Molecular and Cellular Biochemistry

, Volume 379, Issue 1–2, pp 77–85

Chromosome 9p21 rs10757278 polymorphism is associated with the risk of metabolic syndrome

  • Burcu Bayoglu
  • Huseyin Altug Cakmak
  • Husniye Yuksel
  • Gunay Can
  • Bilgehan Karadag
  • Turgut Ulutin
  • Vural Ali Vural
  • Mujgan Cengiz


Metabolic syndrome (MetS) is a common multifactorial disorder that involves abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. Genome-wide association studies have identified a major risk locus for coronary artery disease and myocardial infarction on chromosome 9p21. Here, we examined the frequency of single nucleotide polymorphisms (SNPs) on chromosome 9p21 in a sample of Turkish patients with MetS and further investigated the correlation between regional SNPs, haplotypes, and MetS. The real-time polymerase chain reaction (RT-PCR) was used to analyze 4 SNPs (rs10757274 A/G, rs2383207 A/G, rs10757278 A/G, rs1333049 C/G) in 291 MetS patients and 247 controls. Analysis of 4 SNPs revealed a significant difference in the genotype distribution for rs2383207, rs10757278, and rs1333049 between MetS patients and controls (p = 0.041, p = 0.005, p = 0.023, respectively) but not for rs10757274 (p = 0.211). MetS and control allelic frequencies for rs2383207, rs10757278, and rs1333049 were statistically different (p < 0.05). The rs2383207 AG variant, was identified as a MetS risk factor (p = 0.012, OR = 33.271; 95 % CI: 2.193–504.805) and the AA haplotype in block 1 and the GC, AG haplotypes in block 2 were associated with MetS (χ2 = 3.875, p = 0.049; χ2 = 9.334, p = 0.0022; χ2 = 9.134, p = 0.0025, respectively). In this study, we found that chromosome 9p21 SNP rs10757278 and related haplotypes correlate with MetS risk. This is the first report showing an association between a 9p21 variant and MetS and suggests that rs10757278 polymorphism may confer increased risk for disease.


Metabolic syndrome Chromosome 9p21 Genetic variation Haplotype 


  1. 1.
    Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA et al (2009) Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640–1645PubMedCrossRefGoogle Scholar
  2. 2.
    Bosy-Westphal A, Onur S, Geisler C, Wolf A, Korth O, Pfeufferm M et al (2007) Common familial influences on clustering of metabolic syndrome traits with central obesity and insülin resistance: the Kiel obesity prevention study. Int J Obes (Lond) 31:784–790Google Scholar
  3. 3.
    Bellia A, Giardina E, Lauro D, Tesauro M, Di Fede G, Cusumano G et al (2009) The Linosa Study: epidemiological and heritability data of the metabolic syndrome in a Caucasian genetic isolate. Nutr Metab Cardiovasc Dis 19(7):455–461PubMedCrossRefGoogle Scholar
  4. 4.
    Henneman P, Aulchenko YS, Frants RR, van Dijk KW, Oostra BA, van Duijn CM (2008) Prevalence and heritability of the metabolic syndrome and its individual components in a Dutch isolate: the Erasmus Rucphen Family study. J Med Genet 45:572–577PubMedCrossRefGoogle Scholar
  5. 5.
    Devaney JM, Gordish-Dressman H, Harmon BT, Bradbury MK, Devaney SA, Harris TB et al (2011) AKT1 polymorphisms are associated with risk for metabolic syndrome. Hum Genet 129(2):129–139PubMedCrossRefGoogle Scholar
  6. 6.
    Oguri M, Kato K, Yoshida T, Fujimaki T, Horibe H, Yokoi K et al (2011) Association of a genetic variant of BTN2A1 with metabolic syndrome in East Asian populations. J Med Genet 48(11):787–792PubMedCrossRefGoogle Scholar
  7. 7.
    Sobti RC, Kler R, Sharma YP, Talwar KK, Singh N (2012) Risk of obesity and type 2 diabetes with tumor necrosis factor-α 308G/A gene polymorphism in metabolic syndrome and coronary artery disease subjects. Mol Cell Biochem 360(1–2):1–7PubMedCrossRefGoogle Scholar
  8. 8.
    Wang H, Dong S, Xu H, Qian J, Yang J (2012) Genetic variants in FTO associated with metabolic syndrome: a meta- and gene-based analysis. Mol Biol Rep 39(5):5691–5698PubMedCrossRefGoogle Scholar
  9. 9.
    Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C (2004) American Heart Association; National Heart, Lung, and Blood Institute. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109:433–438PubMedCrossRefGoogle Scholar
  10. 10.
    Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K, Pyorala K, DECODE Study Group (2004) Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med 164:1066–1076PubMedCrossRefGoogle Scholar
  11. 11.
    Ninomiya T, Kubo M, Doi Y, Yonemoto K, Tanizaki Y, Rahman M et al (2007) Impact of metabolic syndrome on the development of cardiovascular disease in a general Japanese population: the Hisayama study. Stroke 38:2063–2069PubMedCrossRefGoogle Scholar
  12. 12.
    McNeill AM, Rosamond WD, Girman CJ, Golden SH, Schmidt MI, East HE et al (2005) The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study. Diabetes Care 28:385–390PubMedCrossRefGoogle Scholar
  13. 13.
    Park YM, Province MA, Gao X, Feitosa M, Wu J, Ma D et al (2009) Longitudinal trends in the association of metabolic syndrome with 550 k single nucleotide polymorphisms in the Framingham Heart Study. BMC Proc 3:S116PubMedCrossRefGoogle Scholar
  14. 14.
    Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, Wellcome Trust Case Control Consortium et al (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40:638–645PubMedCrossRefGoogle Scholar
  15. 15.
    Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM et al (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894PubMedCrossRefGoogle Scholar
  16. 16.
    Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678CrossRefGoogle Scholar
  17. 17.
    McPherson R, Pertsemlidis A, Kavaslar N et al (2007) A common allele on chromosome 9 associated with coronary heart disease. Science 316:1488–1491PubMedCrossRefGoogle Scholar
  18. 18.
    Helgadottir A, Thorleifsson G, Manolescu A et al (2007) A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316:1491–1493PubMedCrossRefGoogle Scholar
  19. 19.
    Samani NJ, Erdmann J, Hall AS et al (2007) Genome-wide association analysis of coronary artery disease. N Engl J Med 357:443–453PubMedCrossRefGoogle Scholar
  20. 20.
    Hamsten A, Eriksson P (2008) Identifying the susceptibility genes for coronary artery disease: from hyperbole through doubt to cautious optimism. J Intern Med 263(5):538–552PubMedCrossRefGoogle Scholar
  21. 21.
    Cunnington MS, Santibanez Koref M, Mayosi BM, Burn J, Keavney B (2010) Chromosome 9p21 SNPs associated with multiple disease phenotypes correlate with anril expression. PLoS Genet 6:e1000899PubMedCrossRefGoogle Scholar
  22. 22.
    Dupont WD, Plummer WD (1990) Power and sample size calculations: a review and computer program. Control Clin Trials 11:116–128PubMedCrossRefGoogle Scholar
  23. 23.
    Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRefGoogle Scholar
  24. 24.
    Sato K, Nakagawa H, Tajima A, Yoshida K, Inoue I (2010) ANRIL is implicated in the regulation of nucleus and potential transcriptional target of E2F1. Oncol Rep 24(3):701–707PubMedGoogle Scholar
  25. 25.
    Anderson JL, Horne BD, Kolek MJ et al (2008) Genetic variation at the 9p21 locus predicts angiographic coronary artery disease prevalence but not extent and has clinical utility. Am Heart J 156:1155–1162PubMedCrossRefGoogle Scholar
  26. 26.
    Muendlein A, Saely CH, Rhomberg S et al (2009) Evaluation of the association of genetic variants on the chromosomal loci 9p21.3, 6q25.1, and 2q36.3 with angiographically characterized coronary artery disease. Atherosclerosis 205:174–180PubMedCrossRefGoogle Scholar
  27. 27.
    Ye S, Willeit J, Kronenberg F, Xu Q, Kiechl S (2008) Association of genetic variation on chromosome 9p21 with susceptibility and progression of atherosclerosis: a population-based, prospective study. J Am Coll Cardiol 52:378–384PubMedCrossRefGoogle Scholar
  28. 28.
    Bhanushali AA, Parmar N, Contractor A, Shah VT, Das BR (2011) Variant on 9p21 is strongly associated with coronary artery disease but lacks association with myocardial infarction and disease severity in a population in Western India. Arch Med Res 42(6):469–474PubMedCrossRefGoogle Scholar
  29. 29.
    Yamagishi K, Folsom AR, Rosamond WD, Boerwinkle E, Investigators ARIC (2009) A genetic variant on chromosome 9p21 and incident heart failure in the ARIC study. Eur Heart J 30(10):1222–1228PubMedCrossRefGoogle Scholar
  30. 30.
    Björck HM, Länne T, Alehagen U, Persson K, Rundkvist L, Hamsten A, Dahlström U, Eriksson P (2009) Association of genetic variation on chromosome 9p21.3 and arterial stiffness. J Intern Med 265(3):373–381PubMedCrossRefGoogle Scholar
  31. 31.
    Ujcic-Voortman JK, Bos G, Baan CA, Verhoeff AP, Seidell JC (2011) Obesity and body fat distribution: ethnic differences and the role of socio-economic status. Obes Facts 4(1):53–60PubMedCrossRefGoogle Scholar
  32. 32.
    Diabetes Genetics Initiative (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336CrossRefGoogle Scholar
  33. 33.
    Scott LJ et al (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341–1345PubMedCrossRefGoogle Scholar
  34. 34.
    Zeggini E et al (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341PubMedCrossRefGoogle Scholar
  35. 35.
    Assimes TL, Knowles JW, Basu A et al (2008) Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study. Hum Mol Genet 17:2320–2328PubMedCrossRefGoogle Scholar
  36. 36.
    Congrains A, Kamide K, Katsuya T, Yasuda O, Oguro R, Yamamoto K, Ohishi M, Rakugi H (2012) CVD-associated non-coding RNA, ANRIL, modulates expression of atherogenic pathways in VSMC. Biochem Biophys Res Commun 419(4):612–616PubMedCrossRefGoogle Scholar
  37. 37.
    Bayoglu B, Cengiz M, Cakmak HA, Uysal O, Yuksel H (2011) Association of a Common Variant on Chromosome 9p21 in Turkish Patients with Metabolic Syndrome. IV.International Congress of Molecular Medicine, p 61–62, 27–30 June 2011, Istanbul, TurkeyGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Burcu Bayoglu
    • 1
  • Huseyin Altug Cakmak
    • 2
  • Husniye Yuksel
    • 2
  • Gunay Can
    • 3
  • Bilgehan Karadag
    • 2
  • Turgut Ulutin
    • 1
  • Vural Ali Vural
    • 2
  • Mujgan Cengiz
    • 1
  1. 1.Department of Medical Biology, Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Fatih/IstanbulTurkey
  2. 2.Department of Cardiology, Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Fatih/IstanbulTurkey
  3. 3.Department of Public Health, Cerrahpasa Medical FacultyIstanbul UniversityCerrahpasa Fatih/IstanbulTurkey

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