Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes.
Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes.
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DOI：
10.1001/jama.2013.276305
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发表时间：
2013-08-28
影响因子：
120.7
通讯作者：
Doria, Alessandro
中科院分区：
文献类型：
--
作者：
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
糖尿病与冠心病（CHD）的风险增加有关。先前的研究表明，糖尿病和非糖尿病参与者中导致心血管风险过高的遗传因素可能不同。确定糖尿病患者特有的冠心病遗传决定因素。我们研究了来自护士健康研究的五组独立的冠心病病例和冠心病阴性对照（NHS; 1976年入组，随访至2008年），卫生专业人员随访研究（HPFS; 1986年入组，随访至2008年），Joslin心脏研究（2001-2008年入组）、Gargano心脏研究（2001-2008年入组）和Catanzaro研究（2004-2010年入组）。共纳入1，517例CHD病例和2，671例CHD阴性对照，均患有2型糖尿病。将糖尿病患者的结果与来自NHS和HPFS队列的737例非糖尿病CHD病例和1，637例非糖尿病CHD阴性对照进行比较。2，543，016种常见的遗传变异发生在整个基因组中。CHD定义为致死性或非致死性心肌梗死、冠状动脉旁路移植术、经皮腔内冠状动脉成形术或冠状动脉显著狭窄的血管造影证据。我们确定了染色体1 q25上的一个变异体（rs 10911021）与糖尿病受试者的CHD风险始终相关，比值比为1.36（95%置信区间[CI] 1.22-1.51，P=2×10−8）。在非糖尿病参与者中未检测到该变异与CHD之间的关联（OR=0.99，P=0.89），与CHD风险的显著基因-糖尿病相互作用（P=2×10−4）一致。与保护性等位基因纯合子相比，rs 10911021风险等位基因纯合子的特征在于人内皮细胞中相邻谷氨酸-氨连接酶（GLUL）基因的表达降低32%（P=0.0048）。在两项独立研究中，还显示γ-谷氨酰循环中间体焦谷氨酸和谷氨酸的血浆水平比值降低（分别为P=0.029和P=0.003）。在糖尿病患者中发现了一种与CHD显着相关的SNP，但在非糖尿病患者中则不然。该SNP在功能上与谷氨酸代谢相关，表明存在机制联系。
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 non-diabetic participants. To identify genetic determinants of CHD that are specific to diabetic patients. We studied five independent sets of CHD cases and CHD-negative controls from the Nurses Health Study (NHS; enrolled in 1976 and followed through 2008), Health Professionals Follow-up Study (HPFS; enrolled in 1986 and followed 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 1,517 CHD cases and 2,671 CHD-negative controls, all with type 2 diabetes. Results in diabetic patients were compared with those in 737 non-diabetic CHD cases and 1,637 non-diabetic CHD-negative controls from the NHS and HPFS cohorts. 2,543,016 common genetic variants occurring throughout the genome. CHD defined as fatal or non-fatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or angiographic evidence of significant stenosis of the coronary arteries. We identified a variant on chromosome 1q25 (rs10911021) consistently associated with CHD risk among diabetic participants with an odds ratio of 1.36 (95% confidence interval [CI] 1.22-1.51, P=2×10−8). No association between this variant and CHD was detected among non-diabetic participants (OR=0.99, P=0.89), consistent with a significant gene-by-diabetes interaction on CHD risk (P=2×10−4). As compared to 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=0.0048). They also showed a decreased ratio between plasma levels of γ-glutamyl cycle intermediates pyroglutamic and glutamic acid in two independent studies (P=0.029 and P=0.003, respectively). A SNP was identified that was significantly associated with CHD among persons with diabetes but not in those without diabetes. This SNP was functionally related to glutamic acid metabolism, suggesting a mechanistic link.
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影响因子：
37.8
作者：
Cheng S;Rhee EP;Larson MG;Lewis GD;McCabe EL;Shen D;Palma MJ;Roberts LD;Dejam A;Souza AL;Deik AA;Magnusson M;Fox CS;O'Donnell CJ;Vasan RS;Melander O;Clish CB;Gerszten RE;Wang TJ
通讯作者：
Wang TJ
影响因子：
3.7
作者：
GORFIEN, S;SPECTOR, A;WEISS, S
通讯作者：
WEISS, S
影响因子：
7.1
作者：
Biolo, Gianni;Agostini, Francesco;Narici, Marco V.
通讯作者：
Narici, Marco V.
影响因子：
8.2
作者：
Carobbio, S;Ishihara, H;Maechler, P
通讯作者：
Maechler, P
影响因子：
2.1
作者：
Li, Yun;Willer, Cristen J.;Ding, Jun;Scheet, Paul;Abecasis, Goncalo R.
通讯作者：
Abecasis, Goncalo R.