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:

Single nucleotide polymorphism identification in candidate gene systems of obesity

The Pharmacogenomics Journal volume 1, pages 193–203 (2001)Cite this article

Abstract

We have constructed a large panel of single nucleotide polymorphisms (SNP) identified in 68 candidate genes for obesity. Our panel combines novel SNP identification methods based on EST data, with public SNP data from large-scale genomic sequencing, to produce a total of 218 SNPs in the coding regions of obesity candidate genes, 178 SNPs in untranslated regions, and over 1000 intronic SNPs. These include new non-conservative amino acid changes in thyroid receptor beta, esterase D, acid phosphatase 1. Our data show evidence of negative selection among these polymorphisms implying functional impacts of the non-conservative mutations. Comparison of overlap between SNPs identified independently from EST data vs genomic sequencing indicate that together they may constitute about one half of the actual total number of amino acid polymorphisms in these genes that are common in the human population (defined here as a population allele frequency above 5%). We have analyzed our polymorphism panel to construct a database of detailed information about their location in the gene structure and effect on protein coding, available on the web at http://www.bioinformatics.ucla.edu/snp/obesity. We believe this panel can serve as a valuable new resource for genetic and pharmacogenomic studies of the causes of obesity.

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
Figure 2

Similar content being viewed by others

Abbreviations

SNP:

Single Nucleotide Polymorphism

cSNP:

coding region Single Nucleotide Polymorphism

eSNP:

expressed Single Nucleotide Polymorphism

UTR:

untranslated region

References

  1. Venter JC et al. The sequence of the human genome Science 2001 291: 1304–1351

    Article  CAS  Google Scholar 

  2. International Human Genome Sequencing Consortium . Initial sequencing and analysis of the human genome Nature 2001 409: 860–921

    Article  Google Scholar 

  3. Weiss KM, Terwilliger JD . How many diseases does it take to map a gene with SNPs? Nature Genet 2000 26: 151–157

    Article  CAS  Google Scholar 

  4. Halushka MK et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis Nature Genet 1999 22: 239–246

    Article  CAS  Google Scholar 

  5. Prevention C . f.D.C.a. Update: Prevalence of overweight among children, adolescents, and adults—United States, 1988–1994 MMWR Weekly 1997 46: 199–202

    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 Nature Genet 1998 20: 113–114

    Article  CAS  Google Scholar 

  7. Yeo GS et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity Nature Genet 1998 20: 111–112

    Article  CAS  Google Scholar 

  8. Clément K et al . A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction Nature 1998 392: 398–401

    Article  Google Scholar 

  9. Ozata M, Ozdemir IC, Licinio J . Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decrased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects J Clin Endocrinol Metab 1999 84: 3686–3695

    Article  CAS  Google Scholar 

  10. Montague CT et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans Nature 1997 387: 903–908

    Article  CAS  Google Scholar 

  11. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD . A leptin missense mutation associated with hypogonadism and morbid obesity Nature Genet 1998 18: 213–215

    Article  CAS  Google Scholar 

  12. Krude H et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans Nature Genet 1998 19: 155–157

    Article  CAS  Google Scholar 

  13. Jackson RS et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene Nature Genet 1997 16: 303–306

    Article  CAS  Google Scholar 

  14. Scheen AJ, Lefebvre PJ . Pharmacological treatment of obesity: present status Int J Obes Relat Metab Disord 1999 23 Suppl 1: 47–53

    Article  CAS  Google Scholar 

  15. Stock MJ . Sibutramine: a review of the pharmacology of a novel anti-obesity agent Int J Obes Relat Metab Disord 1997 21 Suppl 1: S25–29

    CAS  PubMed  Google Scholar 

  16. Van Gaal LF, Wauters MA, Peiffer FW, De Leeuw IH . Sibutramine and fat distribution: is there a role for pharmacotherapy in abdominal/visceral fat reduction? Int J Obes Relat Metab Disord 1998 22 Suppl 1: S38–42

    CAS  PubMed  Google Scholar 

  17. Weintraub M, Rubio A, Golik A, Byrne L, Scheinbaum ML . Sibutramine in weight control: a dose-ranging, efficacy study Clin Pharmacol Ther 1991 50: 330–337

    Article  CAS  Google Scholar 

  18. Flier JS, Maratos FE . Obesity and the hypothalamus: novel peptides for new pathways Cells 1998 92: 437–440

    Article  CAS  Google Scholar 

  19. Chagnon YC, Perusse L . Weisnagel SJ, Rankinen T, Bouchard C. The human obesity gene map: the 1999 update Obes Res 2000 8: 89–117

    Article  CAS  Google Scholar 

  20. Elmquist JK, Maratos-Flier E, Saper CB, Flier JS . Unraveling the central nervous system pathways underlying responses to leptin Nature Neurosci 1998 1: 445–450

    Article  CAS  Google Scholar 

  21. Woods SC, Schwartz MW, Baskin DG, Seeley RJ . Food intake and the regulation of body weight Annu Rev Psychol 2000 51: 255–277

    Article  CAS  Google Scholar 

  22. Woods SC, Seeley RJ . Adiposity signals and the control of energy homeostasis Nutrition 2000 16: 894–902

    Article  CAS  Google Scholar 

  23. Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG . Central nervous system control of food intake Nature 2000 404: 661–671

    Article  CAS  Google Scholar 

  24. Thorburn AW, Proietto J . Neuropeptides, the hypothalamus and obesity: insights into the central control of body weight Pathology 1998 30: 229–236

    Article  CAS  Google Scholar 

  25. Nickerson DA et al. Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene Genome Res 2000 10: 1532–1545

    Article  CAS  Google Scholar 

  26. Tang J et al. TAPI polymorphisms in several human ethnic groups: characteristics, evolution, and genotyping strategies Hum Immunol 2001 62: 256–268

    Article  CAS  Google Scholar 

  27. Irizarry K et al. Genome-wide analysis of single-nucleotide polymorphisms in human expressed sequences Nature Genet 2000 26: 233–236

    Article  CAS  Google Scholar 

  28. Reference deleted in proof

  29. Bairoch A, Apweiler R . The SWISS-PROT protein sequence data bank and its supplement TrEMBL in 1998 Nucleic Acids Res 1998 26: 38–42

    Article  CAS  Google Scholar 

  30. International SNP Map Working Group . A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms Nature 2001 409: 928–933

    Article  Google Scholar 

  31. Sherry ST, Ward M, Sirotkin K . dbSNP-database for single nucleotide polymorphisms and other classes of minor genetic variation Genome Res 1999 9: 677–679

    CAS  PubMed  Google Scholar 

  32. Ewing B, Hillier L, Wendl MC, Green P . Base-calling of automated sequencer traces using phred. I. Accuracy assessment Genome Res 1998 8: 175–185

    Article  CAS  Google Scholar 

  33. Ewing B, Green P . Base-calling of automated sequencer traces using phred. II. Error probabilities Genome Res 1998 8: 186–194

    Article  CAS  Google Scholar 

  34. Boguski MS, Lowe TM, Tolstoshev CM . dbEST—database for ‘expressed sequence tags’ Nature Genet 1993 4: 332–333

    Article  CAS  Google Scholar 

  35. Turki J, Pak J, Green SA, Martin RJ, Liggett SB . Genetic polymorphisms of the beta-2-adrenergic receptor in nocturnal and nonnocturnal asthma: evidence that gly16 correlates with the nocturnal phenotype J Clin Invest 1995 95: 1635–1641

    Article  CAS  Google Scholar 

  36. Large V et al. Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function J Clin Invest 1997 100: 3005–3013

    Article  CAS  Google Scholar 

  37. Thompson DB et al. Association of the GLN223ARG polymorphism in the leptin receptor gene with plasma leptin levels, insulin secretion and NIDDM in Pima Indians Diabetolia 1997 40: A177

    Google Scholar 

  38. Quinton ND, Lee AJ, Ross RJM, Eastell R, Blakemore AIF . A single nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat mass and leptin levels in postmenopausal Caucasian women Hum Genet 2001 108: 233–236

    Article  CAS  Google Scholar 

  39. Hegele RA et al. Paraoxonase-2 gene (PON2) G148 variant associated with elevated fasting plasma glucose in noninsulin-dependent diabetes mellitus J Clin Endocr Metab 1997 82: 3373–3377

    CAS  PubMed  Google Scholar 

  40. Sanghera DK, Aston CE, Saha N, Kamboh MI . DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease Am J Hum Genet 1998 62: 36–44

    Article  CAS  Google Scholar 

  41. Lee C, Grasso C, Sharlow M . Multiple sequence alignment using partial order graphs Bioinformatics (in press)

Download references

Acknowledgements

This work was supported by the following grants and awards: Department of Energy grant DEFG0387ER60615 to CL, Searle Scholar Award to CL, NIH grants K30HL0426, R01DK58851, U01GM61394 to JL, Dana Foundation award to JL, Stanley Foundation award to JL, NIH grants P50AT00151–020002 and R21MH/NS62777 to M-LW, NARSAD award to M-LW, support for KI from USPHS National Research Service Award GM08375, and support for KI from NSF IGERT award number 9987641.

Author information

Authors and Affiliations

  1. Dept of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    K Irizarry, G Hu & C J Lee

  2. Laboratory of Pharmacogenomics, Neuropsychiatric Institute, University of California, Los Angeles, CA, USA

    M-L Wong & J Licinio

  3. UCLA-DOE Laboratory for Structural Biology and Molecular Medicine, University of California, Los Angeles, CA, USA

    K Irizarry, G Hu & C J Lee

Authors
  1. K Irizarry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M-L Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Licinio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C J Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C J Lee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Irizarry, K., Hu, G., Wong, ML. et al. Single nucleotide polymorphism identification in candidate gene systems of obesity. Pharmacogenomics J 1, 193–203 (2001). https://doi.org/10.1038/sj.tpj.6500042

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500042

Keywords

This article is cited by

Search

Advanced search

Quick links