Legg; Scott M Wasserman; Robert Scott; Michael J Koren; Evan A Stein Journal: N Engl J Med Date: 2015-03-15 Impact factor: 91.245
Authors: Thomas W Winkler; Felix R Day; Damien C Croteau-Chonka; Andrew R Wood; Adam E Locke; Reedik Mägi; Teresa Ferreira; Tove Fall; Mariaelisa Graff; Anne E Justice; Jian'an Luan; Stefan Gustafsson; Joshua C Randall; Sailaja Vedantam; Tsegaselassie Workalemahu; Tuomas O Kilpeläinen; André Scherag; Tonu Esko; Zoltán Kutalik; Iris M Heid; Ruth J F Loos Journal: Nat Protoc Date: 2014-04-24 Impact factor: 13.491
Authors: Christopher P Cannon; Bertrand Cariou; Dirk Blom; James M McKenney; Christelle Lorenzato; Robert Pordy; Umesh Chaudhari; Helen M Colhoun Journal: Eur Heart J Date: 2015-02-16 Impact factor: 29.983
Authors: Roby Joehanes; Xiaoling Zhang; Tianxiao Huan; Chen Yao; Sai-Xia Ying; Quang Tri Nguyen; Cumhur Yusuf Demirkale; Michael L Feolo; Nataliya R Sharopova; Anne Sturcke; Alejandro A Schäffer; Nancy Heard-Costa; Han Chen; Po-Ching Liu; Richard Wang; Kimberly A Woodhouse; Kahraman Tanriverdi; Jane E Freedman; Nalini Raghavachari; Josée Dupuis; Andrew D Johnson; Christopher J O'Donnell; Daniel Levy; Peter J Munson Journal: Genome Biol Date: 2017-01-25 Impact factor: 13.583
Authors: Annalisa Buniello; Jacqueline A L MacArthur; Maria Cerezo; Laura W Harris; James Hayhurst; Cinzia Malangone; Aoife McMahon; Joannella Morales; Edward Mountjoy; Elliot Sollis; Daniel Suveges; Olga Vrousgou; Patricia L Whetzel; Ridwan Amode; Jose A Guillen; Harpreet S Riat; Stephen J Trevanion; Peggy Hall; Heather Junkins; Paul Flicek; Tony Burdett; Lucia A Hindorff; Fiona Cunningham; Helen Parkinson Journal: Nucleic Acids Res Date: 2019-01-08 Impact factor: 16.971
Authors: Harm-Jan Westra; Marjolein J Peters; Tõnu Esko; Hanieh Yaghootkar; Claudia Schurmann; Johannes Kettunen; Mark W Christiansen; Bruce M Psaty; Samuli Ripatti; Alexander Teumer; Timothy M Frayling; Andres Metspalu; Joyce B J van Meurs; Lude Franke; Benjamin P Fairfax; Katharina Schramm; Joseph E Powell; Alexandra Zhernakova; Daria V Zhernakova; Jan H Veldink; Leonard H Van den Berg; Juha Karjalainen; Sebo Withoff; André G Uitterlinden; Albert Hofman; Fernando Rivadeneira; Peter A C 't Hoen; Eva Reinmaa; Krista Fischer; Mari Nelis; Lili Milani; David Melzer; Luigi Ferrucci; Andrew B Singleton; Dena G Hernandez; Michael A Nalls; Georg Homuth; Matthias Nauck; Dörte Radke; Uwe Völker; Markus Perola; Veikko Salomaa; Jennifer Brody; Astrid Suchy-Dicey; Sina A Gharib; Daniel A Enquobahrie; Thomas Lumley; Grant W Montgomery; Seiko Makino; Holger Prokisch; Christian Herder; Michael Roden; Harald Grallert; Thomas Meitinger; Konstantin Strauch; Yang Li; Ritsert C Jansen; Peter M Visscher; Julian C Knight Journal: Nat Genet Date: 2013-09-08 Impact factor: 38.330