Skip to main content

Advertisement

SpringerLink
Log in

Genetics of metabolic syndrome

  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Metabolic syndrome (MetS) is a common phenotype, affecting about 24% of the US population. It is associated with an increased risk for type 2 diabetes and cardiovascular disease. Although there is no universally accepted definition for MetS, affected individuals commonly have a cluster of features, including abdominal obesity, hypertension, dyslipidemia, and dysglycemia. Recently, there has been extensive interest in potential genetic contributions to MetS. At present, no single gene or cluster of genes has been consistently replicated for MetS among different populations, likely due to the complex interplay between gene and environment necessary for expression of this phenotype. We review recent studies regarding the genetic contributions to MetS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. WHO: Definition, diagnosis, and classification of diabetes mellitus and its complications. Report of a WHO Consultation. Available at http://www.staff.newcastle.ac.uk/philip. home/who_dmc.htm. Accessed December 6, 2007.

  2. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III) [no authors listed]. JAMA 2001, 285:2486–2497.

  3. Alberti KG, Zimmet P, Shaw J: The metabolic syndrome—a new worldwide definition. Lancet 2005, 366:1059–1062.

    Article  PubMed  Google Scholar 

  4. Balkau B, Charles MA: Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med 1999, 16:442–443.

    Article  PubMed  CAS  Google Scholar 

  5. Einhorn D, Reaven GM, Cobin RH, et al.: American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract 2003, 9:237–252.

    PubMed  Google Scholar 

  6. Grundy SM, Cleeman JI, Daniels SR, et al.: Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005, 112:2735–2752.

    Article  PubMed  Google Scholar 

  7. Ford ES, Giles WH, Dietz WH: Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002, 287:356–359.

    Article  PubMed  Google Scholar 

  8. Carmelli D, Cardon LR, Fabsitz R: Clustering of hypertension, diabetes, and obesity in adult male twins: same genes or same environments? Am J Hum Genet 1994, 55:566–573.

    PubMed  CAS  Google Scholar 

  9. Edwards KL, Newman B, Mayer E, et al.: Heritability of factors of the insulin resistance syndrome in women twins. Genet Epidemiol 1997, 14:241–253.

    Article  PubMed  CAS  Google Scholar 

  10. Lin HF, Boden-Albala B, Juo SH, et al.: Heritabilities of the metabolic syndrome and its components in the Northern Manhattan Family Study. Diabetologia 2005, 48:2006–2012.

    Article  PubMed  Google Scholar 

  11. Kissebah AH, Sonnenberg GE, Myklebust J, et al.: Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci U S A 2000, 97:14478–14483.

    Article  PubMed  CAS  Google Scholar 

  12. Arya R, Blangero J, Williams K, et al.: Factors of insulin resistance syndrome—related phenotypes are linked to genetic locations on chromosomes 6 and 7 in nondiabetic Mexican-Americans. Diabetes 2002, 51:841–847.

    Article  PubMed  CAS  Google Scholar 

  13. Langefeld CD, Wagenknecht LE, Rotter JI, et al.: Linkage of the metabolic syndrome to 1q23–q31 in Hispanic families: the Insulin Resistance Atherosclerosis Study Family Study. Diabetes 2004, 53:1170–1174.

    Article  PubMed  CAS  Google Scholar 

  14. Loos RJ, Katzmarzyk PT, Rao DC, et al.: Genome-wide linkage scan for the metabolic syndrome in the HERITAGE Family Study. J Clin Endocrinol Metab 2003, 88:5935–5943.

    Article  PubMed  CAS  Google Scholar 

  15. Hsueh WC, St Jean PL, Mitchell BD, et al.: Genome-wide and fine-mapping linkage studies of type 2 diabetes and glucose traits in the Old Order Amish: evidence for a new diabetes locus on chromosome 14q11 and confirmation of a locus on chromosome 1q21–q24. Diabetes 2003, 52:550–557.

    Article  PubMed  CAS  Google Scholar 

  16. Ng MC, So WY, Cox NJ, et al.: Genome-wide scan for type 2 diabetes loci in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21–q25. Diabetes 2004, 53:1609–1613.

    Article  PubMed  CAS  Google Scholar 

  17. Das SK, Hasstedt SJ, Zhang Z, Elbein SC: Linkage and association mapping of a chromosome 1q21–q24 type 2 diabetes susceptibility locus in northern European Caucasians. Diabetes 2004, 53:492–499.

    Article  PubMed  CAS  Google Scholar 

  18. Vionnet N, Hani EH, Dupont S, et al.: Genomewide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21–q24. Am J Hum Genet 2000, 67:1470–1480.

    Article  PubMed  CAS  Google Scholar 

  19. Thameem F, Farook VS, Bogardus C, Prochazka M: Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21–q23 with type 2 diabetes in Pima Indians. Diabetes 2006, 55:839–842.

    Article  PubMed  CAS  Google Scholar 

  20. Ng MC, So WY, Lam VK, et al.: Genome-wide scan for metabolic syndrome and related quantitative traits in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21–q25. Diabetes 2004, 53:2676–2683.

    Article  PubMed  CAS  Google Scholar 

  21. Hoffmann K, Mattheisen M, Dahm S, et al.: A German genome-wide linkage scan for type 2 diabetes supports the existence of a metabolic syndrome locus on chromosome 1p36.13 and a type 2 diabetes locus on chromosome 16p12.2. Diabetologia 2007, 50:1418–1422.

    Article  PubMed  CAS  Google Scholar 

  22. Bowden DW, Rudock M, Ziegler J, et al.: Coincident linkage of type 2 diabetes, metabolic syndrome, and measures of cardiovascular disease in a genome scan of the diabetes heart study. Diabetes 2006, 55:1985–1994.

    Article  PubMed  CAS  Google Scholar 

  23. Yang WS, Yang YC, Chen CL, et al.: Adiponectin SNP276 is associated with obesity, the metabolic syndrome, and diabetes in the elderly. Am J Clin Nutr 2007, 86:509–513.

    PubMed  CAS  Google Scholar 

  24. Norata GD, Ongari M, Garlaschelli K, et al.: Effect of the −420C/G variant of the resistin gene promoter on metabolic syndrome, obesity, myocardial infarction and kidney dysfunction. J Intern Med 2007, 262:104–112.

    Article  PubMed  CAS  Google Scholar 

  25. Mousavinasab F, Tahtinen T, Jokelainen J, et al.: The Pro12Ala polymorphism of the PPAR gamma 2 gene influences sex hormone-binding globulin level and its relationship to the development of the metabolic syndrome in young Finnish men. Endocrine 2006, 30:185–190.

    Article  PubMed  CAS  Google Scholar 

  26. Rhee EJ, Oh KW, Lee WY, et al.: Effects of two common polymorphisms of peroxisome proliferator-activated receptor-gamma gene on metabolic syndrome. Arch Med Res 2006, 37:86–94.

    Article  PubMed  CAS  Google Scholar 

  27. Tonjes A, Scholz M, Loeffler M, Stumvoll M: Association of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma with pre-diabetic phenotypes: meta-analysis of 57 studies on nondiabetic individuals. Diabetes Care 2006, 29:2489–2497.

    Article  PubMed  CAS  Google Scholar 

  28. Meirhaeghe A, Cottel D, Amouyel P, Dallongeville J: Association between peroxisome proliferator-activated receptor gamma haplotypes and the metabolic syndrome in French men and women. Diabetes 2005, 54:3043–3048.

    Article  PubMed  CAS  Google Scholar 

  29. Robitaille J, Brouillette C, Houde A, et al.: Association between the PPARalpha-L162V polymorphism and components of the metabolic syndrome. J Hum Genet 2004, 49:482–489.

    Article  PubMed  CAS  Google Scholar 

  30. Robitaille J, Gaudet D, Perusse L, Vohl MC: Features of the metabolic syndrome are modulated by an interaction between the peroxisome proliferator-activated receptor-delta-87T>C polymorphism and dietary fat in French-Canadians. Int J Obes (Lond) 2007, 31:411–417.

    Article  CAS  Google Scholar 

  31. Miller M, Rhyne J, Chen H, et al.: APOC3 promoter polymorphisms C-482T and T-455C are associated with the metabolic syndrome. Arch Med Res 2007, 38:444–451.

    Article  PubMed  CAS  Google Scholar 

  32. Pennacchio LA, Olivier M, Hubacek JA, et al.: An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science 2001, 294:169–173.

    Article  PubMed  CAS  Google Scholar 

  33. Yamada Y, Kato K, Hibino T, et al.: Prediction of genetic risk for metabolic syndrome. Atherosclerosis 2007, 191:298–304.

    Article  PubMed  CAS  Google Scholar 

  34. Grallert H, Sedlmeier EM, Huth C, et al.: APOA5 variants and metabolic syndrome in Caucasians. J Lipid Res 2007, 48:2614–2621.

    Article  PubMed  CAS  Google Scholar 

  35. Komurcu-Bayrak E, Onat A, Poda M, et al.: The S447X variant of lipoprotein lipase gene is associated with metabolic syndrome and lipid levels among Turks. Clin Chim Acta 2007, 383:110–115.

    Article  PubMed  CAS  Google Scholar 

  36. Hamid YH, Rose CS, Urhammer SA, et al.: Variations of the interleukin-6 promoter are associated with features of the metabolic syndrome in Caucasian Danes. Diabetologia 2005, 48:251–260.

    Article  PubMed  CAS  Google Scholar 

  37. Stephens JW, Hurel SJ, Lowe GD, et al.: Association between plasma IL-6, the IL6-174G>C gene variant and the metabolic syndrome in type 2 diabetes mellitus. Mol Genet Metab 2007, 90:422–428.

    Article  PubMed  CAS  Google Scholar 

  38. Sedlmeier EM, Grallert H, Hutch C, et al.: Gene variants of monocyte chemoattractant protein 1 and components of metabolic syndrome in KORA S4, Augusburg. Eur J Endocrinol 2007, 156:377–385.

    Article  PubMed  CAS  Google Scholar 

  39. Sookoian SC, Gonzalez C, Pirola CJ: Meta-analysis on the G-308A tumor necrosis factor alpha gene variant and phenotypes associated with the metabolic syndrome. Obes Res 2005, 13:2122–2131.

    PubMed  Google Scholar 

  40. Carballo E, Lai WS, Blackshear PJ: Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science 1998, 281:1001–1005.

    Article  PubMed  CAS  Google Scholar 

  41. Bouchard L, Tchernof A, Deshaies Y, et al.: ZFP36: a promising candidate gene for obesity-related metabolic complications identified by converging genomics. Obes Surg 2007, 17:372–382.

    Article  PubMed  Google Scholar 

  42. Bosse Y, Despres JP, Chagnon YC, et al.: Quantitative trait locus on 15q for a metabolic syndrome variable derived from factor analysis. Obesity (Silver Spring) 2007, 15:544–550.

    CAS  Google Scholar 

  43. Hegele RA, Anderson CM, Wang J, et al.: Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes. Genome Res 2000, 10:652–658.

    Article  PubMed  CAS  Google Scholar 

  44. Cao H, Hegele RA: Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 2000, 9:109–112.

    Article  PubMed  CAS  Google Scholar 

  45. Shackleton S, Lloyd DJ, Jackson SN, et al.: LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet 2000, 24:153–156.

    Article  PubMed  CAS  Google Scholar 

  46. Mesa JL, Loos RJ, Franks PW, et al.: Lamin A/C polymorphisms, type 2 diabetes, and the metabolic syndrome: case-control and quantitative trait studies. Diabetes 2007, 56:884–889.

    Article  PubMed  CAS  Google Scholar 

  47. Robitaille J, Brouillette C, Houde A, et al.: Molecular screening of the 11beta-HSD1 gene in men characterized by the metabolic syndrome. Obes Res 2004, 12:1570–1575.

    Article  PubMed  CAS  Google Scholar 

  48. Seckl JR, Morton NM, Chapman KE, Walker BR: Glucocorticoids and 11beta-hydroxysteroid dehydrogenase in adipose tissue. Recent Prog Horm Res 2004, 59:359–393.

    Article  PubMed  CAS  Google Scholar 

  49. Oakley RH, Jewell CM, Yudt MR, et al.: The dominant negative activity of the human glucocorticoid receptor beta isoform. Specificity and mechanisms of action. J Biol Chem 1999, 274:27857–27866.

    Article  PubMed  CAS  Google Scholar 

  50. Derijk RH, Schaaf MJ, Turner G, et al.: A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis. J Rheumatol 2001, 28:2383–2388.

    PubMed  CAS  Google Scholar 

  51. Syed AA, Irving JA, Redfern CP, et al.: Association of glucocorticoid receptor polymorphism A3669G in exon 9beta with reduced central adiposity in women. Obesity (Silver Spring) 2006, 14:759–764.

    Article  CAS  Google Scholar 

  52. Gallagher CJ, Langefeld CD, Gordon CJ, et al.: Association of the estrogen receptor-alpha gene with the metabolic syndrome and its component traits in African-American families: the Insulin Resistance Atherosclerosis Family Study. Diabetes 2007, 56:2135–2141.

    Article  PubMed  CAS  Google Scholar 

  53. Dong H, Maddux BA, Altomonte J, et al.: Increased hepatic levels of the insulin receptor inhibitor, PC-1/NPP1, induce insulin resistance and glucose intolerance. Diabetes 2005, 54:367–372.

    Article  PubMed  CAS  Google Scholar 

  54. Tasic I, Milojkovic M, Sunder-Plassmann R, et al.: The association of PC-1 (ENPP1) K121Q polymorphism with metabolic syndrome in patients with coronary heart disease. Clin Chim Acta 2007, 377:237–242.

    Article  PubMed  CAS  Google Scholar 

  55. Higaki Y, Hirshman MF, Fujii N, Goodyear LJ: Nitric oxide increases glucose uptake through a mechanism that is distinct from the insulin and contraction pathways in rat skeletal muscle. Diabetes 2001, 50:241–247.

    Article  PubMed  CAS  Google Scholar 

  56. Pieper GM: Enhanced, unaltered and impaired nitric oxide-mediated endothelium-dependent relaxation in experimental diabetes mellitus: importance of disease duration. Diabetologia 1999, 42:204–213.

    Article  PubMed  CAS  Google Scholar 

  57. Gonzalez-Sanchez JL, Martinez-Larrad MT, Saez ME, et al.: Endothelial nitric oxide synthase haplotypes are associated with features of metabolic syndrome. Clin Chem 2007, 53:91–97.

    Article  PubMed  CAS  Google Scholar 

  58. Krief S, Lonnqvist F, Raimbault S, et al.: Tissue distribution of beta 3-adrenergic receptor mRNA in man. J Clin Invest 1993, 91:344–349.

    Article  PubMed  CAS  Google Scholar 

  59. Emorine LJ, Marullo S, Briend-Sutren MM, et al.: Molecular characterization of the human beta 3-adrenergic receptor. Science 1989, 245:1118–1121.

    Article  PubMed  CAS  Google Scholar 

  60. Tamaki S, Nakamura Y, Tabara Y, et al.: Relationship between metabolic syndrome and Trp64arg polymorphism of the beta-adrenergic receptor gene in a general sample: the Shigaraki study. Hypertens Res 2006, 29:891–896.

    Article  PubMed  CAS  Google Scholar 

  61. Fleury C, Neverova M, Collins S, et al.: Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet 1997, 15:269–272.

    Article  PubMed  CAS  Google Scholar 

  62. Chan CB, Saleh MC, Koshkin V, Wheeler MB: Uncoupling protein 2 and islet function. Diabetes 2004, 53(Suppl 1):S136–S142.

    Article  PubMed  CAS  Google Scholar 

  63. Himms-Hagen J, Harper ME: Physiological role of UCP3 may be export of fatty acids from mitochondria when fatty acid oxidation predominates: an hypothesis. Exp Biol Med 2001, 226:78–84.

    CAS  Google Scholar 

  64. Shen H, Qi L, Tai ES, et al.: Uncoupling protein 2 promoter polymorphism-866G/A, central adiposity, and metabolic syndrome in Asians. Obesity (Silver Spring) 2006, 14:656–661.

    Article  CAS  Google Scholar 

  65. Wang H, Chu WS, Lu T, et al.: Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am J Physiol 2004, 286:E1–E7.

    Article  CAS  Google Scholar 

  66. Yamada Y, Ichihara S, Kato K, et al.: Genetic risk for metabolic syndrome: examination of candidate gene polymorphisms related to lipid metabolism in Japanese individuals. J Med Genet 2008, 45:22–28.

    Article  PubMed  CAS  Google Scholar 

  67. Shapiro L, Scherer PE: The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor. Curr Biol 1998, 8:335–338.

    Article  PubMed  CAS  Google Scholar 

  68. Lee YH, Nair S, Rousseau E, et al.: Microarray profiling of isolated abdominal subcutaneous adipocytes from obese vs non-obese Pima Indians: increased expression of inflammation-related genes. Diabetologia 2005, 48:1776–1783.

    Article  PubMed  CAS  Google Scholar 

  69. McCarthy JJ, Meyer J, Moliterno DJ, et al.: Evidence for substantial effect modification by gender in a large-scale genetic association study of the metabolic syndrome among coronary heart disease patients. Hum Genet 2003, 114:87–98.

    Article  PubMed  CAS  Google Scholar 

  70. Russo P, Lauria F, Loguercio M, et al.: -344C/T Variant in the promoter of the aldosterone synthase gene (CYP11B2) is associated with metabolic syndrome in men. Am J Hypertens 2007, 20:218–222.

    Article  PubMed  CAS  Google Scholar 

  71. Tanaka M, Fuku N, Nishigaki Y, et al.: Women with mitochondrial haplogroup N9a are protected against metabolic syndrome. Diabetes 2007, 56:518–521.

    Article  PubMed  CAS  Google Scholar 

  72. Wang B, Chehab FF: Deletion of the serotonin 2c receptor from transgenic mice overexpressing leptin does not affect their lipodystrophy but exacerbates their diet-induced obesity. Biochem Biophys Res Comm 2006, 351:418–423.

    Article  PubMed  CAS  Google Scholar 

  73. Mulder H, Franke B, van der-Beek van der AA, et al.: The association between HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia. J Clin Psychopharmacol 2007, 27:338–343.

    Article  PubMed  CAS  Google Scholar 

  74. Frayling TM, Timpson NJ, Weedon MN, et al.: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007, 316:889–894.

    Article  PubMed  CAS  Google Scholar 

  75. Dina C, Meyre D, Gallina S, et al.: Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007, 39:724–726.

    Article  PubMed  CAS  Google Scholar 

  76. Lyon HN, Emilsson V, Hinney A, et al.: The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts. PLoS Genet 2007, 3:e61.

    Article  PubMed  CAS  Google Scholar 

  77. Pollex RL, Hanley AJ, Zinman B, et al.: Metabolic syndrome in aboriginal Canadians: prevalence and genetic associations. Atherosclerosis 2006, 184:121–129.

    Article  PubMed  CAS  Google Scholar 

  78. Lahiry P, Pollex RL, Hegele RA: Uncloaking the genetic determinants of metabolic syndrome. Nutrigenetics Nutrigenomics 2008, in press.

Download references

Author information

Authors and Affiliations

  1. Blackburn Cardiovascular Genetics Laboratory, Scientist, Vascular Biology Research Group, Robarts Research Institute, 406-100 Perth Drive, London, Ontario, N6A 5K8, Canada

    Robert A. Hegele

Authors
  1. Tisha Joy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Piya Lahiry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rebecca L. Pollex
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert A. Hegele
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert A. Hegele.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Joy, T., Lahiry, P., Pollex, R.L. et al. Genetics of metabolic syndrome. Curr Diab Rep 8, 141–148 (2008). https://doi.org/10.1007/s11892-008-0025-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-008-0025-y

Keywords

Search

Navigation