Large-scale gene-centric analysis identifies novel variants for coronary artery disease.

6533b857fe1ef96bd12b4ec2

RESEARCH PRODUCT

Large-scale gene-centric analysis identifies novel variants for coronary artery disease.

As Butterworth Ps Braund M Farrall Rj Hardwick D Saleheen Jf Peden N Soranzo Jc Chambers S Sivapalaratnam Me Kleber B Keating A Qasim N Klopp J Erdmann Tl Assimes Sg Ball Aj Balmforth Ta Barnes H Basart J Baumert Cr Bezzina E Boerwinkle Bo Boehm J Brocheton P Bugert F Cambien R Clarke V Codd R Collins D Couper La Cupples De Jong Js P Diemert K Ejebe Cc Elbers P Elliott M Fornage Mg Franzosi P Frossard S Garner A Goel Ah Goodall C Hengstenberg Se Hunt Jj Kastelein Oh Klungel H Klüter K Koch Ir König As Kooner R Laaksonen M Lathrop M Li K Liu R Mcpherson Md Musameh S Musani Cp Nelson Cj O'donnell H Ongen G Papanicolaou A Peters Bj Peters S Potter Bm Psaty L Qu Dj Rader A Rasheed C Rice J Scott U Seedorf Js Sehmi N Sotoodehnia K Stark J Stephens Van Der Schoot Ce Van Der Schouw Yt U Thorsteinsdottir M Tomaszewski P Van Der Harst Rs Vasan Aa Wilde C Willenborg Br Winkelmann M Zaidi W Zhang A Ziegler De Bakker Pi W Koenig W Mätz Md Trip Mp Reilly S Kathiresan H Schunkert A Hamsten As Hall Js Kooner Sg Thompson Jr Thompson P Deloukas Wh Ouwehand H Watkins J Danesh Nj Samani T Barnes S Rafelt V Codd M Tomaszewski Wh Ouwehand N Bruinsma Lr Dekker Jp Henriques Kt Koch De Winter Rj M Alings Cf Allaart Ap Gorgels Fw Verheugt Ps Braund Jr Thompson Nj Samani M Mueller C Meisinger S Derohannessian Nn Mehta J Ferguson H Hakonarson W Matthai R Wilensky Jc Hopewell S Parish P Linksted J Notman H Gonzalez A Young T Ostley A Munday N Goodwin V Verdon S Shah L Cobb C Edwards C Mathews R Gunter J Benham C Davies M Cobb L Cobb J Crowther A Richards M Silver S Tochlin S Mozley S Clark M Radley K Kourellias A Silveira B Söderholm P Olsson S Barlera G Tognoni S Rust G Assmann S Heath D Zelenika I Gut F Green M Farrall J Peden A Goel H Ongen Mg Franzosi M Lathrop U Seedorf R Clarke R Collins A Hamsten H Watkins A Aly K Anner K Björklund G Blomgren B Cederschiöld K Danell Toverud P Eriksson U Grundstedt A Hamsten M Heinonen Ml Hellénius F Van't Hooft K Husman J Lagercrantz A Larsson M Larsson M Mossfeldt A Mälarstig G Olsson M Sabater Lleal B Sennblad A Silveira R Strawbridge B Söderholm J ÖHrvik Ks Zaman Nh Mallick M Azhar A Samad M Ishaq N Shah M Samuel H Schunkert Ir König S Kathiresan M Reilly Tl Assimes H Holm M Preuss Af Stewart M Barbalic C Gieger D Absher Z Aherrahrou H Allayee D Altshuler S Anand K Andersen Jl Anderson D Ardissino Sg Ball Aj Balmforth Ta Barnes Lc Becker Dm Becker K Berger Jc Bis Sm Boekholdt E Boerwinkle Ps Braund Mj Brown Ms Burnett I Buysschaert Jf Carlquist L Chen V Codd Rw Davies G Dedoussis A Dehghan S Demissie J Devaney R Do A Doering El Mokhtari Ne Sg Ellis R Elosua Jc Engert S Epstein U De Faire M Fischer Ar Folsom J Freyer B Gigante D Girelli S Gretarsdottir V Gudnason Jr Gulcher S Tennstedt E Halperin N Hammond Sl Hazen A Hofman Bd Horne T Illig C Iribarren Gt Jones Jw Jukema Ma Kaiser Lm Kaplan Jj Kastelein Kt Khaw Jw Knowles G Kolovou A Kong R Laaksonen D Lambrechts K Leander M Li W Lieb P Diemert G Lettre C Loley Aj Lotery Pm Mannucci S Maouche Nicola Martinelli Pp Mckeown C Meisinger T Meitinger Olle Melander Pa Merlini V Mooser T Morgan Tw Mühleisen Jb Muhlestein K Musunuru J Nahrstaedt Cp Nelson Mm Nöthen Oliviero Olivieri F Peyvandi Rs Patel Cc Patterson A Peters L Qu Aa Quyyumi Dj Rader Ls Rallidis C Rice Fr Roosendaal D Rubin V Salomaa Ml Sampietro Ms Sandhu E Schadt A Schäfer A Schillert S Schreiber J Schrezenmeir Sm Schwartz Ds Siscovick M Sivananthan S Sivapalaratnam Av Smith Tb Smith Jd Snoep N Soranzo Ja Spertus K Stark K Stefansson K Stirrups M Stoll Wh Tang G Thorgeirsson G Thorleifsson M Tomaszewski Ag Uitterlinden Van Rij Am Bf Voight Nj Wareham G Awells He Wichmann C Willenborg Jc Witteman Bj Wright S Ye A Ziegler F Cambien Ah Goodall La Cupples T Quertermous W März C Hengstenberg S Blankenberg Wh Ouwehand As Hall P Deloukas U Thorsteinsdottir R Roberts Jr Thompson Cj O'donnell R Mcpherson J Erdmann Nj Samani Onland Moret Nc J Van Setten De Bakker Pi Wm Verschuren Jm Boer C Wijmenga Mh Hofker Maitland Van Der Zee Ah A De Boer De Grobbee T Attwood S Belz P Braund F Cambien J Cooper A Crisp Hihn P Diemert P Deloukas N Foad J Erdmann Ah Goodall J Gracey E Gray R Gwilliams S Heimerl C Hengstenberg J Jolley U Krishnan H Lloyd Jones I Lugauer P Lundmark S Maouche Js Moore D Muir E Murray Cp Nelson J Neudert D Niblett K O'leary Wh Ouwehand H Pollard A Rankin Cm Rice H Sager Nj Samani J Sambrook G Schmitz M Scholz L Schroeder H Schunkert Ac Syvannen S Tennstedt C. Wallace

subject

Male Cancer Research Candidate gene Epidemiology Genome-wide association study Coronary Artery Disease 030204 cardiovascular system & hematology Cardiovascular 0302 clinical medicine GENETICS & HEREDITY Genetics (clinical)Genetics 0303 health sciences Cardiovascular diseases [NCEBP 14]Middle Aged 3. Good health CYP17A1 Genetic Epidemiology Genome-wide association; Myocardial-infarction; Susceptibility loci; Risk; Atherosclerosis; Metanalysis; Lipoprotein Medicine Female Life Sciences & Biomedicine Research Article Asian Continental Ancestry Group Adult Risk SUSCEPTIBILITY LOCI lcsh:QH426-470 European Continental Ancestry Group Biology Polymorphism Single Nucleotide coronary artery disease; genetics White People 03 medical and health sciences SDG 3 - Good Health and Well-being Asian People Genetic variation Genetics Humans Genetic Predisposition to Disease GENOME-WIDE ASSOCIATION Allele Molecular Biology Gene Biology METAANALYSIS Ecology Evolution Behavior and Systematics Genetic Association Studies Cardiovascular Disease Epidemiology Alleles 030304 developmental biology Aged 0604 Genetics Science & Technology Case-control study Genetic Variation Human Genetics Odds ratio large-scale gene analysis coronary artery disease; large-scale gene analysis lcsh:Genetics LIPOPROTEIN MYOCARDIAL-INFARCTION ATHEROSCLEROSIS Case-Control Studies Genetics of Disease IBC 50K CAD Consortium Developmental Biology Genome-Wide Association Study

description

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10−33; LPA:p<10−19; 1p13.3:p<10−17) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10−7). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06–1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.

year	journal	country	edition	language
2011-09-01

10.1371/journal.pgen.1002260 https://ora.ox.ac.uk/objects/uuid:838633a8-7b09-4627-8e9a-ff06661784ba