Emmi Tikkanen1,2, Matti Pirinen3, Antti-Pekka Sarin3, Aki S Havulinna4, Satu Männistö4, Juha Saltevo5, Marja-Liisa Lokki6, Juha Sinisalo7, Annamari Lundqvist4, Antti Jula4, Veikko Salomaa4, Samuli Ripatti8,9,10. 1. Department of Public Health, University of Helsinki, PO Box 20, Tukholmankatu 8 B, FIN-00014, Helsinki, Finland. emmi.tikkanen@helsinki.fi. 2. Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland. emmi.tikkanen@helsinki.fi. 3. Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland. 4. Department of Health, National Institute for Health and Welfare, Helsinki, Finland. 5. Department of Medicine, Central Finland Central Hospital, Jyväskylä, Finland. 6. Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland. 7. Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland. 8. Department of Public Health, University of Helsinki, PO Box 20, Tukholmankatu 8 B, FIN-00014, Helsinki, Finland. samuli.ripatti@fimm.fi. 9. Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland. samuli.ripatti@fimm.fi. 10. Wellcome Trust Sanger Institute, Hinxton, UK. samuli.ripatti@fimm.fi.
Abstract
AIMS/HYPOTHESIS: Epidemiological studies have identified several traits associated with CHD, but few of these have been shown to be causal risk factors and thus suitable targets for treatment. Our aim was to evaluate the causal role of a large set of known CHD risk factors using single-nucleotide polymorphisms (SNPs) as instrumental variables. METHODS: Based on published genome-wide association studies (GWASs), we estimated the associations between the established risk factors (blood lipids, obesity, glycaemic traits and BP) and CHD with two complementary approaches: (1) using summary statistics from GWASs to analyse the accordance of SNP effects on risk factors and on CHD; and (2) individual-level analysis where we constructed genetic risk scores (GRSs) in a large Finnish dataset (N = 26,554, CHD events n = 4016). We used a weighted regression-based method for summary-level data to evaluate the causality of risk factors. The associations between the GRSs and CHD in the Finnish dataset were evaluated with logistic and conditional logistic regression models. RESULTS: The summary-level data analysis revealed causal effects between glycaemic traits (insulin and glucose) and CHD. The individual-level data analysis supported the causal role of insulin, but not of glucose, on CHD. The GRS for insulin was associated with CHD in the Finnish cohort (OR 1.06 per SD in GRS, 95% CI 1.02, 1.10, p = 0.002). CONCLUSIONS/ INTERPRETATION: These results support the causal role of insulin in the pathogenesis of CHD. Efficient treatment and prevention of insulin resistance is essential to prevent future CHD events.
AIMS/HYPOTHESIS: Epidemiological studies have identified several traits associated with CHD, but few of these have been shown to be causal risk factors and thus suitable targets for treatment. Our aim was to evaluate the causal role of a large set of known CHD risk factors using single-nucleotide polymorphisms (SNPs) as instrumental variables. METHODS: Based on published genome-wide association studies (GWASs), we estimated the associations between the established risk factors (blood lipids, obesity, glycaemic traits and BP) and CHD with two complementary approaches: (1) using summary statistics from GWASs to analyse the accordance of SNP effects on risk factors and on CHD; and (2) individual-level analysis where we constructed genetic risk scores (GRSs) in a large Finnish dataset (N = 26,554, CHD events n = 4016). We used a weighted regression-based method for summary-level data to evaluate the causality of risk factors. The associations between the GRSs and CHD in the Finnish dataset were evaluated with logistic and conditional logistic regression models. RESULTS: The summary-level data analysis revealed causal effects between glycaemic traits (insulin and glucose) and CHD. The individual-level data analysis supported the causal role of insulin, but not of glucose, on CHD. The GRS for insulin was associated with CHD in the Finnish cohort (OR 1.06 per SD in GRS, 95% CI 1.02, 1.10, p = 0.002). CONCLUSIONS/ INTERPRETATION: These results support the causal role of insulin in the pathogenesis of CHD. Efficient treatment and prevention of insulin resistance is essential to prevent future CHD events.
Authors: Enzo Bonora; Stefan Kiechl; Johann Willeit; Friedrich Oberhollenzer; Georg Egger; James B Meigs; Riccardo C Bonadonna; Michele Muggeo Journal: Diabetes Care Date: 2007-02 Impact factor: 19.112
Authors: J Shepherd; S M Cobbe; I Ford; C G Isles; A R Lorimer; P W MacFarlane; J H McKillop; C J Packard Journal: N Engl J Med Date: 1995-11-16 Impact factor: 91.245
Authors: Michael V Holmes; Leslie A Lange; Tom Palmer; Matthew B Lanktree; Kari E North; Berta Almoguera; Sarah Buxbaum; Hareesh R Chandrupatla; Clara C Elbers; Yiran Guo; Ron C Hoogeveen; Jin Li; Yun R Li; Daniel I Swerdlow; Mary Cushman; Tom S Price; Sean P Curtis; Myriam Fornage; Hakon Hakonarson; Sanjay R Patel; Susan Redline; David S Siscovick; Michael Y Tsai; James G Wilson; Yvonne T van der Schouw; Garret A FitzGerald; Aroon D Hingorani; Juan P Casas; Paul I W de Bakker; Stephen S Rich; Eric E Schadt; Folkert W Asselbergs; Alex P Reiner; Brendan J Keating Journal: Am J Hum Genet Date: 2014-01-23 Impact factor: 11.025
Authors: Majid Nikpay; Anuj Goel; Hong-Hee Won; Leanne M Hall; Christina Willenborg; Stavroula Kanoni; Danish Saleheen; Theodosios Kyriakou; Christopher P Nelson; Jemma C Hopewell; Thomas R Webb; Lingyao Zeng; Abbas Dehghan; Maris Alver; Sebastian M Armasu; Kirsi Auro; Andrew Bjonnes; Daniel I Chasman; Shufeng Chen; Ian Ford; Nora Franceschini; Christian Gieger; Christopher Grace; Stefan Gustafsson; Jie Huang; Shih-Jen Hwang; Yun Kyoung Kim; Marcus E Kleber; King Wai Lau; Xiangfeng Lu; Yingchang Lu; Leo-Pekka Lyytikäinen; Evelin Mihailov; Alanna C Morrison; Natalia Pervjakova; Liming Qu; Lynda M Rose; Elias Salfati; Richa Saxena; Markus Scholz; Albert V Smith; Emmi Tikkanen; Andre Uitterlinden; Xueli Yang; Weihua Zhang; Wei Zhao; Mariza de Andrade; Paul S de Vries; Natalie R van Zuydam; Sonia S Anand; Lars Bertram; Frank Beutner; George Dedoussis; Philippe Frossard; Dominique Gauguier; Alison H Goodall; Omri Gottesman; Marc Haber; Bok-Ghee Han; Jianfeng Huang; Shapour Jalilzadeh; Thorsten Kessler; Inke R König; Lars Lannfelt; Wolfgang Lieb; Lars Lind; Cecilia M Lindgren; Marja-Liisa Lokki; Patrik K Magnusson; Nadeem H Mallick; Narinder Mehra; Thomas Meitinger; Fazal-Ur-Rehman Memon; Andrew P Morris; Markku S Nieminen; Nancy L Pedersen; Annette Peters; Loukianos S Rallidis; Asif Rasheed; Maria Samuel; Svati H Shah; Juha Sinisalo; Kathleen E Stirrups; Stella Trompet; Laiyuan Wang; Khan S Zaman; Diego Ardissino; Eric Boerwinkle; Ingrid B Borecki; Erwin P Bottinger; Julie E Buring; John C Chambers; Rory Collins; L Adrienne Cupples; John Danesh; Ilja Demuth; Roberto Elosua; Stephen E Epstein; Tõnu Esko; Mary F Feitosa; Oscar H Franco; Maria Grazia Franzosi; Christopher B Granger; Dongfeng Gu; Vilmundur Gudnason; Alistair S Hall; Anders Hamsten; Tamara B Harris; Stanley L Hazen; Christian Hengstenberg; Albert Hofman; Erik Ingelsson; Carlos Iribarren; J Wouter Jukema; Pekka J Karhunen; Bong-Jo Kim; Jaspal S Kooner; Iftikhar J Kullo; Terho Lehtimäki; Ruth J F Loos; Olle Melander; Andres Metspalu; Winfried März; Colin N Palmer; Markus Perola; Thomas Quertermous; Daniel J Rader; Paul M Ridker; Samuli Ripatti; Robert Roberts; Veikko Salomaa; Dharambir K Sanghera; Stephen M Schwartz; Udo Seedorf; Alexandre F Stewart; David J Stott; Joachim Thiery; Pierre A Zalloua; Christopher J O'Donnell; Muredach P Reilly; Themistocles L Assimes; John R Thompson; Jeanette Erdmann; Robert Clarke; Hugh Watkins; Sekar Kathiresan; Ruth McPherson; Panos Deloukas; Heribert Schunkert; Nilesh J Samani; Martin Farrall Journal: Nat Genet Date: 2015-09-07 Impact factor: 38.330
Authors: Ron Do; Cristen J Willer; Ellen M Schmidt; Sebanti Sengupta; Chi Gao; Gina M Peloso; Stefan Gustafsson; Stavroula Kanoni; Andrea Ganna; Jin Chen; Martin L Buchkovich; Samia Mora; Jacques S Beckmann; Jennifer L Bragg-Gresham; Hsing-Yi Chang; Ayşe Demirkan; Heleen M Den Hertog; Louise A Donnelly; Georg B Ehret; Tõnu Esko; Mary F Feitosa; Teresa Ferreira; Krista Fischer; Pierre Fontanillas; Ross M Fraser; Daniel F Freitag; Deepti Gurdasani; Kauko Heikkilä; Elina Hyppönen; Aaron Isaacs; Anne U Jackson; Asa Johansson; Toby Johnson; Marika Kaakinen; Johannes Kettunen; Marcus E Kleber; Xiaohui Li; Jian'an Luan; Leo-Pekka Lyytikäinen; Patrik K E Magnusson; Massimo Mangino; Evelin Mihailov; May E Montasser; Martina Müller-Nurasyid; Ilja M Nolte; Jeffrey R O'Connell; Cameron D Palmer; Markus Perola; Ann-Kristin Petersen; Serena Sanna; Richa Saxena; Susan K Service; Sonia Shah; Dmitry Shungin; Carlo Sidore; Ci Song; Rona J Strawbridge; Ida Surakka; Toshiko Tanaka; Tanya M Teslovich; Gudmar Thorleifsson; Evita G Van den Herik; Benjamin F Voight; Kelly A Volcik; Lindsay L Waite; Andrew Wong; Ying Wu; Weihua Zhang; Devin Absher; Gershim Asiki; Inês Barroso; Latonya F Been; Jennifer L Bolton; Lori L Bonnycastle; Paolo Brambilla; Mary S Burnett; Giancarlo Cesana; Maria Dimitriou; Alex S F Doney; Angela Döring; Paul Elliott; Stephen E Epstein; Gudmundur Ingi Eyjolfsson; Bruna Gigante; Mark O Goodarzi; Harald Grallert; Martha L Gravito; Christopher J Groves; Göran Hallmans; Anna-Liisa Hartikainen; Caroline Hayward; Dena Hernandez; Andrew A Hicks; Hilma Holm; Yi-Jen Hung; Thomas Illig; Michelle R Jones; Pontiano Kaleebu; John J P Kastelein; Kay-Tee Khaw; Eric Kim; Norman Klopp; Pirjo Komulainen; Meena Kumari; Claudia Langenberg; Terho Lehtimäki; Shih-Yi Lin; Jaana Lindström; Ruth J F Loos; François Mach; Wendy L McArdle; Christa Meisinger; Braxton D Mitchell; Gabrielle Müller; Ramaiah Nagaraja; Narisu Narisu; Tuomo V M Nieminen; Rebecca N Nsubuga; Isleifur Olafsson; Ken K Ong; Aarno Palotie; Theodore Papamarkou; Cristina Pomilla; Anneli Pouta; Daniel J Rader; Muredach P Reilly; Paul M Ridker; Fernando Rivadeneira; Igor Rudan; Aimo Ruokonen; Nilesh Samani; Hubert Scharnagl; Janet Seeley; Kaisa Silander; Alena Stančáková; Kathleen Stirrups; Amy J Swift; Laurence Tiret; Andre G Uitterlinden; L Joost van Pelt; Sailaja Vedantam; Nicholas Wainwright; Cisca Wijmenga; Sarah H Wild; Gonneke Willemsen; Tom Wilsgaard; James F Wilson; Elizabeth H Young; Jing Hua Zhao; Linda S Adair; Dominique Arveiler; Themistocles L Assimes; Stefania Bandinelli; Franklyn Bennett; Murielle Bochud; Bernhard O Boehm; Dorret I Boomsma; Ingrid B Borecki; Stefan R Bornstein; Pascal Bovet; Michel Burnier; Harry Campbell; Aravinda Chakravarti; John C Chambers; Yii-Der Ida Chen; Francis S Collins; Richard S Cooper; John Danesh; George Dedoussis; Ulf de Faire; Alan B Feranil; Jean Ferrières; Luigi Ferrucci; Nelson B Freimer; Christian Gieger; Leif C Groop; Vilmundur Gudnason; Ulf Gyllensten; Anders Hamsten; Tamara B Harris; Aroon Hingorani; Joel N Hirschhorn; Albert Hofman; G Kees Hovingh; Chao Agnes Hsiung; Steve E Humphries; Steven C Hunt; Kristian Hveem; Carlos Iribarren; Marjo-Riitta Järvelin; Antti Jula; Mika Kähönen; Jaakko Kaprio; Antero Kesäniemi; Mika Kivimaki; Jaspal S Kooner; Peter J Koudstaal; Ronald M Krauss; Diana Kuh; Johanna Kuusisto; Kirsten O Kyvik; Markku Laakso; Timo A Lakka; Lars Lind; Cecilia M Lindgren; Nicholas G Martin; Winfried März; Mark I McCarthy; Colin A McKenzie; Pierre Meneton; Andres Metspalu; Leena Moilanen; Andrew D Morris; Patricia B Munroe; Inger Njølstad; Nancy L Pedersen; Chris Power; Peter P Pramstaller; Jackie F Price; Bruce M Psaty; Thomas Quertermous; Rainer Rauramaa; Danish Saleheen; Veikko Salomaa; Dharambir K Sanghera; Jouko Saramies; Peter E H Schwarz; Wayne H-H Sheu; Alan R Shuldiner; Agneta Siegbahn; Tim D Spector; Kari Stefansson; David P Strachan; Bamidele O Tayo; Elena Tremoli; Jaakko Tuomilehto; Matti Uusitupa; Cornelia M van Duijn; Peter Vollenweider; Lars Wallentin; Nicholas J Wareham; John B Whitfield; Bruce H R Wolffenbuttel; David Altshuler; Jose M Ordovas; Eric Boerwinkle; Colin N A Palmer; Unnur Thorsteinsdottir; Daniel I Chasman; Jerome I Rotter; Paul W Franks; Samuli Ripatti; L Adrienne Cupples; Manjinder S Sandhu; Stephen S Rich; Michael Boehnke; Panos Deloukas; Karen L Mohlke; Erik Ingelsson; Goncalo R Abecasis; Mark J Daly; Benjamin M Neale; Sekar Kathiresan Journal: Nat Genet Date: 2013-10-06 Impact factor: 38.330
Authors: Cristen J Willer; Ellen M Schmidt; Sebanti Sengupta; Michael Boehnke; Panos Deloukas; Sekar Kathiresan; Karen L Mohlke; Erik Ingelsson; Gonçalo R Abecasis; Gina M Peloso; Stefan Gustafsson; Stavroula Kanoni; Andrea Ganna; Jin Chen; Martin L Buchkovich; Samia Mora; Jacques S Beckmann; Jennifer L Bragg-Gresham; Hsing-Yi Chang; Ayşe Demirkan; Heleen M Den Hertog; Ron Do; Louise A Donnelly; Georg B Ehret; Tõnu Esko; Mary F Feitosa; Teresa Ferreira; Krista Fischer; Pierre Fontanillas; Ross M Fraser; Daniel F Freitag; Deepti Gurdasani; Kauko Heikkilä; Elina Hyppönen; Aaron Isaacs; Anne U Jackson; Åsa Johansson; Toby Johnson; Marika Kaakinen; Johannes Kettunen; Marcus E Kleber; Xiaohui Li; Jian'an Luan; Leo-Pekka Lyytikäinen; Patrik K E Magnusson; Massimo Mangino; Evelin Mihailov; May E Montasser; Martina Müller-Nurasyid; Ilja M Nolte; Jeffrey R O'Connell; Cameron D Palmer; Markus Perola; Ann-Kristin Petersen; Serena Sanna; Richa Saxena; Susan K Service; Sonia Shah; Dmitry Shungin; Carlo Sidore; Ci Song; Rona J Strawbridge; Ida Surakka; Toshiko Tanaka; Tanya M Teslovich; Gudmar Thorleifsson; Evita G Van den Herik; Benjamin F Voight; Kelly A Volcik; Lindsay L Waite; Andrew Wong; Ying Wu; Weihua Zhang; Devin Absher; Gershim Asiki; Inês Barroso; Latonya F Been; Jennifer L Bolton; Lori L Bonnycastle; Paolo Brambilla; Mary S Burnett; Giancarlo Cesana; Maria Dimitriou; Alex S F Doney; Angela Döring; Paul Elliott; Stephen E Epstein; Gudmundur Ingi Eyjolfsson; Bruna Gigante; Mark O Goodarzi; Harald Grallert; Martha L Gravito; Christopher J Groves; Göran Hallmans; Anna-Liisa Hartikainen; Caroline Hayward; Dena Hernandez; Andrew A Hicks; Hilma Holm; Yi-Jen Hung; Thomas Illig; Michelle R Jones; Pontiano Kaleebu; John J P Kastelein; Kay-Tee Khaw; Eric Kim; Norman Klopp; Pirjo Komulainen; Meena Kumari; Claudia Langenberg; Terho Lehtimäki; Shih-Yi Lin; Jaana Lindström; Ruth J F Loos; François Mach; Wendy L McArdle; Christa Meisinger; Braxton D Mitchell; Gabrielle Müller; Ramaiah Nagaraja; Narisu Narisu; Tuomo V M Nieminen; Rebecca N Nsubuga; Isleifur Olafsson; Ken K Ong; Aarno Palotie; Theodore Papamarkou; Cristina Pomilla; Anneli Pouta; Daniel J Rader; Muredach P Reilly; Paul M Ridker; Fernando Rivadeneira; Igor Rudan; Aimo Ruokonen; Nilesh Samani; Hubert Scharnagl; Janet Seeley; Kaisa Silander; Alena Stančáková; Kathleen Stirrups; Amy J Swift; Laurence Tiret; Andre G Uitterlinden; L Joost van Pelt; Sailaja Vedantam; Nicholas Wainwright; Cisca Wijmenga; Sarah H Wild; Gonneke Willemsen; Tom Wilsgaard; James F Wilson; Elizabeth H Young; Jing Hua Zhao; Linda S Adair; Dominique Arveiler; Themistocles L Assimes; Stefania Bandinelli; Franklyn Bennett; Murielle Bochud; Bernhard O Boehm; Dorret I Boomsma; Ingrid B Borecki; Stefan R Bornstein; Pascal Bovet; Michel Burnier; Harry Campbell; Aravinda Chakravarti; John C Chambers; Yii-Der Ida Chen; Francis S Collins; Richard S Cooper; John Danesh; George Dedoussis; Ulf de Faire; Alan B Feranil; Jean Ferrières; Luigi Ferrucci; Nelson B Freimer; Christian Gieger; Leif C Groop; Vilmundur Gudnason; Ulf Gyllensten; Anders Hamsten; Tamara B Harris; Aroon Hingorani; Joel N Hirschhorn; Albert Hofman; G Kees Hovingh; Chao Agnes Hsiung; Steve E Humphries; Steven C Hunt; Kristian Hveem; Carlos Iribarren; Marjo-Riitta Järvelin; Antti Jula; Mika Kähönen; Jaakko Kaprio; Antero Kesäniemi; Mika Kivimaki; Jaspal S Kooner; Peter J Koudstaal; Ronald M Krauss; Diana Kuh; Johanna Kuusisto; Kirsten O Kyvik; Markku Laakso; Timo A Lakka; Lars Lind; Cecilia M Lindgren; Nicholas G Martin; Winfried März; Mark I McCarthy; Colin A McKenzie; Pierre Meneton; Andres Metspalu; Leena Moilanen; Andrew D Morris; Patricia B Munroe; Inger Njølstad; Nancy L Pedersen; Chris Power; Peter P Pramstaller; Jackie F Price; Bruce M Psaty; Thomas Quertermous; Rainer Rauramaa; Danish Saleheen; Veikko Salomaa; Dharambir K Sanghera; Jouko Saramies; Peter E H Schwarz; Wayne H-H Sheu; Alan R Shuldiner; Agneta Siegbahn; Tim D Spector; Kari Stefansson; David P Strachan; Bamidele O Tayo; Elena Tremoli; Jaakko Tuomilehto; Matti Uusitupa; Cornelia M van Duijn; Peter Vollenweider; Lars Wallentin; Nicholas J Wareham; John B Whitfield; Bruce H R Wolffenbuttel; Jose M Ordovas; Eric Boerwinkle; Colin N A Palmer; Unnur Thorsteinsdottir; Daniel I Chasman; Jerome I Rotter; Paul W Franks; Samuli Ripatti; L Adrienne Cupples; Manjinder S Sandhu; Stephen S Rich Journal: Nat Genet Date: 2013-10-06 Impact factor: 38.330