BACKGROUND: Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG). METHODS AND RESULTS: We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency ≥1%), which were independently meta-analyzed. A 3' untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency <1%) did not yield statistically significant associations. However, we observed nominal associations for rare variants in CCDC71L and SLC17A3 with cIMT and of the entire 7q22 region with plaque (P=0.05). CONCLUSIONS: Common and rare variants in PIK3CG and SLC17A4 regions demonstrated modest association with subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples.
BACKGROUND:Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG). METHODS AND RESULTS: We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency ≥1%), which were independently meta-analyzed. A 3' untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency <1%) did not yield statistically significant associations. However, we observed nominal associations for rare variants in CCDC71L and SLC17A3 with cIMT and of the entire 7q22 region with plaque (P=0.05). CONCLUSIONS: Common and rare variants in PIK3CG and SLC17A4 regions demonstrated modest association with subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples.
Authors: James H Stein; Claudia E Korcarz; R Todd Hurst; Eva Lonn; Christopher B Kendall; Emile R Mohler; Samer S Najjar; Christopher M Rembold; Wendy S Post Journal: J Am Soc Echocardiogr Date: 2008-02 Impact factor: 5.251
Authors: L P Fried; N O Borhani; P Enright; C D Furberg; J M Gardin; R A Kronmal; L H Kuller; T A Manolio; M B Mittelmark; A Newman Journal: Ann Epidemiol Date: 1991-02 Impact factor: 3.797
Authors: Greta Lee Splansky; Diane Corey; Qiong Yang; Larry D Atwood; L Adrienne Cupples; Emelia J Benjamin; Ralph B D'Agostino; Caroline S Fox; Martin G Larson; Joanne M Murabito; Christopher J O'Donnell; Ramachandran S Vasan; Philip A Wolf; Daniel Levy Journal: Am J Epidemiol Date: 2007-03-19 Impact factor: 4.897
Authors: Stephen J Onufrak; Antonio Bellasi; Leslee J Shaw; Charles A Herzog; Francesca Cardarelli; Peter W Wilson; Viola Vaccarino; Paolo Raggi Journal: Atherosclerosis Date: 2008-02-21 Impact factor: 5.162
Authors: Abbas Dehghan; Anna Köttgen; Qiong Yang; Shih-Jen Hwang; Wh Linda Kao; Fernando Rivadeneira; Eric Boerwinkle; Daniel Levy; Albert Hofman; Brad C Astor; Emelia J Benjamin; Cornelia M van Duijn; Jacqueline C Witteman; Josef Coresh; Caroline S Fox Journal: Lancet Date: 2008-10-01 Impact factor: 79.321
Authors: Nicole Soranzo; Augusto Rendon; Christian Gieger; Chris I Jones; Nicholas A Watkins; Stephan Menzel; Angela Döring; Jonathan Stephens; Holger Prokisch; Wendy Erber; Simon C Potter; Sarah L Bray; Philippa Burns; Jennifer Jolley; Mario Falchi; Brigitte Kühnel; Jeanette Erdmann; Heribert Schunkert; Nilesh J Samani; Thomas Illig; Stephen F Garner; Angela Rankin; Christa Meisinger; John R Bradley; Swee Lay Thein; Alison H Goodall; Tim D Spector; Panos Deloukas; Willem H Ouwehand Journal: Blood Date: 2009-02-12 Impact factor: 22.113
Authors: Melanie Kolz; Toby Johnson; Serena Sanna; Alexander Teumer; Veronique Vitart; Markus Perola; Massimo Mangino; Eva Albrecht; Chris Wallace; Martin Farrall; Asa Johansson; Dale R Nyholt; Yurii Aulchenko; Jacques S Beckmann; Sven Bergmann; Murielle Bochud; Morris Brown; Harry Campbell; John Connell; Anna Dominiczak; Georg Homuth; Claudia Lamina; Mark I McCarthy; Thomas Meitinger; Vincent Mooser; Patricia Munroe; Matthias Nauck; John Peden; Holger Prokisch; Perttu Salo; Veikko Salomaa; Nilesh J Samani; David Schlessinger; Manuela Uda; Uwe Völker; Gérard Waeber; Dawn Waterworth; Rui Wang-Sattler; Alan F Wright; Jerzy Adamski; John B Whitfield; Ulf Gyllensten; James F Wilson; Igor Rudan; Peter Pramstaller; Hugh Watkins; Angela Doering; H-Erich Wichmann; Tim D Spector; Leena Peltonen; Henry Völzke; Ramaiah Nagaraja; Peter Vollenweider; Mark Caulfield; Thomas Illig; Christian Gieger Journal: PLoS Genet Date: 2009-06-05 Impact factor: 5.917
Authors: Liyong Wang; Ashley Beecham; Nicole Dueker; Susan H Blanton; Tatjana Rundek; Ralph L Sacco Journal: Hum Genet Date: 2015-08-30 Impact factor: 4.132
Authors: Andy B Castaneda; Lauren E Petty; Markus Scholz; Rick Jansen; Stefan Weiss; Xiaoling Zhang; Katharina Schramm; Frank Beutner; Holger Kirsten; Ulf Schminke; Shih-Jen Hwang; Carola Marzi; Klodian Dhana; Adrie Seldenrijk; Knut Krohn; Georg Homuth; Petra Wolf; Marjolein J Peters; Marcus Dörr; Annette Peters; Joyce B J van Meurs; André G Uitterlinden; Maryam Kavousi; Daniel Levy; Christian Herder; Gerard van Grootheest; Melanie Waldenberger; Christa Meisinger; Wolfgang Rathmann; Joachim Thiery; Joseph Polak; Wolfgang Koenig; Jochen Seissler; Joshua C Bis; Nora Franceshini; Claudia Giambartolomei; Albert Hofman; Oscar H Franco; Brenda W J H Penninx; Holger Prokisch; Henry Völzke; Markus Loeffler; Christopher J O'Donnell; Jennifer E Below; Abbas Dehghan; Paul S de Vries Journal: Hum Mol Genet Date: 2022-03-31 Impact factor: 5.121
Authors: Rector Arya; Agustin Escalante; Vidya S Farook; Jose F Restrepo; Daniel F Battafarano; Marcio Almeida; Mark Z Kos; Marcel J Fourcaudot; Srinivas Mummidi; Satish Kumar; Joanne E Curran; Christopher P Jenkinson; John Blangero; Ravindranath Duggirala; Inmaculada Del Rincon Journal: Atherosclerosis Date: 2017-11-26 Impact factor: 5.162
Authors: Rector Arya; Agustin Escalante; Vidya S Farook; Jose F Restrepo; Daniel F Battafarano; Marcio Almeida; Mark Z Kos; Marcel J Fourcaudot; Srinivas Mummidi; Satish Kumar; Joanne E Curran; Christopher P Jenkinson; John Blangero; Ravindranath Duggirala; Inmaculada Del Rincon Journal: Data Brief Date: 2018-02-08
Authors: Nicole D Dueker; Ashley Beecham; Liyong Wang; Susan H Blanton; Shengru Guo; Tatjana Rundek; Ralph L Sacco Journal: PLoS One Date: 2016-12-09 Impact factor: 3.240
Authors: Aditi Shendre; Howard W Wiener; Marguerite R Irvin; Bradley E Aouizerat; Edgar T Overton; Jason Lazar; Chenglong Liu; Howard N Hodis; Nita A Limdi; Kathleen M Weber; Stephen J Gange; Degui Zhi; Michelle A Floris-Moore; Ighovwerha Ofotokun; Qibin Qi; David B Hanna; Robert C Kaplan; Sadeep Shrestha Journal: PLoS One Date: 2017-12-04 Impact factor: 3.240
Authors: Dina Vojinovic; Maryam Kavousi; Mohsen Ghanbari; Rutger W W Brouwer; Jeroen G J van Rooij; Mirjam C G N van den Hout; Robert Kraaij; Wilfred F J van Ijcken; Andre G Uitterlinden; Cornelia M van Duijn; Najaf Amin Journal: Front Genet Date: 2018-10-09 Impact factor: 4.599