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JAMA. 2013 Aug 28;310(8):821-8. doi: 10.1001/jama.2013.276305.

Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes.

Author information

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
IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy.
4
Research Division, Joslin Diabetes Center, Boston, Massachusetts.
5
Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy.
6
Department of Experimental and Clinical Sciences, University 'G. d'Annunzio', Aging Research Center, Ce.S.I., 'G. d'Annunzio' University Foundation, Chieti-Pescara, Italy.
7
Department of Medical, Surgical and Health Sciences, University of Trieste, Italy.
8
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
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.
#
Contributed equally

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.

PMID:
23982368
PMCID:
PMC3858847
DOI:
10.1001/jama.2013.276305
[Indexed for MEDLINE]
Free PMC Article
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