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

Lu Qi, Qibin Qi, Sabrina Prudente, Christine Mendonca, Francesco Andreozzi, Natalia Di Pietro, Mariella Sturma, Valeria Novelli, Gaia Chiara Mannino, Gloria Formoso, Ernest V. Gervino, Thomas H. Hauser, Jochen D. Muehlschlegel, Monika A. Niewczas, Andrzej S. Krolewski, Gianni Biolo, Assunta Pandolfi, Eric Rimm, Giorgio Sesti, Vincenzo TrischittaFrank Hu, Alessandro Doria

Research output: Contribution to journalArticle

66 Citations (Scopus)

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 x 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.

Original languageEnglish (US)
Pages (from-to)821-828
Number of pages8
JournalJAMA - Journal of the American Medical Association
Volume310
Issue number8
DOIs
StatePublished - 2013
Externally publishedYes

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Type 2 Diabetes Mellitus
Coronary Disease
Glutamic Acid
Homozygote
Alleles
Health
Gene Frequency
Odds Ratio
Nurses
Glutamate-Ammonia Ligase
Coronary Balloon Angioplasty
Coronary Stenosis
Coronary Artery Bypass
Causality
Genes
Single Nucleotide Polymorphism
Endothelial Cells
Chromosomes
Myocardial Infarction
Genome

ASJC Scopus subject areas

  • Medicine(all)

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Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes. / Qi, Lu; Qi, Qibin; Prudente, Sabrina; Mendonca, Christine; Andreozzi, Francesco; Di Pietro, Natalia; Sturma, Mariella; Novelli, Valeria; Mannino, Gaia Chiara; Formoso, Gloria; Gervino, Ernest V.; Hauser, Thomas H.; Muehlschlegel, Jochen D.; Niewczas, Monika A.; Krolewski, Andrzej S.; Biolo, Gianni; Pandolfi, Assunta; Rimm, Eric; Sesti, Giorgio; Trischitta, Vincenzo; Hu, Frank; Doria, Alessandro.

In: JAMA - Journal of the American Medical Association, Vol. 310, No. 8, 2013, p. 821-828.

Research output: Contribution to journalArticle

Qi, L, Qi, Q, Prudente, S, Mendonca, C, Andreozzi, F, Di Pietro, N, Sturma, M, Novelli, V, Mannino, GC, Formoso, G, Gervino, EV, Hauser, TH, Muehlschlegel, JD, Niewczas, MA, Krolewski, AS, Biolo, G, Pandolfi, A, Rimm, E, Sesti, G, Trischitta, V, Hu, F & Doria, A 2013, 'Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes', JAMA - Journal of the American Medical Association, vol. 310, no. 8, pp. 821-828. https://doi.org/10.1001/jama.2013.276305
Qi, Lu ; Qi, Qibin ; Prudente, Sabrina ; Mendonca, Christine ; Andreozzi, Francesco ; Di Pietro, Natalia ; Sturma, Mariella ; Novelli, Valeria ; Mannino, Gaia Chiara ; Formoso, Gloria ; Gervino, Ernest V. ; Hauser, Thomas H. ; Muehlschlegel, Jochen D. ; Niewczas, Monika A. ; Krolewski, Andrzej S. ; Biolo, Gianni ; Pandolfi, Assunta ; Rimm, Eric ; Sesti, Giorgio ; Trischitta, Vincenzo ; Hu, Frank ; Doria, Alessandro. / Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes. In: JAMA - Journal of the American Medical Association. 2013 ; Vol. 310, No. 8. pp. 821-828.
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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 x 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.",
author = "Lu Qi and Qibin Qi and Sabrina Prudente and Christine Mendonca and Francesco Andreozzi and {Di Pietro}, Natalia and Mariella Sturma and Valeria Novelli and Mannino, {Gaia Chiara} and Gloria Formoso and Gervino, {Ernest V.} and Hauser, {Thomas H.} and Muehlschlegel, {Jochen D.} and Niewczas, {Monika A.} and Krolewski, {Andrzej S.} and Gianni Biolo and Assunta Pandolfi and Eric Rimm and Giorgio Sesti and Vincenzo Trischitta and Frank Hu and Alessandro Doria",
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language = "English (US)",
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TY - JOUR

T1 - Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes

AU - Qi, Lu

AU - Qi, Qibin

AU - Prudente, Sabrina

AU - Mendonca, Christine

AU - Andreozzi, Francesco

AU - Di Pietro, Natalia

AU - Sturma, Mariella

AU - Novelli, Valeria

AU - Mannino, Gaia Chiara

AU - Formoso, Gloria

AU - Gervino, Ernest V.

AU - Hauser, Thomas H.

AU - Muehlschlegel, Jochen D.

AU - Niewczas, Monika A.

AU - Krolewski, Andrzej S.

AU - Biolo, Gianni

AU - Pandolfi, Assunta

AU - Rimm, Eric

AU - Sesti, Giorgio

AU - Trischitta, Vincenzo

AU - Hu, Frank

AU - Doria, Alessandro

PY - 2013

Y1 - 2013

N2 - 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 x 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.

AB - 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 x 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.

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