CCR2、CCR5或CX3CR1中的常见和罕见基因变异与动脉粥样硬化性冠心病风险及糖代谢特征
Common and Rare Genetic Variation in CCR2, CCR5, or CX3CR1 and Risk of Atherosclerotic Coronary Heart Disease and Glucometabolic Traits.
作者信息
Golbus Jessica R, Stitziel Nathan O, Zhao Wei, Xue Chenyi, Farrall Martin, McPherson Ruth, Erdmann Jeanette, Deloukas Panos, Watkins Hugh, Schunkert Heribert, Samani Nilesh J, Saleheen Danish, Kathiresan Sekar, Reilly Muredach P
机构信息
From the Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia (J.R.G.); Cardiovascular Division, Department of Medicine (N.O.S.), Department of Genetics and McDonnell Genome Institute (N.O.S.), Washington University School of Medicine, St. Louis, MO; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia (W.Z., C.X., D.S.); Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F., H.W.); Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.M.); Medizinische Klinik II, University of Lübeck, Lübeck, Germany (J.E.); William Harvey Research Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom (P.D.); Deutsches Herzzentrum München, Technische Universität München, DZHK, Munich Heart Alliance, München, Germany (H.S.); Department of Cardiovascular Sciences, University of Leicester & NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); Center for Human Genetic Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.K.); Department of Medicine, Harvard Medical School, Boston, MA (S.K.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (S.K.); and Department of Medicine, Columbia University, New York, NY (M.P.R.).
出版信息
Circ Cardiovasc Genet. 2016 Jun;9(3):250-8. doi: 10.1161/CIRCGENETICS.115.001374. Epub 2016 Mar 24.
BACKGROUND
The chemokine receptors CCR2, CCR5, and CX3CR1 coordinate monocyte trafficking in homeostatic and inflammatory states. Multiple small human genetic studies have variably linked single nucleotide polymorphisms in these genes to cardiometabolic disease. We interrogated genome-wide association, exome sequencing, and exome array genotyping studies to ascertain the relationship between variation in these genes and coronary artery disease (CAD), myocardial infarction (MI), and glucometabolic traits.
METHODS AND RESULTS
We interrogated the CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) (60 801 cases and 123 504 controls), the MIGen and CARDIoGRAM Exome consortia (42 335 cases and 78 240 controls), and Exome Sequencing Project and Early-Onset Myocardial Infarction (ESP EOMI; 4703 cases and 5090 controls) data sets to ascertain the relationship between common, low frequency, and rare variation in CCR2, CCR5, or CX3CR1 with CAD and MI. We did not identify any variant associated with CAD or MI. We then explored common and low-frequency variation in South Asians through Pakistan Risk of Myocardial Infarction Study (PROMIS; 9058 cases and 8379 controls), identifying 6 variants associated with MI including CX3CR1 V249I. Finally, reanalysis of the European HapMap imputed Diabetes Genetics Replication and Meta-Analysis (DIAGRAM), Global Lipids Genetics Consortium (GLGC), Genetic Investigation of Anthropometric Traits (GIANT), and Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC) data sets revealed no association with glucometabolic traits although 3 single nucleotide polymorphisms in PROMIS were associated with type II diabetes mellitus.
CONCLUSIONS
No chemokine receptor variant was associated with CAD, MI, or glucometabolic traits in large European ancestry cohorts. In a South Asian cohort, we identified single nucleotide polymorphism associations with MI and type II diabetes mellitus but these did not meet significance in cohorts of European ancestry. These findings suggest the need for larger studies in South Asians but exclude clinically meaningful associations with CAD and glucometabolic traits in Europeans.
背景
趋化因子受体CCR2、CCR5和CX3CR1在稳态和炎症状态下协调单核细胞的运输。多项小型人类遗传学研究将这些基因中的单核苷酸多态性与心脏代谢疾病进行了不同程度的关联。我们对全基因组关联研究、外显子组测序和外显子组阵列基因分型研究进行了分析，以确定这些基因的变异与冠状动脉疾病（CAD）、心肌梗死（MI）和糖代谢性状之间的关系。
方法与结果
我们分析了CARDIoGRAMplusC4D（冠状动脉疾病全基因组复制和荟萃分析[CARDIoGRAM]加上冠状动脉疾病[C4D]遗传学）（60801例病例和123504例对照）、MIGen和CARDIoGRAM外显子组联盟（42335例病例和78240例对照）以及外显子组测序项目和早发性心肌梗死（ESP EOMI；4703例病例和5090例对照）数据集，以确定CCR2、CCR5或CX3CR1中常见、低频和罕见变异与CAD和MI之间的关系。我们未发现任何与CAD或MI相关的变异。然后，我们通过巴基斯坦心肌梗死风险研究（PROMIS；9058例病例和8379例对照）探索了南亚人群中的常见和低频变异，确定了6个与MI相关的变异，包括CX3CR1 V249I。最后，对欧洲HapMap推算的糖尿病遗传学复制和荟萃分析（DIAGRAM）、全球脂质遗传学联盟（GLGC）、人体测量性状遗传学研究（GIANT）以及葡萄糖和胰岛素相关性状联盟荟萃分析（MAGIC）数据集的重新分析显示，尽管PROMIS中的3个单核苷酸多态性与II型糖尿病相关，但与糖代谢性状无关联。
结论
在欧洲血统的大型队列中，没有趋化因子受体变异与CAD、MI或糖代谢性状相关。在一个南亚队列中，我们确定了与MI和II型糖尿病相关的单核苷酸多态性关联，但这些在欧洲血统队列中未达到显著水平。这些发现表明需要在南亚人群中进行更大规模的研究，但排除了在欧洲人与CAD和糖代谢性状的临床意义上的关联。
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