Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes,Circulation: Genomic and Precision Medicine

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Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes
Circulation: Genomic and Precision Medicine ( IF 7.4 ) Pub Date : 2021-07-09 , DOI: 10.1161/circgen.120.003258
Yingchang Lu ₁ , Latchezar Dimitrov ₂ , Shyh-Huei Chen ₃ , Lawrence F Bielak ₄ , Joshua C Bis ₅ , Mary F Feitosa ₆ , Lingyi Lu ₃ , Maryam Kavousi ₇ , Laura M Raffield ₈ , Albert V Smith _{9,

10,

11} , Lihua Wang ₆ , Stefan Weiss _{12,

13} , Jie Yao ₁₄ , Jiaxi Zhu ₆ , Elias F Gudmundsson _{10,

11} , Valborg Gudmundsdottir _{10,

11} , Daniel Bos _{7,

15} , Mohsen Ghanbari ₇ , M Arfan Ikram ₇ , Shih-Jen Hwang _{16,

17} , Kent D Taylor ₁₄ , Matthew J Budoff ₁₈ , Gauti K Gíslason _{10,

11} , Christopher J O'Donnell _{19,

20,

21} , Ping An ₆ , Nora Franceschini ₂₂ , Barry I Freedman ₂₃ , Yi-Ping Fu _{17,

24} , Xiuqing Guo ₁₄ , Gerardo Heiss ₂₂ , Sharon L R Kardia ₄ , James G Wilson _{25,

26} , Carl D Langefeld _{2,

3} , Ulf Schminke ₂₇ , André G Uitterlinden _{7,

28} , Leslie A Lange ₂₉ , Patricia A Peyser ₄ , Vilmundur G Gudnason _{10,

11} , Bruce M Psaty ₃₀ , Jerome I Rotter ₁₄ , Donald W Bowden _{2,

31} , Maggie C Y Ng _{1,

2}

Affiliation

Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN (Y.L., M.C.Y.N.).
Center for Precision Medicine (L.D., C.D.L., D.W.B., M.C.Y.N.), Wake Forest School of Medicine, Winston-Salem, NC.
Department of Biostatistics and Data Science (S.-H.C., L.L., C.D.L.), Wake Forest School of Medicine, Winston-Salem, NC.
Department of Epidemiology (L.F.B., S.L.R.K., P.A.P.).
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services (J.C.B.), University of Washington, Seattle.
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, Farrell Learning Center, St Louis, MO (M.F.F., L.W., J.Z., P.A.).
Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands (M.K., D.B., M.G., M.A.I., A.G.U.).
Department of Genetics (L.M.R.), University of North Carolina, Chapel Hill.
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI (A.V.S.).
Faculty of Medicine, University of Iceland, Reykjavik (A.V.S., E.F.G., V.G., G.K.G., V.G.G.).
Icelandic Heart Association, Kopavogur (A.V.S., E.F.G., V.G., G.K.G., V.G.G.).
Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University of Greifswald and University Medicine Greifswald, Germany (S.W.).
DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Germany (S.W.).
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (J.Y., K.D.T., X.G., J.I.R.).
Department of Radiology and Nuclear Medicine (D.B.).
The Population Sciences Branch, Division of Intramural Research (S.-J.H), National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
The Framingham Heart Study, National Heart, Lung and Blood Institute, National Institutes of Health, Framingham, MA (S.-J.H., Y.-P.F.).
Division of Cardiology, Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA (M.J.B.).
VA Boston Healthcare System (C.J.O.), Harvard Medical School, Boston, MA.
Department of Medicine, Brigham Women's Hospital (C.J.O.), Harvard Medical School, Boston, MA.
Department of Medicine (C.J.O.), Harvard Medical School, Boston, MA.
Department of Epidemiology (N.F., G.H.), University of North Carolina, Chapel Hill.
Department of Internal Medicine (B.I.F.), Wake Forest School of Medicine, Winston-Salem, NC.
Office of Biostatistics Research (Y.-P.F.), National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.).
Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA (J.G.W.).
Department of Neurology, University Medicine Greifswald, Germany (U.S.).
Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands (A.G.U.).
Division of Biomedical Informatics and Personalized Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora (L.A.L.).
Departments of Epidemiology and Health Services (B.M.P.), University of Washington, Seattle.
Department of Biochemistry (D.W.B.), Wake Forest School of Medicine, Winston-Salem, NC.

Background:Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.Methods:We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.Results:We replicated 2 loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P=2.0×10^-8 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints POSTN, encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (P<3.1×10^-4) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near CDKN2B-AS1 and rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for cIMT).Conclusions:Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.

中文翻译：

2 型糖尿病患者亚临床动脉粥样硬化的多种族全基因组关联研究

背景：冠状动脉钙化（CAC）和颈动脉内膜中层厚度（cIMT）是无症状个体亚临床动脉粥样硬化的衡量标准，也是心血管疾病的强烈危险因素。2 型糖尿病 (T2D) 是加速动脉粥样硬化的独立心血管疾病危险因素。方法：我们对多达 2500 名欧洲血统 (EA) 的 T2D 个体和 1590 名非洲血统的 T2D 个体进行了全基因组关联研究的荟萃分析，其中或在不排除流行的心血管疾病的情况下，通过心脏计算机断层扫描测量 CAC，以及通过 CHARGE（基因组流行病学心脏和衰老研究队列）联盟内的超声检查测量 3608 名 EA 个体和 838 名非洲血统 T2D 个体的 cIMT。结果：我们复制了先前在一般 EA 群体中报道的CAC 的 2 个基因座（靠近PHACTR1 的rs9369640和 rs9349379 以及靠近CDKN2B的 rs10757278 ）和 1 个 cIMT 基因座（靠近APOE-APOC1 的rs7412 和 rs445925 ）。我们在 EA 中鉴定出一个新的 CAC 基因座（rs8000449，靠近CSNK1A1L/LINC00547/POSTN，位于 13q13.3），P = 2.0×10 ^{-8 。}对 EA 和非洲血统的荟萃分析未发现其他基因座。对来自基因型-组织表达项目的动脉壁和代谢组织的附近表达基因进行的表达数量性状位点分析确定了POSTN，编码参与骨形成和骨基质组织的基质细胞蛋白，作为该位点的潜在候选基因。此外，我们发现3个先前报道的冠状动脉疾病位点与这些亚临床动脉粥样硬化表型有显着关联（ P <3.1×10 ^{-4 ）（对于CAC}，CDKN2B-AS1附近的rs2891168和FLJ12825附近的rs11170820 ，对于cIMT， APOE附近的rs7412 ）。结论：我们的结果提供了潜在的生物学机制，可以将 CAC 和 cIMT 与 T2D 患者心血管疾病风险增加联系起来。

更新日期：2021-08-17

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