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.

  • Paper
  • Published:

Association of dopamine D2 receptor polymorphisms Ser311Cys and TaqIA with obesity or type 2 diabetes mellitus in Pima Indians

International Journal of Obesity volume 24, pages 1233–1238 (2000)Cite this article

Abstract

OBJECTIVES: To investigate whether (a) variants within the dopamine D2 receptor gene (DRD2) are associated with obesity and type 2 diabetes in Pima Indians, and (b) whether variation in this gene could be responsible for previously observed linkage to these phenotypes, at chromosome location 11q23–24, in this population.

DESIGN: Two single nucleotide polymorphisms (SNPs), Ser311Cys and TaqIA, within the DRD2 gene were genotyped by allelic discrimination PCR in subjects who had provided evidence of linkage to diabetes and obesity in an autosome-wide scan.

SUBJECTS: A total of 1187 subjects were genotyped, including 947 full heritage Pima Indians (80%). Descriptive statistics for all subjects analyzed, for whom clinical data were available, were (mean±s.d.): age at time of last exam=41±15 y; birth year=1950±14; age-sex-adjusted body mass index (BMI; adjusted to a mean age of 35 y)=36±8 kg/m2; male=44%; diabetic=57%. For full heritage Pimas only: age=43±15 y; birth year=1948±14; sex–age-adjusted BMI=36±8 kg/m2; male=43%; diabetic=59%.

RESULTS: Neither polymorphism was significantly associated with diabetes in full heritage Pimas. Individuals with a ‘CG’ genotype at the Ser311Cys SNP had a higher BMI than those with a ‘CC’ genotype (36.7 vs 35.5 kg/m2, P=0.04). Linkage analysis of BMI, adjusted for either polymorphism, resulted in LOD scores that were similar to those obtained without adjustment.

CONCLUSION: Heterozygotes at the Ser311Cys DRD2 polymorphism had a slightly higher BMI than homozygotes, however neither the Ser311Cys nor the TaqIA polymorphism accounted for the linkage with BMI on chromosome 11 in Pima Indians.

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

References

  1. Mietus-Snyder M, Charmley P, Korf B, Ladias JA, Gatti RA, Karathanasis SK . Genetic linkage of the human apolipoprotein AI-CIII-AIV gene cluster and the neural cell adhesion molecule (NCAM) gene Genomics 1990 7: 633–637.

    Article  CAS  Google Scholar 

  2. Eubanks JH, Djabali M, Selleri L et al. Structure and linkage of the D2 dopamine receptor and neural cell adhesion molecule genes on human chromosome 11q23 Genomics 1992 14: 1010–1018.

    Article  CAS  Google Scholar 

  3. Esni F, Taljedal IB, Perl AK, Cremer H, Christofori G, Semb H . Neural cell adhesion molecule (N-CAM) is required for cell type segregation and normal ultrastructure in pancreatic islets J Cell Biol 1999 144: 325–337.

    Article  CAS  Google Scholar 

  4. Tunnacliffe A, Jones C, Le Paslier D et al. Localization of Jacobsen syndrome breakpoints on a 40-Mb physical map of distal chromosome 11q Genome Res 1999 9: 44–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Luo S, Meier AH, Cincotta AH . Bromocriptine reduces obesity, glucose intolerance and extracellular monoamine metabolite levels in the ventromedial hypothalamus of Syrian hamsters Neuroendocrinology 1998 68: 1–10.

    Article  CAS  Google Scholar 

  6. Luo S, Liang Y, Cincotta AH . Intracerebroventricular administration of bromocriptine ameliorates the insulin-resistant/ glucose-intolerant state in hamsters Neuroendocrinology 1999 69: 160–166.

    Article  CAS  Google Scholar 

  7. Balcioglu A, Wurtman RJ . Effects of phentermine on striatal dopamine and serotonin release in conscious rats: in vivo microdialysis study Int J Obes Relat Metab Disord 1998 22: 325–328.

    Article  CAS  Google Scholar 

  8. Balcioglu A, Wurtman RJ . Dexfenfluramine enhances striatal dopamine release in conscious rats via a serotoninergic mechanism J Pharmac Exp Ther 1998 284: 991–997.

    CAS  Google Scholar 

  9. Figlewicz DP, Patterson TA, Johnson LB, Zavosh A, Israel PA, Szot P . Dopamine transporter mRNA is increased in the CNS of Zucker fatty (fa/fa) rats Brain Res Bull 1998 46: 199–202.

    Article  CAS  Google Scholar 

  10. Meguid MM, Fetissov SO, Miyata G, Torelli GF . Feeding pattern in obese Zucker rats after dopaminergic and serotonergic LHA grafts Neuroreport 1999 10: 1049–1053.

    Article  CAS  Google Scholar 

  11. Knowler WC, Saad MF, Pettitt DJ, Nelson RG, Bennett PH . Determinants of diabetes mellitus in the Pima Indians Diabetes Care 1993 16: 216–227.

    Article  CAS  Google Scholar 

  12. Comings DE, Flanagan SD, Dietz G, Muhleman D, Knell E, Gysin R . The dopamine D2 receptor (DRD2) as a major gene in obesity and height Biochem Med Metab Biol 1993 50: 176–185.

    Article  CAS  Google Scholar 

  13. Noble EP, Noble RE, Ritchie T et al. D2 dopamine receptor gene and obesity Int J Eat Disord 1994 15: 205–217.

    Article  CAS  Google Scholar 

  14. Comings DE, Gade R, MacMurray JP, Muhleman D, Peters WR . Genetic variants of the human obesity (OB) gene: association with body mass index in young women, psychiatric symptoms, and interaction with the dopamine D2 receptor (DRD2) gene Mol Psychiatry 1996 1: 325–335.

    CAS  PubMed  Google Scholar 

  15. Blum K, Braverman ER, Wood RC et al. Increased prevalence of the Taq I A1 allele of the dopamine receptor gene (DRD2) in obesity with comorbid substance use disorder: a preliminary report Pharmacogenetics 1996 6: 297–305.

    Article  CAS  Google Scholar 

  16. Hanson RL, Ehm MG, Pettitt DJ et al. An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians Am J Hum Genet 1998 63: 1130–1138.

    Article  CAS  Google Scholar 

  17. Dupont S, Gallina S, Dina C et al. Genome wide search for non insulin dependent diabetes mellitus (NIDDM) susceptibility genes in a large pedigree from France Diabetes 1999 48: A187.

    Google Scholar 

  18. Jaquish CE, Fabsitz RR, Larson MG, Cupples LA, Myers RH, Levy D . A genome scan for quantitative trait loci influencing adiposity in the Framingham Heart Study Am J Hum Genet 1998 63: A329.

    Article  Google Scholar 

  19. Elbein SC, Hoffman MD, Teng K, Leppert MF, Hasstedt SJ . A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians Diabetes 1999 48: 1175–1182.

    Article  CAS  Google Scholar 

  20. Pérusse L, Rice T, Chagnon YC, Roy S, Locaille M, Ho-Kim M-A, Chagnon M, Province M, Rao DC, Bouchard C . A genome-wide search for genes related to abdominal fat measured by CT-scan in the Québec family Study Obes Res 1999 7: 50.

    Article  Google Scholar 

  21. Wei S, Wei K, Moralejo DH et al. Mapping and characterization of quantitative trait loci for non-insulin-dependent diabetes mellitus with an improved genetic map in the Otsuka Long-Evans Tokushima fatty rat Mamm Genome 1999 10: 249–258.

    Article  CAS  Google Scholar 

  22. Roberts SB, MacLean CJ, Neale MC, Eaves LJ, Kendler KS . Replication of linkage studies of complex traits: an estimation of variation in location estimates Am J Hum Genet 1999 65: 876–884.

    Article  CAS  Google Scholar 

  23. Hauser ER, Boehnke M . Confirmation of linkage results in affected sib-pair linkage analysis for complex genetic traits Am J Hum Genet 1997 61 (Suppl): A278.

    Google Scholar 

  24. Itokawa M, Arinami T, Futamura N, Hamaguchi H, Toru M . A structural polymorphism of human dopamine D2 receptor, D2(Ser311→Cys) Biochem Biophys Res Commun 1993 196: 1369–1375.

    Article  CAS  Google Scholar 

  25. Cravchik A, Sibley DR, Gejman PV . Functional analysis of the human D2 dopamine receptor missense variants J Biol Chem 1996 271: 26013–26017.

    Article  CAS  Google Scholar 

  26. Bennett PH, Burch TA, Miller M . Diabetes mellitus in American (Pima) Indians Lancet 1971 ii: 125–128.

    Article  Google Scholar 

  27. WHO Study Group on Diabetes Mellitus. Diabetes mellitus, WHO Technical Report no. 727 World Health Organization: Geneva 1985.

  28. Williams RC, Knowler WC, Pettitt DJ, Long JC, Rokala DA, Polesky HF, Hackenberg RA, Steinberg AG, Bennett PH . The magnitude and origin of European-American admixture in the Gila River Indian Community of Arizona: a union of genetics and demography Am J Hum Genet 1992 51: 101–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Livak KJ, Flood SJA, Marmaro J, Giusti W, Deetz K . Oligonucleotides with fluorescent dyes at opposite ends provide a quenched probe system useful for detecting PCR product and nucleic acid hybridization PCR Methods Appl 1995 4: 357–362.

    Article  CAS  Google Scholar 

  30. Taqman® Allelic Discrimination . Demonstration kit. Protocol P/N 4303267 Rev. B. PE Applied Biosystems 1999.

  31. Zeger SL, Liang KY . Longitudinal data analysis for discrete and continuous outcomes Biometrics 1986 42: 121–130.

    Article  CAS  Google Scholar 

  32. Kleinbaum DG, Kupper LL, Morgenstern H . Modeling: theoretical considerations. In: Kleinbaum DG, Kupper LL, Morgenstern H (eds) Epidemiologic Research: Principles and Quantitative Methods Van Nostrand Reinhold: New York 1982, pp 419–446.

    Google Scholar 

  33. Amos CI . Robust variance-components approach for assessing genetic linkage in pedigrees Am J Hum Genet 1994 54: 535–543.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Fulker DW, Cherny SS, Cardon LR . Multipoint interval mapping of quantitative traits using sib-pairs Am J Hum Genet 1995 56: 1224–1233.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Noble EP . The D2 dopamine receptor gene: a review of association studies in alcoholism and phenotypes Alcohol 1998 16: 33–45.

    Article  CAS  Google Scholar 

  36. Almasy L, Blangero J . Identifying a functional polymorphism through linkage analysis conditional on measured genotype Genet Epidemiol 1999 17: 222–223.

    Google Scholar 

  37. Knowler WC, Williams RC, Pettitt DJ, Steinberg AG . Gm3; 5, 13, 14 and type 2 diabetes mellitus: an association in American Indians with genetic admixture Am J Hum Genet 1988 43: 520–526.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sheffield VC, Stone EM, Carmi R . Use of isolated inbred human populations for identification of disease genes Trends Genet 1998 14: 391–396.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the members of the Gila River Indian Community for their participation in these studies. Staff members of the Phoenix Epidemiology and Clinical Research Branch collected the DNA and pedigree data.

Author information

Authors and Affiliations

  1. Phoenix Epidemiology and Clinical Research Branch, National Institute of Digestive Diabetes and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA

    CP Jenkinson, R Hanson, K Cray, C Wiedrich, WC Knowler, C Bogardus & L Baier

Authors
  1. CP Jenkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Hanson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Cray
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Wiedrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. WC Knowler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Bogardus
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Baier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to CP Jenkinson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jenkinson, C., Hanson, R., Cray, K. et al. Association of dopamine D2 receptor polymorphisms Ser311Cys and TaqIA with obesity or type 2 diabetes mellitus in Pima Indians. Int J Obes 24, 1233–1238 (2000). https://doi.org/10.1038/sj.ijo.0801381

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0801381

Keywords

This article is cited by

Search

Advanced search

Quick links