title: Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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: Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Lu
authors: L
authors: Qi
authors: Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.
authors: Qibin
authors: Q
authors: Qi
authors: IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy.
authors: Sabrina
authors: S
authors: Prudente
authors: Research Division, Joslin Diabetes Center, Boston, Massachusetts.
authors: Christine
authors: C
authors: Mendonca
authors: Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy.
authors: Francesco
authors: F
authors: Andreozzi
authors: Department of Experimental and Clinical Sciences, University 'G. d'Annunzio', Aging Research Center, Ce.S.I., 'G. d'Annunzio' University Foundation, Chieti-Pescara, Italy.
authors: Natalia
authors: N
authors: di Pietro
authors: Department of Medical, Surgical and Health Sciences, University of Trieste, Italy.
authors: Mariella
authors: M
authors: Sturma
authors: Research Division, Joslin Diabetes Center, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors: Valeria
authors: V
authors: Novelli
authors: Research Division, Joslin Diabetes Center, Boston, Massachusetts.|Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy.
authors: Gaia Chiara
authors: GC
authors: Mannino
authors: Department of Medicine and Aging Sciences, University 'G. d'Annunzio', Aging Research Center, Ce.S.I., 'G. d'Annunzio' University Foundation, Chieti-Pescara, Italy.
authors: Gloria
authors: G
authors: Formoso
authors: Department of Medicine, Harvard Medical School, Boston, Massachusetts.|Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors: Ernest V
authors: EV
authors: Gervino
authors: Department of Medicine, Harvard Medical School, Boston, Massachusetts.|Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors: Thomas H
authors: TH
authors: Hauser
authors: Department of Medicine, Harvard Medical School, Boston, Massachusetts.|Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Jochen D
authors: JD
authors: Muehlschlegel
authors: Research Division, Joslin Diabetes Center, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors: Monika A
authors: MA
authors: Niewczas
authors: Research Division, Joslin Diabetes Center, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors: Andrzej S
authors: AS
authors: Krolewski
authors: Department of Medical, Surgical and Health Sciences, University of Trieste, Italy.
authors: Gianni
authors: G
authors: Biolo
authors: Department of Experimental and Clinical Sciences, University 'G. d'Annunzio', Aging Research Center, Ce.S.I., 'G. d'Annunzio' University Foundation, Chieti-Pescara, Italy.
authors: Assunta
authors: A
authors: Pandolfi
authors: Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Eric
authors: E
authors: Rimm
authors: Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy.
authors: Giorgio
authors: G
authors: Sesti
authors: IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy.|Research Unit of Diabetes and Endocrine Diseases, IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.|Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors: Vincenzo
authors: V
authors: Trischitta
authors: Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Frank
authors: F
authors: Hu
authors: Research Division, Joslin Diabetes Center, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors: Alessandro
authors: A
authors: Doria
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1; D003327:Coronary Disease / Q000453:epidemiology* / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology*; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D005838:Genotype; D005974:Glutamate-Ammonia Ligase / Q000235:genetics*; D018698:Glutamic Acid / Q000097:blood / Q000378:metabolism*; D005973:Glutamine / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D014481:United States / Q000453:epidemiology
chemical_list: D005973:Glutamine; D018698:Glutamic Acid; D005974:Glutamate-Ammonia Ligase
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