Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Agouti-related protein promoter variant associated with leanness and decreased risk for diabetes in West Africans

International Journal of Obesity volume 30, pages 715–721 (2006)Cite this article

Abstract

Objective:

The role of the central melanocortin system in the development of obesity has been extensively studied. Single-nucleotide polymorphisms (SNPs) within several candidate genes have been associated with food intake and obesity-related phenotypes; however, few of these associations have been replicated. SNPs in the agouti-related protein (AGRP) gene coding (Ala67Thr, 199G/A) and promoter (−38C/T) have been reported to be associated with body mass index (BMI), fat mass (FM) and percent body fat, in populations of European and African descent. In this study, we evaluated the association between the functional AGRP −38C/T promoter SNP and weight-related traits, namely BMI, FM and fat-free mass (FFM), as well as diabetes status.

Design:

An association study of the AGRP −38C/T SNP and indices of obesity and diabetes status.

Subjects:

A well-characterized population of 538 West Africans from Ghana and Nigeria recruited in the AADM (Africa America Diabetes Mellitus) study (mean age 52 years, 41.3% males, 71% diabetic).

Measurements:

Genotyping of the AGRP −38C/T SNP, BMI, FM, FFM and fasting plasma glucose.

Results:

Women carrying two copies of the variant T allele had significantly lower BMI (OR=0.47; 95% CI, 0.25–0.87). Also, men with at least one copy of the variant T allele were over two times less likely to be diabetic than other men (OR=0.44; 95% CI, 0.22–0.89).

Conclusion:

Our results replicate previous findings and implicate the AGRP −38C/T SNP in the regulation of body weight in West Africans.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Clement K, Ferre P . Genetics and the pathophysiology of obesity. Pediatr Res 2003; 53: 721–725.

    Article  PubMed  Google Scholar 

  2. Comuzzie A, Allison D . The search for human obesity genes. Science 1998; 280: 1374–1377.

    Article  CAS  PubMed  Google Scholar 

  3. Comuzzie A . The emerging pattern of the genetic contribution to human obesity. Best Pract Res Clin Endocrinol Metab 2002; 16: 611–621.

    Article  PubMed  Google Scholar 

  4. Geller F, Reichwald K, Dempfle A, Illig T, Vollmert C, Herpertz S et al. Melanocortin-4 receptor gene variant I103 is negatively associated with obesity. Am J Hum Genet 2004; 74: 572–581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hinney A, Hohmann S, Geller F, Vogel C, Hess C, Wermter A et al. Melanocortin-4 receptor gene: case–control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity. J Clin Endocrinol Metab 2003; 88: 4258–4267.

    Article  CAS  PubMed  Google Scholar 

  6. Vaisse C, Clement K, Guy-Grand B, Froguel P . A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 1998; 20: 113–114.

    Article  CAS  PubMed  Google Scholar 

  7. Li W, Reed D, Lee J, Xu W, Kilker R, Sodam B et al. Sequence variants in the 5′ flanking region of the leptin gene are associated with obesity in women. Ann Hum Genet 1999; 63: 227–234.

    Article  CAS  PubMed  Google Scholar 

  8. Liu Y, Rocha-Sanchez S, Liu P, Long J, Lu Y, Elze L et al. Tests of linkage and/or association of the LEPR gene polymorphisms with obesity phenotypes in Caucasian nuclear families. Physiol Genomics 2004; 17: 101–106.

    Article  CAS  PubMed  Google Scholar 

  9. Krude H, Biebermann H, Gruters A . Mutations in the human proopiomelanocortin gene. Ann NY Acad Sci 2003; 994: 233–239.

    Article  CAS  PubMed  Google Scholar 

  10. Jackson R, Creemers J, Ohagi S, Raffin-Sanson M, Sanders L, Montague C et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 1997; 16: 303–306.

    Article  CAS  PubMed  Google Scholar 

  11. Ellacott K, Cone R . The central melanocortin system and the integration of short and long-term regulators of energy homeostasis. Recent Prog Horm Res 2004; 59: 395–408.

    Article  CAS  PubMed  Google Scholar 

  12. Mayfield D, Brown A, Page G, Garvey W, Shriver M, Argyropoulos G . A role for the agouti-related protein promoter in obesity and type 2 diabetes. Biochem Biophys Res Commun 2001; 287: 568–573.

    Article  CAS  PubMed  Google Scholar 

  13. Mountjoy K, Wong J . Obesity, diabetes and functions for proopiomelanocortin-derived peptides. Mol Cell Endocrinol 1997; 128: 171–177.

    Article  CAS  PubMed  Google Scholar 

  14. Marks D, Boucher N, Lanouette C, Perusse L, Brookhart G, Comuzzie A et al. Ala67Thr polymorphism in the agouti-related peptide gene is associated with inherited leanness in humans. Am J Med Genet 2004; 126A: 267–271.

    Article  PubMed  Google Scholar 

  15. Ollmann M, Wilson B, Yang Y, Kerns J, Chen Y, Gantz I et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997; 278: 135–138.

    Article  CAS  PubMed  Google Scholar 

  16. Qu S, Yang Y, Li J, Zeng Q, Gantz I . Agouti-related protein is a mediator of diabetic hyperphagia. Regul Pept 2001; 98: 69–75.

    Article  CAS  PubMed  Google Scholar 

  17. Mizuno T, Makimura H, Silverstein J, Roberts J, Lopingco T, Mobbs C . Fasting regulates hypothalamic neuropeptide Y, agouti-related peptide, and proopiomelanocortin in diabetic mice independent of changes in leptin or insulin. Endocrinology 1999; 140: 4551–4557.

    Article  CAS  PubMed  Google Scholar 

  18. Graham M, Shutter J, Sarmiento U, Sarosi I, Stark K . Overexpression of Agrt leads to obesity in transgenic mice. Nat Genet 1997; 17: 273–274.

    Article  CAS  PubMed  Google Scholar 

  19. Michaud E, Mynatt R, Miltenberger R, Klebig M, Wilkinson J, Zemel M et al. Role of the agouti gene in obesity. J Endocrinol 1997; 155: 207–209.

    Article  CAS  PubMed  Google Scholar 

  20. Shutter J, Graham M, Kinsey A, Scully S, Luthy R, Stark K . Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev 1997; 11: 593–602.

    Article  CAS  PubMed  Google Scholar 

  21. Katsuki A, Sumida Y, Gabazza E, Murashima S, Tanaka T, Furuta M et al. Plasma levels of agouti-related protein are increased in obese men. J Clin Endocrinol Metab 2001; 86: 1921–1924.

    Article  CAS  PubMed  Google Scholar 

  22. Vink T, Hinney A, van Elburg A, van Goozen S, Sandkuijl L, Sinke R et al. Association between an agouti-related protein gene polymorphism and anorexia nervosa. Mol Psychiatry 2001; 6: 325–328.

    Article  CAS  PubMed  Google Scholar 

  23. Brown A, Mayfield D, Volaufova J, Argyropoulos G . The gene structure and minimal promoter of the human agouti related protein. Gene 2001; 277: 231–238.

    Article  CAS  PubMed  Google Scholar 

  24. Argyropoulos G, Rankinen T, Neufeld D, Rice T, Province M, Leon A et al. A polymorphism in the human agouti-related protein is associated with late-onset obesity. J Clin Endocrinol Metab 2002; 87: 4198–4202.

    Article  CAS  PubMed  Google Scholar 

  25. Rotimi C, Dunston G, Berg K, Akinsete O, Amoah A, Owusu S et al. In search of susceptibility genes for type 2 diabetes in West Africa: the design and results of the first phase of the AADM study. Ann Epidemiol 2001; 11: 51–58.

    Article  CAS  PubMed  Google Scholar 

  26. Luke A, Durazo-Arvizu R, Rotimi C, Prewitt T, Forrester T, Wilks R et al. Relation between body mass index and body fat in black population samples from Nigeria, Jamaica, and the United States. Am J Epidemiol 1997; 145: 620–628.

    Article  CAS  PubMed  Google Scholar 

  27. Pan W, Flegal K, Chang H, Yeh W, Yeh C, Lee W . Body mass index and obesity-related metabolic disorders in Taiwanese and US whites and blacks: implications for definition of overweight and obesity for Asians. Am J Clin Nutr 2004; 79: 31–39.

    Article  CAS  PubMed  Google Scholar 

  28. Storey J, Tibshirani R . Statistical significance for genomewide studies. Proc Natl Acad Sci 2003; 100: 9440–9445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Argyropoulos G, Rankinen T, Bai F, Rice T, Province M, Leon A et al. The agouti-related protein and body fatness in humans. Int J Obes Relat Metab Disord 2003; 27: 276–280.

    Article  CAS  PubMed  Google Scholar 

  30. Morton G, Schwartz M . The NPY/AgRP neuron and energy homeostasis. Int J Obes Relat Metab Disord 2001; 25: S56–S62.

    Article  CAS  PubMed  Google Scholar 

  31. Boden G . Free fatty acids (FFA), a link between obesity and insulin resistance. Front Biosci 1998; 3: D169–D175.

    Article  CAS  PubMed  Google Scholar 

  32. Fan W, Dinulescu D, Butler A, Zhou J, Marks D, Cone R . The central melanocortin system can directly regulate serum insulin levels. Endocrinology 2000; 141: 3072–3079.

    Article  CAS  PubMed  Google Scholar 

  33. Roemmich J, Clark P, Berr S, Mai V, Mantzoros C, Flier J et al. Gender differences in leptin levels during puberty are related to the subcutaneous fat depot and sex steroids. Am J Physiol 1998; 275: E543–E551.

    CAS  PubMed  Google Scholar 

  34. Charbonneau C, Bai F, Richards B, Argyropoulos G . Central and peripheral interactions between the agouti related protein and leptin. Biochem Biophys Res Commun 2004; 319: 518–524.

    Article  CAS  PubMed  Google Scholar 

  35. Bai F, Rankinen T, Charbonneau C, Belsham D, Rao D, Bouchard C et al. Functional dimorphism of two hAgRP promoter SNPs in linkage disequilibrium. J Med Genet 2004; 41: 350–353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Schoeller D, Luke A . Bioelectrical impedance analysis prediction equations differ between African Americans and Caucasians, but it is not clear why. Ann NY Acad Sci 2000; 904: 225–226.

    Article  CAS  PubMed  Google Scholar 

  37. Chumlea W, Siervogel R, Yixun W, Hall G, Guo S . Bioelectrical impedance spectroscopy and body composition. Ann NY Acad Sci 2000; 904: 210–213.

    Article  CAS  PubMed  Google Scholar 

  38. Ward L, Heitmann B, Craig P, Stroud D, Azinge E, Jebb S et al. Association between ethnicity, body mass index, and bioelectrical impedance. Implications for the population specificity of prediction equations. Ann NY Acad Sci 2000; 904: 199–202.

    Article  CAS  PubMed  Google Scholar 

  39. Loos R, Rankinen T, Tremblay A, Perusse L, Chagnon Y, Bouchard C . Melanocortin-4 receptor gene and physical activity in the Quebec Family Study. Int J Obes Relat Metab Disord 2005; 29: 420–428.

    Article  CAS  Google Scholar 

  40. Chen G, Adeyemo A, Johnson T, Zhou J, Amoah A, Owusu S et al. A genome-wide scan for quantitative trait loci linked to obesity phenotypes among West Africans. Int J Obes Relat Metab Disord 2005; 29: 255–259.

    Article  CAS  Google Scholar 

  41. Rotimi C, Chen G, Adeyemo A, Furbert-Harris P, Guass D, Zhou J et al. A genome-wide search for type 2 diabetes susceptibility genes in West Africans. Diabetes 2004; 53: 838–841.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to all individuals who volunteered for this study. We thank Kofi Bonney for programming assistance. Support for this work was provided by the National Institutes of Health Office of Research on Minority Health (ORMH), the National Center for Research Resources (NCRR) and the National Human Genome Research Institute (NHGRI).

Author information

Author notes

  1. C Bonilla and R K Panguluri: These authors contributed equally to the work.

Authors and Affiliations

  1. National Human Genome Center at Howard University, Washington, DC, USA

    C Bonilla, R K Panguluri, L Taliaferro-Smith, G Chen, A A Adeyemo, Y Chen, G M Dunston, C Rotimi & R A Kittles

  2. Pennington Biomedical Research Center, Baton Rouge, LA, USA

    G Argyropoulos

  3. College of Medicine, University of Ibadan, Ibadan, Nigeria

    A A Adeyemo & F Abbiyesuku

  4. Department of Medicine, University of Ghana Medical School, Accra, Ghana

    A Amoah & S Owusu

  5. Department of Medicine, University of Science and Technology, Kumasi, Ghana

    J Acheampong, K Agyenim-Boateng & B A Eghan Jr

  6. Department of Medicine, University of Nigeria Teaching Hospital, Enugu, Nigeria

    J Oli & G Okafor

  7. College of Medicine, Endocrine and Metabolic Unit, University of Lagos, Lagos, Nigeria

    T Johnson, T Rufus & O Fasanmade

  8. National Human Genome Research Institute, NIH, Bethesda, MD, USA

    F S Collins

Authors
  1. C Bonilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R K Panguluri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Taliaferro-Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Argyropoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A A Adeyemo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Amoah
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Owusu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J Acheampong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. K Agyenim-Boateng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. B A Eghan Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J Oli
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. G Okafor
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. F Abbiyesuku
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. T Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. T Rufus
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. O Fasanmade
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Y Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. F S Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. G M Dunston
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. C Rotimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. R A Kittles
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R A Kittles.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bonilla, C., Panguluri, R., Taliaferro-Smith, L. et al. Agouti-related protein promoter variant associated with leanness and decreased risk for diabetes in West Africans. Int J Obes 30, 715–721 (2006). https://doi.org/10.1038/sj.ijo.0803047

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0803047

Keywords

This article is cited by

Search

Advanced search

Quick links