Lu Qi1,2, Alessandro Doria3,4, Qibin Qi1, Sabrina Prudente5, Christine Mendonca3, Francesco Andreozzi6, Natalia di Pietro7, Mariella Sturma8, Valeria Novelli3,4, Gaia Chiara Mannino3,6, Gloria Formoso9, Ernest V Gervino4,10, Thomas H Hauser4,10, Jochen D Muehlschlegel4,11, Monika A Niewczas3,4, Andrzej S Krolewski3,4, Gianni Biolo8, Assunta Pandolfi7, Eric Rimm1,2, Giorgio Sesti6, Vincenzo Trischitta5,12,13, Frank Hu1,2. 1. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts. 2. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. 3. Research Division, Joslin Diabetes Center, Boston, Massachusetts. 4. Department of Medicine, Harvard Medical School, Boston, Massachusetts. 5. IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy. 6. Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy. 7. Department of Experimental and Clinical Sciences, University 'G. d'Annunzio', Aging Research Center, Ce.S.I., 'G. d'Annunzio' University Foundation, Chieti-Pescara, Italy. 8. Department of Medical, Surgical and Health Sciences, University of Trieste, Italy. 9. Department of Medicine and Aging Sciences, University 'G. d'Annunzio', Aging Research Center, Ce.S.I., 'G. d'Annunzio' University Foundation, Chieti-Pescara, Italy. 10. Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts. 11. Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts. 12. Research Unit of Diabetes and Endocrine Diseases, IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. 13. Department of Experimental Medicine, Sapienza University, Rome, Italy.
Abstract
IMPORTANCE: Diabetes is associated with an elevated risk of coronary heart disease (CHD). Previous studies have suggested that the genetic factors predisposing to excess cardiovascular risk may be different in diabetic and nondiabetic individuals. OBJECTIVE: To identify genetic determinants of CHD that are specific to patients with diabetes. DESIGN, SETTING, AND PARTICIPANTS: We studied 5 independent sets of CHD cases and CHD-negative controls from the Nurses' Health Study (enrolled in 1976 and followed up through 2008), Health Professionals Follow-up Study (enrolled in 1986 and followed up through 2008), Joslin Heart Study (enrolled in 2001-2008), Gargano Heart Study (enrolled in 2001-2008), and Catanzaro Study (enrolled in 2004-2010). Included were a total of 1517 CHD cases and 2671 CHD-negative controls, all with type 2 diabetes. Results in diabetic patients were compared with those in 737 nondiabetic CHD cases and 1637 nondiabetic CHD-negative controls from the Nurses' Health Study and Health Professionals Follow-up Study cohorts. Exposures included 2,543,016 common genetic variants occurring throughout the genome. MAIN OUTCOMES AND MEASURES: Coronary heart disease--defined as fatal or nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or angiographic evidence of significant stenosis of the coronary arteries. RESULTS: A variant on chromosome 1q25 (rs10911021) was consistently associated with CHD risk among diabetic participants, with risk allele frequencies of 0.733 in cases vs 0.679 in controls (odds ratio, 1.36 [95% CI, 1.22-1.51]; P = 2 × 10(-8)). No association between this variant and CHD was detected among nondiabetic participants, with risk allele frequencies of 0.697 in cases vs 0.696 in controls (odds ratio, 0.99 [95% CI, 0.87-1.13]; P = .89), consistent with a significant gene × diabetes interaction on CHD risk (P = 2 × 10(-4)). Compared with protective allele homozygotes, rs10911021 risk allele homozygotes were characterized by a 32% decrease in the expression of the neighboring glutamate-ammonia ligase (GLUL) gene in human endothelial cells (P = .0048). A decreased ratio between plasma levels of γ-glutamyl cycle intermediates pyroglutamic and glutamic acid was also shown in risk allele homozygotes (P = .029). CONCLUSION AND RELEVANCE: A single-nucleotide polymorphism (rs10911021) was identified that was significantly associated with CHD among persons with diabetes but not in those without diabetes and was functionally related to glutamic acid metabolism, suggesting a mechanistic link.
IMPORTANCE: Diabetes is associated with an elevated risk of coronary heart disease (CHD). Previous studies have suggested that the genetic factors predisposing to excess cardiovascular risk may be different in diabetic and nondiabetic individuals. OBJECTIVE: To identify genetic determinants of CHD that are specific to patients with diabetes. DESIGN, SETTING, AND PARTICIPANTS: We studied 5 independent sets of CHD cases and CHD-negative controls from the Nurses' Health Study (enrolled in 1976 and followed up through 2008), Health Professionals Follow-up Study (enrolled in 1986 and followed up through 2008), Joslin Heart Study (enrolled in 2001-2008), Gargano Heart Study (enrolled in 2001-2008), and Catanzaro Study (enrolled in 2004-2010). Included were a total of 1517 CHD cases and 2671 CHD-negative controls, all with type 2 diabetes. Results in diabeticpatients were compared with those in 737 nondiabetic CHD cases and 1637 nondiabetic CHD-negative controls from the Nurses' Health Study and Health Professionals Follow-up Study cohorts. Exposures included 2,543,016 common genetic variants occurring throughout the genome. MAIN OUTCOMES AND MEASURES: Coronary heart disease--defined as fatal or nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or angiographic evidence of significant stenosis of the coronary arteries. RESULTS: A variant on chromosome 1q25 (rs10911021) was consistently associated with CHD risk among diabeticparticipants, with risk allele frequencies of 0.733 in cases vs 0.679 in controls (odds ratio, 1.36 [95% CI, 1.22-1.51]; P = 2 × 10(-8)). No association between this variant and CHD was detected among nondiabetic participants, with risk allele frequencies of 0.697 in cases vs 0.696 in controls (odds ratio, 0.99 [95% CI, 0.87-1.13]; P = .89), consistent with a significant gene × diabetes interaction on CHD risk (P = 2 × 10(-4)). Compared with protective allele homozygotes, rs10911021 risk allele homozygotes were characterized by a 32% decrease in the expression of the neighboring glutamate-ammonia ligase (GLUL) gene in human endothelial cells (P = .0048). A decreased ratio between plasma levels of γ-glutamyl cycle intermediates pyroglutamic and glutamic acid was also shown in risk allele homozygotes (P = .029). CONCLUSION AND RELEVANCE: A single-nucleotide polymorphism (rs10911021) was identified that was significantly associated with CHD among persons with diabetes but not in those without diabetes and was functionally related to glutamic acid metabolism, suggesting a mechanistic link.
Authors: Lu Qi; Marilyn C Cornelis; Peter Kraft; Kristopher J Stanya; W H Linda Kao; James S Pankow; Josée Dupuis; Jose C Florez; Caroline S Fox; Guillaume Paré; Qi Sun; Cynthia J Girman; Cathy C Laurie; Daniel B Mirel; Teri A Manolio; Daniel I Chasman; Eric Boerwinkle; Paul M Ridker; David J Hunter; James B Meigs; Chih-Hao Lee; Frank B Hu; Rob M van Dam Journal: Hum Mol Genet Date: 2010-04-23 Impact factor: 6.150
Authors: Anna Helgadottir; Gudmar Thorleifsson; Andrei Manolescu; Solveig Gretarsdottir; Thorarinn Blondal; Aslaug Jonasdottir; Adalbjorg Jonasdottir; Asgeir Sigurdsson; Adam Baker; Arnar Palsson; Gisli Masson; Daniel F Gudbjartsson; Kristinn P Magnusson; Karl Andersen; Allan I Levey; Valgerdur M Backman; Sigurborg Matthiasdottir; Thorbjorg Jonsdottir; Stefan Palsson; Helga Einarsdottir; Steinunn Gunnarsdottir; Arnaldur Gylfason; Viola Vaccarino; W Craig Hooper; Muredach P Reilly; Christopher B Granger; Harland Austin; Daniel J Rader; Svati H Shah; Arshed A Quyyumi; Jeffrey R Gulcher; Gudmundur Thorgeirsson; Unnur Thorsteinsdottir; Augustine Kong; Kari Stefansson Journal: Science Date: 2007-05-03 Impact factor: 47.728
Authors: Peter Holmans; Elaine K Green; Jaspreet Singh Pahwa; Manuel A R Ferreira; Shaun M Purcell; Pamela Sklar; Michael J Owen; Michael C O'Donovan; Nick Craddock Journal: Am J Hum Genet Date: 2009-06-18 Impact factor: 11.025
Authors: Nicholas L Smith; Janine F Felix; Alanna C Morrison; Serkalem Demissie; Nicole L Glazer; Laura R Loehr; L Adrienne Cupples; Abbas Dehghan; Thomas Lumley; Wayne D Rosamond; Wolfgang Lieb; Fernando Rivadeneira; Joshua C Bis; Aaron R Folsom; Emelia Benjamin; Yurii S Aulchenko; Talin Haritunians; David Couper; Joanne Murabito; Ying A Wang; Bruno H Stricker; John S Gottdiener; Patricia P Chang; Thomas J Wang; Kenneth M Rice; Albert Hofman; Susan R Heckbert; Ervin R Fox; Christopher J O'Donnell; Andre G Uitterlinden; Jerome I Rotter; James T Willerson; Daniel Levy; Cornelia M van Duijn; Bruce M Psaty; Jacqueline C M Witteman; Eric Boerwinkle; Ramachandran S Vasan Journal: Circ Cardiovasc Genet Date: 2010-05-05
Authors: Lu Qi; Layla Parast; Tianxi Cai; Christine Powers; Ernest V Gervino; Thomas H Hauser; Frank B Hu; Alessandro Doria Journal: J Am Coll Cardiol Date: 2011-12-13 Impact factor: 24.094
Authors: Marissa LeBlanc; Verena Zuber; Bettina Kulle Andreassen; Aree Witoelar; Lingyao Zeng; Francesco Bettella; Yunpeng Wang; Linda K McEvoy; Wesley K Thompson; Andrew J Schork; Sjur Reppe; Elizabeth Barrett-Connor; Symen Ligthart; Abbas Dehghan; Kaare M Gautvik; Christopher P Nelson; Heribert Schunkert; Nilesh J Samani; Paul M Ridker; Daniel I Chasman; Pål Aukrust; Srdjan Djurovic; Arnoldo Frigessi; Rahul S Desikan; Anders M Dale; Ole A Andreassen Journal: Circ Res Date: 2015-10-20 Impact factor: 17.367
Authors: Wenjie Ma; Yoriko Heianza; Tao Huang; Tiange Wang; Dianjianyi Sun; Yan Zheng; Frank B Hu; Kathryn M Rexrode; JoAnn E Manson; Lu Qi Journal: Int J Epidemiol Date: 2018-02-01 Impact factor: 7.196
Authors: Christopher Papandreou; Pablo Hernández-Alonso; Mònica Bulló; Miguel Ruiz-Canela; Jun Li; Marta Guasch-Ferré; Estefanía Toledo; Clary Clish; Dolores Corella; Ramon Estruch; Montserrat Cofán; Montserrat Fitó; Cristina Razquin; Fernando Arós; Miquel Fiol; José M Santos-Lozano; Lluís Serra-Majem; Liming Liang; Miguel A Martínez-González; Frank B Hu; Jordi Salas-Salvadó Journal: J Nutr Date: 2020-11-19 Impact factor: 4.798