Association Between a Genetic Variant Related to Glutamic Acid Metabolism and Coronary Heart Disease in Individuals With Type 2 Diabetes
Articolo
Data di Pubblicazione:
2013
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.
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.
Tipologia CRIS:
1.1 Articolo in rivista
Elenco autori:
Qi, L.; Qi, Q.; Prudente, S.; Mendonca, C.; Andreozzi, F.; Di Pietro, N.; Sturma, M.; Novelli, V.; Mannino, G. C.; Formoso, G.; Gervino, E. V.; Hauser, T. H.; Muehlschlegel, J. D.; Niewczas, M. A.; Krolewski, A. S.; Biolo, G.; Pandolfi, A.; Rimm, E.; Sesti, G.; Trischitta, V.; Hu, F.; Doria, A.
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