Association of genetic variants with coronary artery disease and ischemic stroke in a longitudinal population‑based genetic epidemiological study

Yamada,Yoshiji; Matsui,Kota; Takeuchi,Ichiro; Fujimaki,Tetsuo

doi:10.3892/br.2015.440

Association of genetic variants with coronary artery disease and ischemic stroke in a longitudinal population‑based genetic epidemiological study

Authors:
- Yoshiji Yamada
- Kota Matsui
- Ichiro Takeuchi
- Tetsuo Fujimaki
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Affiliations: Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Mie 514‑8507, Japan, Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Chiyoda‑ku, Tokyo 102‑0075, Japan, Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Mie 511‑0428, Japan
Published online on: March 2, 2015 https://doi.org/10.3892/br.2015.440
Pages: 413-419

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Abstract

Our previous studies identified nine genes and chromosomal region 3q28 as susceptibility loci for myocardial infarction, ischemic stroke or chronic kidney disease by genome‑wide or candidate gene association studies. As coronary artery disease (CAD) and ischemic stroke may share genetic architecture, certain genetic variants may confer susceptibility to the two diseases. The present study examined the association of 13 polymorphisms at these 10 loci with the prevalence of CAD or ischemic stroke in community‑dwelling individuals, with the aim of identifying genetic variants that confer susceptibility to the two conditions. Study subjects (170 with CAD, 117 with ischemic stroke and 5,718 controls) were recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited for an annual health checkup and they were followed up each year (mean follow‑up period, 5 years). Longitudinal analysis with a generalized estimating equation, and with adjustment for age, gender, body mass index, smoking status, the prevalence of hypertension, diabetes mellitus and dyslipidemia and the serum concentration of creatinine, revealed that rs2074380 (G→A) and rs2074381 (A→G) of the α‑kinase 1 (ALPK1) gene and rs8089 (T→G) of the thrombospondin 2 (THBS2) gene were significantly (P<2x10‑16) associated with the prevalence of CAD, with the AA genotype of rs2074380 and GG genotypes of rs2074381 and rs8089 being protective against this condition. Similar analysis revealed that rs9846911 (A→G) at chromosome 3q28, rs2074381 of ALPK1, rs8089 of THBS2 and rs6046 (G→A) of the coagulation factor VII gene were significantly (P<2x10‑16) associated with the prevalence of ischemic stroke, with the GG genotypes of rs9846911, rs2074381 and rs8089 and the AA genotype of rs6046 being protective against this condition. ALPK1 and THBS2 may thus be susceptibility loci for CAD and ischemic stroke.

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1	Mozaffarian D, Benjamin EJ, Go AS, et al: Heart disease and stroke statistics-2015 update: A report from the american heart association. Circulation. 131:e29–e322. 2015. View Article : Google Scholar : PubMed/NCBI
2	Stefanini GG and Holmes DR Jr: Drug-eluting coronary-artery stents. N Engl J Med. 368:254–265. 2013. View Article : Google Scholar : PubMed/NCBI
3	Donnan GA, Fisher M, Macleod M and Davis SM: Stroke. Lancet. 371:1612–1623. 2008. View Article : Google Scholar : PubMed/NCBI
4	Arnett DK, Baird AE, Barkley RA, et al: American Heart Association Council on Epidemiology and Prevention; American Heart Association Stroke Council; Functional Genomics and Translational Biology Interdisciplinary Working Group: Relevance of genetics and genomics for prevention and treatment of cardiovascular disease: A scientific statement from the American Heart Association Council on Epidemiology and Prevention, the Stroke Council and the Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation. 115:2878–2901. 2007. View Article : Google Scholar : PubMed/NCBI
5	Roberts R and Stewart AF: The genetics of coronary artery disease. Curr Opin Cardiol. 27:221–227. 2012. View Article : Google Scholar : PubMed/NCBI
6	Hassan A and Markus HS: Genetics and ischaemic stroke. Brain. 123:1784–1812. 2000. View Article : Google Scholar : PubMed/NCBI
7	Dichgans M: Genetics of ischaemic stroke. Lancet Neurol. 6:149–161. 2007. View Article : Google Scholar : PubMed/NCBI
8	Banerjee A, Lim CC, Silver LE, Welch SJ, Banning AP and Rothwell PM: Familial history of stroke is associated with acute coronary syndromes in women. Circ Cardiovasc Genet. 4:9–15. 2011. View Article : Google Scholar : PubMed/NCBI
9	Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 447:661–678. 2007. View Article : Google Scholar : PubMed/NCBI
10	Helgadottir A, Thorleifsson G, Manolescu A, et al: A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 316:1491–1493. 2007. View Article : Google Scholar : PubMed/NCBI
11	McPherson R, Pertsemlidis A, Kavaslar N, et al: A common allele on chromosome 9 associated with coronary heart disease. Science. 316:1488–1491. 2007. View Article : Google Scholar : PubMed/NCBI
12	Samani NJ, Erdmann J, Hall AS, et al: WTCCC and the Cardiogenics Consortium: Genomewide association analysis of coronary artery disease. N Engl J Med. 357:443–453. 2007. View Article : Google Scholar : PubMed/NCBI
13	Peden JF, Hopewell JC, Saleheen D, et al: Coronary Artery Disease (C4D) Genetics Consortium: A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat Genet. 43:339–344. 2011. View Article : Google Scholar : PubMed/NCBI
14	Schunkert H, König IR, Kathiresan S, et al: Cardiogenics; CARDIoGRAM Consortium: Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet. 43:333–338. 2011. View Article : Google Scholar : PubMed/NCBI
15	Deloukas P, Kanoni S, Willenborg C, et al: CARDIoGRAMplusC4D Consortium; DIAGRAM Consortium; CARDIOGENICS Consortium; MuTHER Consortium; Wellcome Trust Case Control Consortium: Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet. 45:25–33. 2013. View Article : Google Scholar : PubMed/NCBI
16	Gretarsdottir S, Thorleifsson G, Manolescu A, et al: Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke. Ann Neurol. 64:402–409. 2008. View Article : Google Scholar : PubMed/NCBI
17	Ikram MA, Seshadri S, Bis JC, et al: Genomewide association studies of stroke. N Engl J Med. 360:1718–1728. 2009. View Article : Google Scholar : PubMed/NCBI
18	Gudbjartsson DF, Holm H, Gretarsdottir S, et al: A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet. 41:876–878. 2009. View Article : Google Scholar : PubMed/NCBI
19	Bellenguez C, Bevan S, Gschwendtner A, et al: International Stroke Genetics Consortium (ISGC); Wellcome Trust Case Control Consortium 2 (WTCCC2): Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet. 44:328–333. 2012. View Article : Google Scholar : PubMed/NCBI
20	Traylor M, Farrall M, Holliday EG, et al: Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2); International Stroke Genetics Consortium: Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): A meta-analysis of genome-wide association studies. Lancet Neurol. 11:951–962. 2012. View Article : Google Scholar : PubMed/NCBI
21	Kilarski LL, Achterberg S, Devan WJ, et al: GARNET Collaborative Research Group, Wellcome Trust Case Control Consortium 2, Australian Stroke Genetic Collaborative, the METASTROKE Consortium, and the International Stroke Genetics Consortium: Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12. Neurology. 83:678–685. 2014. View Article : Google Scholar : PubMed/NCBI
22	Gschwendtner A, Bevan S, Cole JW, et al: International Stroke Genetics Consortium: Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. Ann Neurol. 65:531–539. 2009. View Article : Google Scholar : PubMed/NCBI
23	Williams FM, Carter AM, Hysi PG, et al: EuroCLOT Investigators; Wellcome Trust Case Control Consortium 2; MOnica Risk, Genetics, Archiving and Monograph; MetaStroke; International Stroke Genetics Consortium: Ischemic stroke is associated with the ABO locus: The EuroCLOT study. Ann Neurol. 73:16–31. 2013. View Article : Google Scholar : PubMed/NCBI
24	Dichgans M, Malik R, König IR, et al: METASTROKE Consortium; CARDIoGRAM Consortium; C4D Consortium; International Stroke Genetics Consortium: Shared genetic susceptibility to ischemic stroke and coronary artery disease: A genome-wide analysis of common variants. Stroke. 45:24–36. 2014. View Article : Google Scholar : PubMed/NCBI
25	Yamada Y, Nishida T, Ichihara S, et al: Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations. Atherosclerosis. 215:145–152. 2011. View Article : Google Scholar : PubMed/NCBI
26	Yamada Y, Fuku N, Tanaka M, et al: Identification of CELSR1 as a susceptibility gene for ischemic stroke in Japanese individuals by a genome-wide association study. Atherosclerosis. 207:144–149. 2009. View Article : Google Scholar : PubMed/NCBI
27	Yamada Y, Nishida T, Ichihara S, et al: Identification of chromosome 3q28 and ALPK1 as susceptibility loci for chronic kidney disease in Japanese individuals by a genome-wide association study. J Med Genet. 50:410–418. 2013. View Article : Google Scholar : PubMed/NCBI
28	Yamada Y, Matsuo H, Segawa T, et al: Assessment of genetic risk for myocardial infarction. Thromb Haemost. 96:220–227. 2006.PubMed/NCBI
29	Fujimaki T, Kato K, Yoshida T, et al: Association of genetic variants with myocardial infarction in Japanese individuals with chronic kidney disease. Thromb Haemost. 101:963–968. 2009.PubMed/NCBI
30	Oguri M, Kato K, Yokoi K, et al: Association of genetic variants with myocardial infarction in Japanese individuals with metabolic syndrome. Atherosclerosis. 206:486–493. 2009. View Article : Google Scholar : PubMed/NCBI
31	Yamada Y, Matsui K, Takeuchi I, Oguri M and Fujimaki T: Association of genetic variants with hypertension in a longitudinal population-based genetic epidemiological study. Int J Mol Med. (In press).
32	Shimokata S, Oguri M, Fujimaki T, Horibe H, Kato K and Yamada Y: Association between polymorphisms of the α-kinase 1 gene and type 2 diabetes mellitus in community-dwelling individuals. Biomed Rep. 1:940–944. 2013.PubMed/NCBI
33	Ueyama C, Horibe H, Fujimaki T, Oguri M, Kato K and Yamada Y: Association of genetic variants of CELSR1 and 3q28 with hypertension in community-dwelling individuals. Biomed Rep. 1:840–844. 2013.PubMed/NCBI
34	Oguri M, Fujimaki T, Horibe H, Kato K, Ichihara S and Yamada Y: Association of a polymorphism of BTN2A1 with chronic kidney disease in community-dwelling individuals. Biomed Rep. 1:868–872. 2013.PubMed/NCBI
35	Fujimaki T, Horibe H, Oguri M, Kato K and Yamada Y: Association of genetic variants of the α-kinase 1 gene with myocardial infarction in community-dwelling individuals. Biomed Rep. 2:127–131. 2014.PubMed/NCBI
36	Horibe H, Ueyama C, Fujimaki T, Oguri M, Kato K, Ichihara S and Yamada Y: Association of a polymorphism of BTN2A1 with dyslipidemia in community-dwelling individuals. Mol Med Rep. 9:808–812. 2014.PubMed/NCBI
37	Murakata Y, Fujimaki T and Yamada Y: Association of a butyrophilin, subfamily 2, member A1 gene polymorphism with hypertension. Biomed Rep. 2:818–822. 2014.PubMed/NCBI
38	Itoh Y, Mizuki N, Shimada T, Azuma F, Itakura M, Kashiwase K, Kikkawa E, Kulski JK, Satake M and Inoko H: High-throughput DNA typing of HLA-A, -B, -C and -DRB1 loci by a PCR-SSOP-Luminex method in the Japanese population. Immunogenetics. 57:717–729. 2005. View Article : Google Scholar : PubMed/NCBI
39	Gibbons RD, Hedeker D and DuToit S: Advances in analysis of longitudinal data. Annu Rev Clin Psychol. 6:79–107. 2010. View Article : Google Scholar : PubMed/NCBI
40	Heine M, Cramm-Behrens CI, Ansari A, Chu HP, Ryazanov AG, Naim HY and Jacob R: α-kinase 1, a new component in apical protein transport. J Biol Chem. 280:25637–25643. 2005. View Article : Google Scholar : PubMed/NCBI
41	Wang SJ, Tu HP, Ko AM, Chiang SL, Chiou SJ, Lee SS, Tsai YS, Lee CP and Ko YC: Lymphocyte α-kinase is a gout-susceptible gene involved in monosodium urate monohydrate-induced inflammatory responses. J Mol Med Berl. 89:1241–1251. 2011. View Article : Google Scholar : PubMed/NCBI
42	Newman DJ, Thakkar H, Edwards RG, Wilkie M, White T, Grubb AO and Price CP: Serum cystatin C measured by automated immunoassay: A more sensitive marker of changes in GFR than serum creatinine. Kidney Int. 47:312–318. 1995. View Article : Google Scholar : PubMed/NCBI
43	Singh D, Whooley MA, Ix JH, Ali S and Shlipak MG: Association of cystatin C and estimated GFR with inflammatory biomarkers: The Heart and Soul Study. Nephrol Dial Transplant. 22:1087–1092. 2007. View Article : Google Scholar : PubMed/NCBI
44	Shlipak MG, Katz R, Cushman M, Sarnak MJ, Stehman-Breen C, Psaty BM, Siscovick D, Tracy RP, Newman A and Fried L: Cystatin-C and inflammatory markers in the ambulatory elderly. Am J Med. 118:14162005. View Article : Google Scholar : PubMed/NCBI
45	Wang GN, Sun K, Hu DL, Wu HH, Wang XZ and Zhang JS: Serum cystatin C levels are associated with coronary artery disease and its severity. Clin Biochem. 47:176–181. 2014. View Article : Google Scholar : PubMed/NCBI
46	Dandana A, Gammoudi I, Chalghoum A, Chahed H, Addad F, Ferchichi S and Miled A: Clinical utility of serum cystatin C in predicting coronary artery disease in patients without chronic kidney disease. J Clin Lab Anal. 28:191–197. 2014. View Article : Google Scholar : PubMed/NCBI
47	Qing X, Furong W, Yunxia L, Jian Z, Xuping W and Ling G: Cystatin C and asymptomatic coronary artery disease in patients with metabolic syndrome and normal glomerular filtration rate. Cardiovasc Diabetol. 11:1082012. View Article : Google Scholar : PubMed/NCBI
48	Patel D, Ahmad S, Silverman A and Lindsay J: Effect of cystatin C levels on angiographic atherosclerosis progression and events among postmenopausal women with angiographically decompensated coronary artery disease (from the Women's Angiographic Vitamin and Estrogen [WAVE] study). Am J Cardiol. 111:1681–1687. 2013. View Article : Google Scholar : PubMed/NCBI
49	Koenig W, Twardella D, Brenner H and Rothenbacher D: Plasma concentrations of cystatin C in patients with coronary heart disease and risk for secondary cardiovascular events: More than simply a marker of glomerular filtration rate. Clin Chem. 51:321–327. 2005. View Article : Google Scholar : PubMed/NCBI
50	Woitas RP, Kleber ME, Meinitzer A, et al: Cystatin C is independently associated with total and cardiovascular mortality in individuals undergoing coronary angiography. The Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Atherosclerosis. 229:541–548. 2013. View Article : Google Scholar : PubMed/NCBI
51	Ni L, Lü J, Hou LB, Yan JT, Fan Q, Hui R, Cianflone K, Wang W and Wang DW: Cystatin C, associated with hemorrhagic and ischemic stroke, is a strong predictor of the risk of cardiovascular events and death in Chinese. Stroke. 38:3287–3288. 2007. View Article : Google Scholar : PubMed/NCBI
52	Seliger SL, Longstreth WT Jr, Katz R, et al: Cystatin C and subclinical brain infarction. J Am Soc Nephrol. 16:3721–3727. 2005. View Article : Google Scholar : PubMed/NCBI
53	Stenina OI, Byzova TV, Adams JC, McCarthy JJ, Topol EJ and Plow EF: Coronary artery disease and the thrombospondin single nucleotide polymorphisms. Int J Biochem Cell Biol. 36:1013–1030. 2004. View Article : Google Scholar : PubMed/NCBI
54	Majack RA, Goodman LV and Dixit VM: Cell surface thrombospondin is functionally essential for vascular smooth muscle cell proliferation. J Cell Biol. 106:415–422. 1988. View Article : Google Scholar : PubMed/NCBI
55	Kyriakides TR, Zhu YH, Smith LT, et al: Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis. J Cell Biol. 140:419–430. 1998. View Article : Google Scholar : PubMed/NCBI
56	Yang Z, Kyriakides TR and Bornstein P: Matricellular proteins as modulators of cell-matrix interactions: Adhesive defect in thrombospondin 2-null fibroblasts is a consequence of increased levels of matrix metalloproteinase-2. Mol Biol Cell. 11:3353–3364. 2000. View Article : Google Scholar : PubMed/NCBI
57	Yang Z, Strickland DK and Bornstein P: Extracellular matrix metalloproteinase 2 levels are regulated by the low density lipoprotein-related scavenger receptor and thrombospondin 2. J Biol Chem. 276:8403–8408. 2001. View Article : Google Scholar : PubMed/NCBI
58	Topol EJ, McCarthy J, Gabriel S, et al: Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Circulation. 104:2641–2644. 2001. View Article : Google Scholar : PubMed/NCBI
59	Boekholdt SM, Trip MD, Peters RJ, Engelen M, Boer JM, Feskens EJ, Zwinderman AH, Kastelein JJ and Reitsma PH: Thrombospondin-2 polymorphism is associated with a reduced risk of premature myocardial infarction. Arterioscler Thromb Vasc Biol. 22:e24–e27. 2002. View Article : Google Scholar : PubMed/NCBI
60	Ehret GB, O'Connor AA, Weder A, Cooper RS and Chakravarti A: Follow-up of a major linkage peak on chromosome 1 reveals suggestive QTLs associated with essential hypertension: GenNet study. Eur J Hum Genet. 17:1650–1657. 2009. View Article : Google Scholar : PubMed/NCBI
61	Shriner D, Adeyemo A and Rotimi CN: Joint ancestry and association testing in admixed individuals. PLoS Comput Biol. 7:e10023252011. View Article : Google Scholar : PubMed/NCBI
62	Smith NL, Chen MH, Dehghan A, et al: Wellcome Trust Case Control Consortium: Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation. 121:1382–1392. 2010. View Article : Google Scholar : PubMed/NCBI
63	Tang W, Schwienbacher C, Lopez LM, et al: Genetic associations for activated partial thromboplastin time and prothrombin time, their gene expression profiles, and risk of coronary artery disease. Am J Hum Genet. 91:152–162. 2012. View Article : Google Scholar : PubMed/NCBI