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:

The PPAR alpha gene is associated with triglyceride, low-density cholesterol and inflammation marker response to fenofibrate intervention: the GOLDN study

The Pharmacogenomics Journal volume 13, pages 312–317 (2013)Cite this article

Subjects

Abstract

As a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fenofibrate favorably modulates dyslipidemia and inflammation markers, which are associated with cardiovascular risk. To determine whether variation in the PPARα receptor gene was associated with lipid and inflammatory marker response, we conducted a 3-week trial of fenofibrate in 861 men and women. Mixed linear models that controlled for age and sex, as well as family pedigree and study center, were constructed using single-nucleotide polymorphisms (SNPs) in the PPARα gene as predictors and changes in fasting triglycerides (TGs), cholesterol and inflammatory markers as outcomes. Significant associations with low-density cholesterol and interleukin-2 (P<0.001) responses to fenofibrate were found. Although there were suggestive associations with tumor necrosis factor-alpha and TG responses (P<0.05), these did not survive the correction for multiple testing. We conclude that variants in the PPARα gene may contribute to future pharmacogenomic paradigms seeking to predict fenofibrate responders from both an anti-dyslipidemic and anti-inflammatory perspective.

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

References

  1. Krauss RM . Triglycerides and atherogenic lipoproteins: rationale for lipid management. Am J Med 1998; 105: 58S–62S.

    Article  CAS  PubMed  Google Scholar 

  2. Wilson PW, Garrison RJ, Castelli WP, Feinleib M, McNamara PM, Kannel WB . Prevalence of coronary heart disease in the Framingham Offspring Study: role of lipoprotein cholesterols. Am J Cardiol 1980; 46: 649–654.

    Article  CAS  PubMed  Google Scholar 

  3. Ballantyne CM, Nambi V . Markers of inflammation and their clinical significance. Atheroscler Suppl 2005; 6: 21–29.

    Article  CAS  PubMed  Google Scholar 

  4. Cesari M, Penninx BW, Newman AB, Newman AB, Kritchevsky SB, Nicklas BJ et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation 2003; 108: 2317–2322.

    Article  CAS  PubMed  Google Scholar 

  5. Cullen P . Evidence that triglycerides are an independent coronary heart disease risk factor. Am J Cardiol 2000; 86: 943–949.

    Article  CAS  PubMed  Google Scholar 

  6. Hausenloy DJ, Yellon DM . Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels. Postgrad Med J 2008; 84: 590–598.

    CAS  PubMed  Google Scholar 

  7. Knopp RH, Walden CE, Warnick GR, Albers JJ, Ginsberg J, McGinnis BM . Effect of fenofibrate treatment on plasma lipoprotein lipids, high-density lipoprotein cholesterol subfractions, and apolipoproteins B, AI, AII, and E. Am J Med 1987; 83: 75–84.

    Article  CAS  PubMed  Google Scholar 

  8. Sebestjen M, Keber I, Zegura B, Simcic S, Bozic M, Fressart MM et al. Statin and fibrate treatment of combined hyperlipidemia: the effects on some novel risk factors. Thromb Haemost 2004; 92: 1129–1135.

    Article  CAS  PubMed  Google Scholar 

  9. Rosenson RS . Effect of fenofibrate on adiponectin and inflammatory biomarkers in metabolic syndrome patients. Obesity 2009; 17: 504–509.

    Article  CAS  PubMed  Google Scholar 

  10. Rosenson RS, Huskin AL, Wolff DA, Helenowski IB, Rademaker AW . Fenofibrate reduces fasting and postprandial inflammatory responses among hypertriglyceridemia patients with the metabolic syndrome. Atherosclerosis 2008; 198: 381–388.

    Article  CAS  PubMed  Google Scholar 

  11. Jonkers IJ, Mohrschladt MF, Westendorp RG, van der Laarse A, Smelt AH . Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial. Am J Med 2002; 112: 275–280.

    Article  CAS  PubMed  Google Scholar 

  12. Okopien B, Krysiak R, Kowalski J, Madej A, Belowski D, Zieliñski M et al. The effect of statins and fibrates on interferon-gamma and interleukin-2 release in patients with primary type II dyslipidemia. Atherosclerosis 2004; 176: 327–335.

    Article  CAS  PubMed  Google Scholar 

  13. Keating GM, Ormrod D . Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidaemia. Drugs 2002; 62: 1909–1944.

    Article  CAS  PubMed  Google Scholar 

  14. Ordovas JM . Pharmacogenetics of lipid diseases. Hum Genomics 2004; 1: 111–125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Smith JA, Arnett DK, Kelly RJ, Ordovas JM, Sun YV, Hopkins PN et al. The genetic architecture of fasting plasma triglyceride response to fenofibrate treatment. Eur J Hum Genet 2008; 16: 603–613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu Y, Ordovas JM, Gao G, Province M, Straka RJ, Tsai MY et al. Pharmacogenetic association of the APOA1/C3/A4/A5 gene cluster and lipid responses to fenofibrate: the genetics of lipid-lowering drugs and diet network study. Pharmacogenet Genomics 2009; 19: 161–169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shen J, Arnett DK, Parnell LD, Peacock JM, Lai CQ, Hixson JE et al. Association of common C-reactive protein (CRP) gene polymorphisms with baseline plasma CRP levels and fenofibrate response: the GOLDN study. Diabetes Care 2008; 31: 910–915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mandard S, Muller M, Kersten S . Peroxisome proliferator-activated receptor alpha target genes. Cell Mol Life Sci 2004; 61: 393–416.

    Article  CAS  PubMed  Google Scholar 

  19. Spinelli SL, O'Brien JJ, Bancos S, Lehmann GM, Springer DL, Blumberg N et al. The PPAR-platelet connection: modulators of inflammation and potential cardiovascular effects. PPAR Res 2008; 2008: 328172.

    Article  CAS  PubMed  Google Scholar 

  20. Rizzo G, Fiorucci S . PPARs and other nuclear receptors in inflammation. Curr Opin Pharmacol 2006; 6: 421–427.

    Article  CAS  PubMed  Google Scholar 

  21. Pankow JS, Province MA, Hunt SC, Arnett DK . Regarding “Testing for population subdivision and association in four case-control studies”. Am J Hum Genet 2002; 71: 1478–1480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Patsch JR, Miesenböck G, Hopferwieser T, Mühlberger V, Knapp E, Dunn JK et al. Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state. Arterioscler Thromb Vasc Biol Am Heart Assoc 1992; 12: 1336–1345.

    CAS  Google Scholar 

  23. Liu Y, Ordovas JM, Gao G, Province M, Straka RJ, Tsai MY et al. The SCARB1 gene is associated with lipid response to dietary and pharmacological interventions. J Hum Genet 2008; 53: 709–717.

    Article  PubMed  Google Scholar 

  24. Straka RJ, Burkhardt RT, Fisher JE . Determination of fenofibric acid concentrations by HPLC after anion exchange solid-phase extraction from human serum. Ther Drug Monit 2007; 29: 197–202.

    Article  CAS  PubMed  Google Scholar 

  25. Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B 1995; 57: 289–300.

    Google Scholar 

  26. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  Google Scholar 

  27. Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM . Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 2004; 26: 61–69.

    Article  PubMed  Google Scholar 

  28. Caslake MJ, Packard CJ, Gaw A, Murray E, Griffin BA, Vallance BD et al. Fenofibrate and LDL metabolic heterogeneity in hypercholesterolemia. Arterioscler Thromb 1993; 13: 702–711.

    Article  CAS  PubMed  Google Scholar 

  29. Kraja AT, Province MA, Straka RJ, Ordovas JM, Borecki IB, Arnett DK . Fenofibrate and metabolic syndrome. Endocr Metab Immune Disord Drug Targets 2010; 10: 138–148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Reinhard W, Stark K, Sedlacek K, Fischer M, Baessler A, Neureuther K et al. Association between PPARalpha gene polymorphisms and myocardial infarction. Clin Sci 2008; 115: 301–308.

    Article  CAS  PubMed  Google Scholar 

  31. Brisson D, Ledoux K, Bosse Y, St-Pierre J, Julien P, Perron P et al. Effect of apolipoprotein E, peroxisome proliferator-activated receptor alpha and lipoprotein lipase gene mutations on the ability of fenofibrate to improve lipid profiles and reach clinical guideline targets among hypertriglyceridemic patients. Pharmacogenetics 2002; 12: 313–320.

    Article  CAS  PubMed  Google Scholar 

  32. Foucher C, Rattier S, Flavell DM, Talmud PJ, Humphries SE, Kastelein JJ et al. Response to micronized fenofibrate treatment is associated with the peroxisome-proliferator-activated receptors alpha G/C intron7 polymorphism in subjects with type 2 diabetes. Pharmacogenetics 2004; 14: 823–829.

    Article  CAS  PubMed  Google Scholar 

  33. Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010; 375: 1875–1884.

    Article  CAS  Google Scholar 

  34. Enquobahrie DA, Smith NL, Bis JC, Carty CL, Rice KM, Lumley T et al. Cholesterol ester transfer protein, interleukin-8, peroxisome proliferator activator receptor alpha, and Toll-like receptor 4 genetic variations and risk of incident nonfatal myocardial infarction and ischemic stroke. Am J Cardiol 2008; 101: 1683–1688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shin T, Kuboki S, Huber N, Eismann T, Galloway E, Schuster R et al. Activation of peroxisome proliferator-activated receptor-gamma during hepatic ischemia is age-dependent. J Surg Res 2008; 147: 200–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Belfort R, Berria R, Cornell J, Cusi K . Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome. J Clin Endocrinol Metab 2010; 95: 829–836.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kon KK, Yeal AJ, Hwan HS, Kyu Jin D, Sik Kim H, Cheon Lee K et al. Effects of fenofibrate on lipoproteins, vasomotor function, and serological markers of inflammation, plaque stabilization, and hemostasis. Atherosclerosis 2004; 174: 379–383.

    Article  Google Scholar 

  38. Okopien B, Krysiak R, Herman ZS . Effects of short-term fenofibrate treatment on circulating markers of inflammation and hemostasis in patients with impaired glucose tolerance. J Clin Endocrinol Metab 2006; 91: 1770–1778.

    Article  CAS  PubMed  Google Scholar 

  39. Delerive P, Fruchart JC, Staels B . Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol 2001; 169: 453–459.

    Article  CAS  PubMed  Google Scholar 

  40. Guay DR . Micronized fenofibrate: a new fibric acid hypolipidemic agent. Ann Pharmacother 1999; 33: 1083–1103.

    Article  CAS  PubMed  Google Scholar 

  41. Michie S, Bobrow M, Marteau TM . Predictive genetic testing in children and adults: a study of emotional impact. J Med Genet 2001; 38: 519–526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to the staff of the GOLDN study for the assistance in data collection and management. This study was funded by National Heart, Lung and Blood Institute grant number U01HL072524.

Author information

Authors and Affiliations

  1. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA

    A C Frazier-Wood & D K Arnett

  2. Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL, USA

    A C Frazier-Wood & H K Tiwari

  3. Jean Mayer-US Department of Agriculture Human Nutrition Research Center on Aging, Nutrition and Genomics Laboratory, Tufts University, Boston, MA, USA

    J M Ordovas

  4. The Department of Epidemiology and Population Genetics, Centro Nacional Investigación Cardiovasculares (CNIC), Madrid, Spain

    J M Ordovas

  5. IMDEA Food, Madrid, Spain

    J M Ordovas

  6. Experimental and Clinical Pharmacology Department, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

    R J Straka

  7. Human Genetics Center, Health Science Center, University of Texas, Houston, TX, USA

    J E Hixson

  8. Division of Statistical Genomics, Department of Genetics, School of Medicine, Washington University, St Louis, MO, USA

    I B Borecki

  9. Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL, USA

    D K Arnett

Authors
  1. A C Frazier-Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J M Ordovas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R J Straka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J E Hixson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I B Borecki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H K Tiwari
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D K Arnett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A C Frazier-Wood.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Frazier-Wood, A., Ordovas, J., Straka, R. et al. The PPAR alpha gene is associated with triglyceride, low-density cholesterol and inflammation marker response to fenofibrate intervention: the GOLDN study. Pharmacogenomics J 13, 312–317 (2013). https://doi.org/10.1038/tpj.2012.9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2012.9

Keywords

This article is cited by

Search

Advanced search

Quick links