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:

Haplotypes in the phospholipid transfer protein gene are associated with obesity-related phenotypes: the Québec Family Study

International Journal of Obesity volume 29, pages 1338–1345 (2005)Cite this article

Abstract

BACKGROUND:

The phospholipid transfer protein (PLTP) may play a role in body fat regulation.

OBJECTIVE:

To investigate the association between PLTP genetic variants and obesity-related phenotypes.

METHODS:

Two intronic variants, one in intron 1 (c.−87G>A) and the other in intron 12 (c.1175+68T>G), were genotyped in 811 participants of the Québec Family Study. Nine obesity-related phenotypes were investigated, including body mass index (BMI), obesity (BMI≥30 kg/m2), and waist circumference, percentage of fat, fat mass and fat-free mass measured by hydrostatic weighing as well as total, visceral and subcutaneous abdominal adipose tissue areas assessed by computed tomography. Single markers and haplotypes were tested for associations in family-based designs using the FBAT program.

RESULTS:

The SNP located in intron 1 showed significant associations with obesity, BMI, waist circumference and fat-free mass (P<0.05). The low-frequency allele (A allele) was associated with higher trait values, suggesting that the transmission of this allele is associated with an increased risk of being obese. Significant associations were observed between haplotypes and obesity, waist circumference, percentage of fat and fat-free mass (P<0.05). The transmission of the AT haplotype (frequency=0.180) was positively associated with obesity-related phenotypes. After sequencing the promoter and the coding regions of the PLTP gene, we were unable to identify a mutation that could replicate these results.

CONCLUSION:

Intronic variants of the PLTP gene are significantly associated with obesity-related phenotypes. Considering the number and the relevance of candidate genes surrounding the PLTP locus and the absence of missense polymorphisms in the coding region, the associations could be mediated by a second gene allele in linkage disequilibrium with the marker locus.

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

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Whitmore TE, Day JR, Albers JJ . Localization of the human phospholipid transfer protein gene to chromosome 20q12–q13.1. Genomics 1995; 28: 599–600.

    Article  CAS  Google Scholar 

  2. Albers JJ, Tu AY, Wolfbauer G, Cheung MC, Marcovina SM . Molecular biology of phospholipid transfer protein. Curr Opin Lipidol 1996; 7: 88–93.

    Article  CAS  Google Scholar 

  3. Day JR, Albers JJ, Lofton-Day CE, Gilbert TL, Ching AF, Grant FJ, O'Hara PJ, Marcovina SM, Adolphson JL . Complete cDNA encoding human phospholipid transfer protein from human endothelial cells. J Biol Chem 1994; 269: 9388–9391.

    CAS  PubMed  Google Scholar 

  4. Dusserre E, Moulin P, Vidal H . Differences in mRNA expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues. Biochim Biophys Acta 2000; 1500: 88–96.

    Article  CAS  Google Scholar 

  5. Linder K, Arner P, Flores-Morales A, Tollet-Egnell P, Norstedt G . Differentially expressed genes in visceral or subcutaneous adipose tissue of obese men and women. J Lipid Res 2004; 45: 148–154.

    Article  CAS  Google Scholar 

  6. Huuskonen J, Wohlfahrt G, Jauhiainen M, Ehnholm C, Teleman O, Olkkonen VM . Structure and phospholipid transfer activity of human PLTP: analysis by molecular modeling and site-directed mutagenesis. J Lipid Res 1999; 40: 1123–1130.

    CAS  PubMed  Google Scholar 

  7. Ponsin G, Qu SJ, Fan HZ, Pownall HJ . Structural and functional determinants of human plasma phospholipid transfer protein activity as revealed by site-directed mutagenesis of charged amino acids. Biochemistry 2003; 42: 4444–4451.

    Article  CAS  Google Scholar 

  8. Tall AR, Krumholz S, Olivecrona T, Deckelbaum RJ . Plasma phospholipid transfer protein enhances transfer and exchange of phospholipids between very low density lipoproteins and high density lipoproteins during lipolysis. J Lipid Res 1985; 26: 842–851.

    CAS  PubMed  Google Scholar 

  9. van Tol A . Phospholipid transfer protein. Curr Opin Lipidol 2002; 13: 135–139.

    Article  CAS  Google Scholar 

  10. Huuskonen J, Ehnholm C . Phospholipid transfer protein in lipid metabolism. Curr Opin Lipidol 2000; 11: 285–289.

    Article  CAS  Google Scholar 

  11. Schlitt A, Bickel C, Thumma P, Blankenberg S, Rupprecht HJ, Meyer J, Jiang XC . High plasma phospholipid transfer protein levels as a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol 2003; 23: 1857–1862.

    Article  CAS  Google Scholar 

  12. Kaser S, Sandhofer A, Foger B, Ebenbichler CF, Igelseder B, Malaimare L, Paulweber B, Patsch JR . Influence of obesity and insulin sensitivity on phospholipid transfer protein activity. Diabetologia 2001; 44: 1111–1117.

    Article  CAS  Google Scholar 

  13. Cheung MC, Knopp RH, Retzlaff B, Kennedy H, Wolfbauer G, Albers JJ . Association of plasma phospholipid transfer protein activity with IDL and buoyant LDL: impact of gender and adiposity. Biochim Biophys Acta 2002; 1587: 53–59.

    Article  CAS  Google Scholar 

  14. Dullaart RP, Sluiter WJ, Dikkeschei LD, Hoogenberg K, Van Tol A . Effect of adiposity on plasma lipid transfer protein activities: a possible link between insulin resistance and high density lipoprotein metabolism. Eur J Clin Invest 1994; 24: 188–194.

    Article  CAS  Google Scholar 

  15. Murdoch SJ, Carr MC, Hokanson JE, Brunzell JD, Albers JJ . PLTP activity in premenopausal women. Relationship with lipoprotein lipase, HDL, LDL, body fat, and insulin resistance. J Lipid Res 2000; 41: 237–244.

    CAS  PubMed  Google Scholar 

  16. Murdoch SJ, Kahn SE, Albers JJ, Brunzell JD, Purnell JQ . PLTP activity decreases with weight loss: changes in PLTP are associated with changes in subcutaneous fat and FFA but not IAF or insulin sensitivity. J Lipid Res 2003; 44: 1705–1712.

    Article  CAS  Google Scholar 

  17. Ashrafi K, Chang FY, Watts JL, Fraser AG, Kamath RS, Ahringer J, Ruvkun G . Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 2003; 421: 268–272.

    Article  CAS  Google Scholar 

  18. Lee JH, Reed DR, Li WD, Xu W, Joo EJ, Kilker RL, Nanthakumar E, North M, Sakul H, Bell C, Price RA . Genome scan for human obesity and linkage to markers in 20q13. Am J Hum Genet 1999; 64: 196–209.

    Article  CAS  Google Scholar 

  19. Norman RA, Tataranni PA, Pratley R, Thompson DB, Hanson RL, Prochazka M, Baier L, Ehm MG, Sakul H, Foroud T, Garvey WT, Burns D, Knowler WC, Bennett PH, Bogardus C, Ravussin E . Autosomal genomic scan for loci linked to obesity and energy metabolism in Pima Indians. Am J Hum Genet 1998; 62: 659–668.

    Article  CAS  Google Scholar 

  20. Lembertas AV, Perusse L, Chagnon YC, Fisler JS, Warden CH, Purcell-Huynh DA, Dionne FT, Gagnon J, Nadeau A, Lusis AJ, Bouchard C . Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the human homologous region 20q. J Clin Invest 1997; 100: 1240–1247.

    Article  CAS  Google Scholar 

  21. Pomp D . Genetic dissection of obesity in polygenic animal models. Behav Genet 1997; 27: 285–306.

    Article  CAS  Google Scholar 

  22. Mehrabian M, Wen PZ, Fisler J, Davis RC, Lusis AJ . Genetic loci controlling body fat, lipoprotein metabolism, and insulin levels in a multifactorial mouse model. J Clin Invest 1998; 101: 2485–2496.

    Article  CAS  Google Scholar 

  23. van Haperen R, van Tol A, van Gent T, Scheek L, Visser P, van der Kamp A, Grosveld F, de Crom R . Increased risk of atherosclerosis by elevated plasma levels of phospholipid transfer protein. J Biol Chem 2002; 277: 48938–48943.

    Article  CAS  Google Scholar 

  24. Jiang XC, Qin S, Qiao C, Kawano K, Lin M, Skold A, Xiao X, Tall AR . Apolipoprotein B secretion and atherosclerosis are decreased in mice with phospholipid-transfer protein deficiency. Nat Med 2001; 7: 847–852.

    Article  CAS  Google Scholar 

  25. Oram JF, Wolfbauer G, Vaughan AM, Tang C, Albers JJ . Phospholipid transfer protein interacts with and stabilizes ABCA1 and enhances cholesterol efflux from cells. J Biol Chem 2003; 278: 52379–52385.

    Article  CAS  Google Scholar 

  26. Bouchard C . Genetic epidemiology, association, and sib-pair linkage: results from the Québec Family Study. In: Bray GA, Ryan DH (eds). Molecular and Genetic Aspects of Obesity. Baton Rouge, LA: Louisiana State University Press; 1996. pp 470–481.

    Google Scholar 

  27. The Airlie (VA) Consensus Conference. In: Lohman T, Roche A, Martorel R (eds). Standardization of Anthropometric Measurements. Champaign, IL: Human Kinetics; 1988. pp 39–80.

  28. Behnke AR, Wilmore JH . Evaluation and Regulation of Body Build and Composition. Englewood Cliffs, NJ: Prentice-Hall; 1974.

    Google Scholar 

  29. Meneely GR, Kaltreider NL . Volume of the lung determined by helium dilution. J Clin Invest 1949; 28: 129–139.

    Article  CAS  Google Scholar 

  30. Siri WE . The gross composition of the body. Adv Biol Med Phys 1956; 4: 239–280.

    Article  CAS  Google Scholar 

  31. Despres JP, Prud'homme D, Pouliot MC, Tremblay A, Bouchard C . Estimation of deep abdominal adipose-tissue accumulation from simple anthropometric measurements in men. Am J Clin Nutr 1991; 54: 471–477.

    Article  CAS  Google Scholar 

  32. den Dunnen JT, Antonarakis SE . Nomenclature for the description of human sequence variations. Hum Genet 2001; 109: 121–124.

    Article  CAS  Google Scholar 

  33. Sun X, Ding H, Hung K, Guo B . A new MALDI-TOF based mini-sequencing assay for genotyping of SNPS. Nucleic Acids Res 2000; 28: E68.

    Article  CAS  Google Scholar 

  34. Tu AY, Wolfbauer G, Albers JJ . Functional characterization of the promoter region of the human phospholipid transfer protein gene. Biochem Biophys Res Commun 1995; 217: 705–711.

    Article  CAS  Google Scholar 

  35. Bonfield JK, Smith K, Staden R . A new DNA sequence assembly program. Nucleic Acids Res 1995; 23: 4992–4999.

    Article  CAS  Google Scholar 

  36. Laird NM, Horvath S, Xu X . Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000; 19 (Suppl 1): S36–S42.

    Article  Google Scholar 

  37. Lunetta KL, Faraone SV, Biederman J, Laird NM . Family-based tests of association and linkage that use unaffected sibs, covariates, and interactions. Am J Hum Genet 2000; 66: 605–614.

    Article  CAS  Google Scholar 

  38. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS . Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 2003; 423: 293–298.

    Article  CAS  Google Scholar 

  39. Tokuhiro S, Yamada R, Chang X, Suzuki A, Kochi Y, Sawada T, Suzuki M, Nagasaki M, Ohtsuki M, Ono M, Furukawa H, Nagashima M, Yoshino S, Mabuchi A, Sekine A, Saito S, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K . An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet 2003; 35: 341–348.

    Article  CAS  Google Scholar 

  40. Ozaki K, Ohnishi Y, Iida A, Sekine A, Yamada R, Tsunoda T, Sato H, Hori M, Nakamura Y, Tanaka T . Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet 2002; 32: 650–654.

    Article  CAS  Google Scholar 

  41. Wolfbauer G, Albers JJ, Oram JF . Phospholipid transfer protein enhances removal of cellular cholesterol and phospholipids by high-density lipoprotein apolipoproteins. Biochim Biophys Acta 1999; 1439: 65–76.

    Article  CAS  Google Scholar 

  42. Langmann T, Klucken J, Reil M, Liebisch G, Luciani MF, Chimini G, Kaminski WE, Schmitz G . Molecular cloning of the human ATP-binding cassette transporter 1 (hABC1): evidence for sterol-dependent regulation in macrophages. Biochem Biophys Res Commun 1999; 257: 29–33.

    Article  CAS  Google Scholar 

  43. Snyder EE, Walts B, Perusse L, Chagnon YC, Weisnagel SJ, Rankinen T, Bouchard C . The human obesity gene map: the 2003 update. Obes Res 2004; 12: 369–439.

    Article  CAS  Google Scholar 

  44. Boucher N, Lanouette CM, Larose M, Perusse L, Bouchard C, Chagnon YC . A +2138InsCAGACC polymorphism of the melanocortin receptor 3 gene is associated in human with fat level and partitioning in interaction with body corpulence. Mol Med 2002; 8: 158–165.

    Article  CAS  Google Scholar 

  45. Bottini E, Gloria-Bottini F . Adenosine deaminase and body mass index in non-insulin-dependent diabetes mellitus. Metabolism 1999; 48: 949–951.

    Article  CAS  Google Scholar 

  46. Wilson BD, Ollmann MM, Kang L, Stoffel M, Bell GI, Barsh GS . Structure and function of ASP, the human homolog of the mouse agouti gene. Hum Mol Genet 1995; 4: 223–230.

    Article  CAS  Google Scholar 

  47. Tanaka T, Yoshida N, Kishimoto T, Akira S . Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J 1997; 16: 7432–7443.

    Article  CAS  Google Scholar 

  48. Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ, Tremblay ML, Kennedy BP . Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 1999; 283: 1544–1548.

    Article  CAS  Google Scholar 

  49. Cai A, Hyde JF . The human growth hormone-releasing hormone transgenic mouse as a model of modest obesity: differential changes in leptin receptor (OBR) gene expression in the anterior pituitary and hypothalamus after fasting and OBR localization in somatotrophs. Endocrinology 1999; 140: 3609–3614.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the Canadian Institutes of Health Research (MOP-13960). We would like to express our gratitude to the subjects for their excellent collaboration and to the staff of the Physical Activity Sciences Laboratory for their contribution to the study. Y Bossé is the recipient of a studentship from the Canadian Institutes of Health Research. L Bouchard is recipient of a studentship from the ‘Fonds de la recherche en santé du Québec (FRSQ)’. MC Vohl is a research scholar of the FRSQ. JP Després is chair professor of human nutrition, lipidology and prevention of cardiovascular disease supported by Provigo and Pfizer Canada. C Bouchard is partially funded by the George A Bray Chair in Nutrition.

Author information

Authors and Affiliations

  1. Lipid Research Center, CHUL Research Center, Laval University, Québec, Canada

    Y Bossé & M-C Vohl

  2. Department of Food Sciences and Nutrition, Laval University, Québec, Canada

    Y Bossé, J-P Després & M-C Vohl

  3. Department of Social and Preventive Medicine, Division of Kinesiology, Laval University, Québec, Canada

    L Bouchard & L Pérusse

  4. The Quebec Heart Institute, Québec, Canada

    J-P Després

  5. Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA

    C Bouchard

Authors
  1. Y Bossé
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Bouchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J-P Després
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Bouchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L Pérusse
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M-C Vohl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M-C Vohl.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bossé, Y., Bouchard, L., Després, JP. et al. Haplotypes in the phospholipid transfer protein gene are associated with obesity-related phenotypes: the Québec Family Study. Int J Obes 29, 1338–1345 (2005). https://doi.org/10.1038/sj.ijo.0803010

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0803010

Keywords

This article is cited by

Search

Advanced search

Quick links