BACKGROUND: Population-based genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with cardiovascular disease or its risk factors. Genes in close proximity to these risk-SNPs are often thought to be pathogenetically important based on their location alone. However, the actual connections between SNPs and disease mechanisms remain largely unknown. METHODS AND RESULTS: To identify novel susceptibility genes, we investigated how 166 SNPs previously found to be associated with increased cardiovascular risk and/or predisposing metabolic traits relate to the expression of nearby genes. Gene expression in 577 samples of aorta, liver, mammary artery, and carotid atherosclerotic plaque was measured using expression arrays. For 47 SNPs, the expression levels of proximal genes (located within 200 kb) were affected (P<0.005). More than 20 of these genes had not previously been identified as candidate genes for cardiovascular or related metabolic traits. SNP-associated gene effects were tissue-specific and the tissue specificity was phenotype-dependent. CONCLUSIONS: This study demonstrates several instances of association between risk-SNPs and genes immediately adjacent to them. It also demonstrates instances in which the associated gene is not the immediately proximal and obvious candidate gene for disease. This shows the necessity of careful studies of genetic marker data as a first step toward application of genome-wide association studies findings in a clinical setting.
BACKGROUND: Population-based genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with cardiovascular disease or its risk factors. Genes in close proximity to these risk-SNPs are often thought to be pathogenetically important based on their location alone. However, the actual connections between SNPs and disease mechanisms remain largely unknown. METHODS AND RESULTS: To identify novel susceptibility genes, we investigated how 166 SNPs previously found to be associated with increased cardiovascular risk and/or predisposing metabolic traits relate to the expression of nearby genes. Gene expression in 577 samples of aorta, liver, mammary artery, and carotid atherosclerotic plaque was measured using expression arrays. For 47 SNPs, the expression levels of proximal genes (located within 200 kb) were affected (P<0.005). More than 20 of these genes had not previously been identified as candidate genes for cardiovascular or related metabolic traits. SNP-associated gene effects were tissue-specific and the tissue specificity was phenotype-dependent. CONCLUSIONS: This study demonstrates several instances of association between risk-SNPs and genes immediately adjacent to them. It also demonstrates instances in which the associated gene is not the immediately proximal and obvious candidate gene for disease. This shows the necessity of careful studies of genetic marker data as a first step toward application of genome-wide association studies findings in a clinical setting.
Authors: Helena Kuivaniemi; Natzi Sakalihasan; Frank A Lederle; Gregory T Jones; Jean-Olivier Defraigne; Nicos Labropoulos; Victor Legrand; Jean-Baptiste Michel; Christoph Nienaber; Marc A Radermecker; John A Elefteriades Journal: Aorta (Stamford) Date: 2013-06-01
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Authors: Gregory T Jones; Matthew J Bown; Solveig Gretarsdottir; Simon P R Romaine; Anna Helgadottir; Grace Yu; Gerard Tromp; Paul E Norman; Cao Jin; Annette F Baas; Jan D Blankensteijn; Iftikhar J Kullo; L Victoria Phillips; Michael J A Williams; Ruth Topless; Tony R Merriman; Thodor M Vasudevan; David R Lewis; Ross D Blair; Andrew A Hill; Robert D Sayers; Janet T Powell; Panagiotis Deloukas; Gudmar Thorleifsson; Stefan E Matthiasson; Unnur Thorsteinsdottir; Jonathan Golledge; Robert A Ariëns; Anne Johnson; Soroush Sohrabi; D Julian Scott; David J Carey; Robert Erdman; James R Elmore; Helena Kuivaniemi; Nilesh J Samani; Kari Stefansson; Andre M van Rij Journal: Hum Mol Genet Date: 2013-03-27 Impact factor: 6.150
Authors: Panos Deloukas; Stavroula Kanoni; Christina Willenborg; Martin Farrall; Themistocles L Assimes; John R Thompson; Erik Ingelsson; Danish Saleheen; Jeanette Erdmann; Benjamin A Goldstein; Kathleen Stirrups; Inke R König; Jean-Baptiste Cazier; Asa Johansson; Alistair S Hall; Jong-Young Lee; Cristen J Willer; John C Chambers; Tõnu Esko; Lasse Folkersen; Anuj Goel; Elin Grundberg; Aki S Havulinna; Weang K Ho; Jemma C Hopewell; Niclas Eriksson; Marcus E Kleber; Kati Kristiansson; Per Lundmark; Leo-Pekka Lyytikäinen; Suzanne Rafelt; Dmitry Shungin; Rona J Strawbridge; Gudmar Thorleifsson; Emmi Tikkanen; Natalie Van Zuydam; Benjamin F Voight; Lindsay L Waite; Weihua Zhang; Andreas Ziegler; Devin Absher; David Altshuler; Anthony J Balmforth; Inês Barroso; Peter S Braund; Christof Burgdorf; Simone Claudi-Boehm; David Cox; Maria Dimitriou; Ron Do; Alex S F Doney; NourEddine El Mokhtari; Per Eriksson; Krista Fischer; Pierre Fontanillas; Anders Franco-Cereceda; Bruna Gigante; Leif Groop; Stefan Gustafsson; Jörg Hager; Göran Hallmans; Bok-Ghee Han; Sarah E Hunt; Hyun M Kang; Thomas Illig; Thorsten Kessler; Joshua W Knowles; Genovefa Kolovou; Johanna Kuusisto; Claudia Langenberg; Cordelia Langford; Karin Leander; Marja-Liisa Lokki; Anders Lundmark; Mark I McCarthy; Christa Meisinger; Olle Melander; Evelin Mihailov; Seraya Maouche; Andrew D Morris; Martina Müller-Nurasyid; Kjell Nikus; John F Peden; N William Rayner; Asif Rasheed; Silke Rosinger; Diana Rubin; Moritz P Rumpf; Arne Schäfer; Mohan Sivananthan; Ci Song; Alexandre F R Stewart; Sian-Tsung Tan; Gudmundur Thorgeirsson; C Ellen van der Schoot; Peter J Wagner; George A Wells; Philipp S Wild; Tsun-Po Yang; Philippe Amouyel; Dominique Arveiler; Hanneke Basart; Michael Boehnke; Eric Boerwinkle; Paolo Brambilla; Francois Cambien; Adrienne L Cupples; Ulf de Faire; Abbas Dehghan; Patrick Diemert; Stephen E Epstein; Alun Evans; Marco M Ferrario; Jean Ferrières; Dominique Gauguier; Alan S Go; Alison H Goodall; Villi Gudnason; Stanley L Hazen; Hilma Holm; Carlos Iribarren; Yangsoo Jang; Mika Kähönen; Frank Kee; Hyo-Soo Kim; Norman Klopp; Wolfgang Koenig; Wolfgang Kratzer; Kari Kuulasmaa; Markku Laakso; Reijo Laaksonen; Ji-Young Lee; Lars Lind; Willem H Ouwehand; Sarah Parish; Jeong E Park; Nancy L Pedersen; Annette Peters; Thomas Quertermous; Daniel J Rader; Veikko Salomaa; Eric Schadt; Svati H Shah; Juha Sinisalo; Klaus Stark; Kari Stefansson; David-Alexandre Trégouët; Jarmo Virtamo; Lars Wallentin; Nicholas Wareham; Martina E Zimmermann; Markku S Nieminen; Christian Hengstenberg; Manjinder S Sandhu; Tomi Pastinen; Ann-Christine Syvänen; G Kees Hovingh; George Dedoussis; Paul W Franks; Terho Lehtimäki; Andres Metspalu; Pierre A Zalloua; Agneta Siegbahn; Stefan Schreiber; Samuli Ripatti; Stefan S Blankenberg; Markus Perola; Robert Clarke; Bernhard O Boehm; Christopher O'Donnell; Muredach P Reilly; Winfried März; Rory Collins; Sekar Kathiresan; Anders Hamsten; Jaspal S Kooner; Unnur Thorsteinsdottir; John Danesh; Colin N A Palmer; Robert Roberts; Hugh Watkins; Heribert Schunkert; Nilesh J Samani Journal: Nat Genet Date: 2012-12-02 Impact factor: 38.330
Authors: Sumeet A Khetarpal; Katrine T Schjoldager; Christina Christoffersen; Avanthi Raghavan; Andrew C Edmondson; Heiko M Reutter; Bouhouche Ahmed; Reda Ouazzani; Gina M Peloso; Cecilia Vitali; Wei Zhao; Amritha Varshini Hanasoge Somasundara; John S Millar; YoSon Park; Gayani Fernando; Valentin Livanov; Seungbum Choi; Eric Noé; Pritesh Patel; Siew Peng Ho; Todd G Kirchgessner; Hans H Wandall; Lars Hansen; Eric P Bennett; Sergey Y Vakhrushev; Danish Saleheen; Sekar Kathiresan; Christopher D Brown; Rami Abou Jamra; Eric LeGuern; Henrik Clausen; Daniel J Rader Journal: Cell Metab Date: 2016-08-09 Impact factor: 27.287