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Promoter polymorphism in the macrophage migration inhibitory factor gene is associated with obesity

International Journal of Obesity volume 30, pages 238–242 (2006)Cite this article

Abstract

Objective:

To explore the association of promoter polymorphisms of macrophage migration inhibitory factor (MIF) gene with obesity.

Subjects:

In total, 213 nondiabetic Japanese subjects. They were divided into three groups according to World Health Organization definitions: lean (body mass index (BMI) <25 kg/m2), overweight (25⩽BMI<30 kg/m2) and obese (BMI⩾30 kg/m2).

Methods:

We examined two polymorphic loci in the MIF gene in the subjects: a single-nucleotide polymorphism at position −173 (G/C) and a CATT-tetranucleotide repeat polymorphism at position −794, which both can affect promoter activity in different cells.

Results:

We detected four alleles: 5-, 6-, 7- and 8-CATT at position −794. Genotypes without the 5-CATT allele (X/X, X refers to 6-, 7- or 8-CATT alleles) were more common in obese subjects than in lean or overweight groups (P=0.013). The X-CATT allele was more frequent in obese subjects than in lean or overweight subjects (P=0.030). In contrast, −173G/C was not associated with obesity. Among the haplotypes of the two promoter polymorphisms, G/5-CATT ((−173G/C)/(−794[CATT]5–8)) was associated with a decreased risk of obesity (P=0.025) and G/6-CATT with an increased risk of overweight (P=0.028).

Conclusion:

Promoter polymorphism in the MIF gene is linked with obesity.

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References

  1. Maes HH, Neale MC, Eaves LJ . Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 1997; 27: 325–351.

    Article  CAS  Google Scholar 

  2. Bernhagen J, Calandra T, Bucala R . Regulation of the immune response by macrophage migration inhibitory factor: biological and structural features. J Mol Med 1998; 76: 151–161.

    Article  CAS  Google Scholar 

  3. Trayhurn P, Wood IS . Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004; 92: 347–355.

    Article  CAS  Google Scholar 

  4. Nishihira J . Novel pathophysiological aspects of macrophage migration inhibitory factor. Int J Mol Med 1998; 2: 17–28.

    CAS  PubMed  Google Scholar 

  5. Waeber G, Calandra T, Roduit R, Haefliger JA, Bonny C, Thompson N et al. Insulin secretion is regulated by the glucose-dependent production of islet β cell macrophage migration inhibitory factor. Proc Natl Acad Sci USA 1997; 94: 4782–4787.

    Article  CAS  Google Scholar 

  6. Benigni F, Atsumi T, Calandra T, Metz C, Echtenacher B, Peng T et al. The proinflammatory mediator macrophage migration inhibitory factor induces glucose catabolism in muscle. J Clin Invest 2000; 106: 1291–1300.

    Article  CAS  Google Scholar 

  7. Hirokawa J, Sakaue S, Furuya Y, Ishii J, Hasegawa A, Tagami S et al. Identification of macrophage migration inhibitory factor in adipose tissue and its induction by tumor necrosis factor-α. Biochem Biophys Res Commun 1997; 235: 94–98.

    Article  CAS  Google Scholar 

  8. Sakaue S, Nishihira J, Hirokawa J, Yoshimura H, Honda T, Aoki K et al. Regulation of macrophage migration inhibitory factor (MIF) expression by glucose and insulin in adipocytes in vitro. Mol Med 1999; 5: 361–371.

    Article  CAS  Google Scholar 

  9. Dandona P, Aljada A, Ghanim H, Mohanty P, Tripathy C, Hofmeyer D et al. Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin. J Clin Endocrinol Metab 2004; 89: 5043–5047.

    Article  CAS  Google Scholar 

  10. Rice T, Chagnon YC, Pérusse L, Borecki IB, Ukkola O, Rankinen T et al. A genomewide linkage scan for abdominal subcutaneous and visceral fat in black and white families: The HERITAGE Family Study. Diabetes 2002; 51: 848–855.

    Article  CAS  Google Scholar 

  11. Baugh JA, Chitnis S, Donnelly SC, Monteiro J, Lin X, Plant BJ et al. A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun 2002; 3: 170–176.

    Article  CAS  Google Scholar 

  12. Donn RP, Shelley E, Ollier WE, Thomson W, British Paediatric Rheumatology Study Group. A novel 5′-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 2001; 44: 1782–1785.

    Article  CAS  Google Scholar 

  13. Hizawa N, Yamaguchi E, Takahashi D, Nishihira J, Nishimura M . Functional polymorphisms in the promoter region of macrophage migration inhibitory factor and atopy. Am J Respir Crit Care Med 2004; 169: 1014–1018.

    Article  Google Scholar 

  14. Donn RP, Plant D, Jury F, Richards HL, Worthington J, Ray DW et al. Macrophage migration inhibitory factor gene polymorphism is associated with psoriasis. J Invest Dermatol 2004; 123: 484–487.

    Article  CAS  Google Scholar 

  15. Donn R, Alourfi Z, De Benedetti F, Meazza C, Zeggini E, Lunt M, et al., British Paediatric Rheumatology Study Group. Mutation screening of the macrophage migration inhibitory factor gene: positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis. Arthritis Rheum 2002; 46: 2402–2409.

    Article  CAS  Google Scholar 

  16. Terwillinger JD, Ott J . Handbook of Human Genetic Linkage. Johns Hopkins University Press: Baltimore, 1994.

    Google Scholar 

  17. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA . Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 2002; 70: 425–434.

    Article  Google Scholar 

  18. Examination Committee of Criteria for ‘Obesity Disease’ in Japan. Japan Society for the Study of Obesity. New criteria for ‘obesity disease’ in Japan. Circ J 2002; 66: 987–992.

    Article  Google Scholar 

  19. Hotamisligil GS, Shargill NS, Spiegelman BM . Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 1993; 259: 87–91.

    Article  CAS  Google Scholar 

  20. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM . Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. J Clin Invest 1995; 95: 2409–2415.

    Article  CAS  Google Scholar 

  21. Hotamisligil GS . The role of TNFα and TNF receptors in obesity and insulin resistance. J Intern Med 1999; 245: 621–625.

    Article  CAS  Google Scholar 

  22. Argiles JM, Lopez-Soriano J, Busquets S, Lopez-Soriano FJ . Journey from cachexia to obesity by TNF. FASEB J 1997; 11: 743–751.

    Article  CAS  Google Scholar 

  23. Warne JP . Tumour necrosis factor α: a key regulator of adipose tissue mass. J Endocrinol 2003; 177: 351–355.

    Article  CAS  Google Scholar 

  24. Norman RA, Bogardus C, Ravussin E . Linkage between obesity and a marker near the tumor necrosis factor-α locus in Pima Indians. J Clin Invest 1995; 96: 158–162.

    Article  CAS  Google Scholar 

  25. Fernandez-Real JM, Gutierrez C, Ricart W, Casamitjana R, Fernandez-Castaner M, Vendrell J et al. The TNF-α gene Nco I polymorphism influences the relationship among insulin resistance, percent body fat, and increased serum leptin levels. Diabetes 1997; 46: 1468–1472.

    Article  CAS  Google Scholar 

  26. Herrmann SM, Ricard S, Nicaud V, Mallet C, Arveiler D, Evans A et al. Polymorphisms of the tumour necrosis factor-α gene, coronary heart disease and obesity. Eur J Clin Invest 1998; 28: 59–66.

    Article  CAS  Google Scholar 

  27. Pausova Z, Deslauriers B, Gaudet D, Tremblay J, Kotchen TA, Larochelle P et al. Role of tumor necrosis factor-α gene locus in obesity and obesity-associated hypertension in French Canadians. Hypertension 2000; 36: 14–19.

    Article  CAS  Google Scholar 

  28. Hoffstedt J, Eriksson P, Hellstrom L, Rossner S, Ryden M, Arner P . Excessive fat accumulation is associated with the TNF α –308 G/A promoter polymorphism in women but not in men. Diabetologia. 2000; 43: 117–120.

    Article  CAS  Google Scholar 

  29. Kamizono S, Yamada K, Seki N, Higuchi T, Kimura A, Nonaka K et al. Susceptible locus for obese type 2 diabetes mellitus in the 5′-flanking region of the tumor necrosis factor-α gene. Tissue Antigens 2000; 55: 449–452.

    Article  CAS  Google Scholar 

  30. Brand E, Schorr U, Kunz I, Kertmen E, Ringel J, Distler A et al. Tumor necrosis factor-α–308 G/A polymorphism in obese Caucasians. Int J Obes Relat Metab Disord 2001; 25: 581–585.

    Article  CAS  Google Scholar 

  31. Dalziel B, Gosby AK, Richman RM, Bryson JM, Caterson ID . Association of the TNF-α –308 G/A promoter polymorphism with insulin resistance in obesity. Obes Res 2002; 10: 401–407.

    Article  CAS  Google Scholar 

  32. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821–1830.

    Article  CAS  Google Scholar 

  33. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW . Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796–1808.

    Article  CAS  Google Scholar 

  34. Bernhagen J, Mitchell RA, Calandra T, Voelter W, Cerami A, Bucala R . Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF). Biochemistry 1994; 33: 14144–14155.

    Article  CAS  Google Scholar 

  35. Skurk T, Herder C, Kraft I, Muller-Scholze S, Hauner H, Kolb H . Production and release of macrophage migration inhibitory factor from human adipocytes. Endocrinology 2005; 146: 1006–1011.

    Article  CAS  Google Scholar 

  36. Donn R, Alourfi Z, Zeggini E, Lamb R, Jury F, Lunt M, et al., British Paediatric Rheumatology Study Group. A functional promoter haplotype of macrophage migration inhibitory factor is linked and associated with juvenile idiopathic arthritis. Arthritis Rheum 2004; 50: 1604–1610.

    Article  Google Scholar 

  37. Shimizu T, Hizawa N, Honda A, Zhao Y, Abe R, Watanabe H et al. Promoter region polymorphism of macrophage migration inhibitory factor is strong risk factor for young onset of extensive alopecia areata. Genes Immun 2005; 6: 285–289.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank all participants in this study. We also thank the nursing staff of Kohnan hospital for blood sampling and Y Obata for valuable technical assistance.

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Authors and Affiliations

  1. First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan

    S Sakaue, S Ishimaru, N Hizawa, Y Ohtsuka, I Tsujino & M Nishimura

  2. Internal Medicine, Kohnan Hospital, Sapporo, Japan

    T Honda, J Suzuki & Y Kawakami

  3. GeneticLab Co., Ltd, Sapporo, Japan

    J Nishihira

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  1. S Sakaue
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  2. S Ishimaru
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Correspondence to S Sakaue.

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Sakaue, S., Ishimaru, S., Hizawa, N. et al. Promoter polymorphism in the macrophage migration inhibitory factor gene is associated with obesity. Int J Obes 30, 238–242 (2006). https://doi.org/10.1038/sj.ijo.0803148

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  • DOI: https://doi.org/10.1038/sj.ijo.0803148

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