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Genetic Variation in the Peroxisome Proliferator Activated Receptor-Gamma Gene Is Associated with Histologically Advanced NAFLD

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Abstract

Background

The peroxisome proliferator activated receptor-gamma (PPARG) is a nuclear receptor that regulates adipocyte differentiation, insulin sensitivity and lipid metabolism, thus, it represents a good candidate gene for non-alcoholic fatty liver disease (NAFLD).

Purpose and Method

We investigated the association of two PPARG variants (Pro12Ala and C1431T) with NAFLD and its histological features. DNA was extracted from 274 archived, formalin-fixed liver biopsy specimens from 212 patients with NAFLD and 62 controls with normal liver histology.

Results

Individual SNPs did not show significant association with NAFLD or its histological features. A haplotype comprised of both minor alleles (GT) was less enriched whereas a haplotype comprised of the two major alleles (CC) was more enriched in subjects with NAFLD compared to controls [9.3% vs. 28.1% for GT (P = 0.001, OR 0.26 (range 0.14–0.48) and 80.4% vs. 64.8% for CC (P = 0.037, OR 2.23 (range 1.30–3.81)]. Both haplotypes were significantly associated with steatosis and fibrosis. The GT haplotype was also associated with lobular inflammation.

Conclusions

Genetic variation in PPARG is associated with NAFLD, and the GT haplotype is associated with inflammatory and fibrotic changes that denote histologically advanced NAFLD.

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References

  1. Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis. 2008;28:339–350.

    Article  PubMed  Google Scholar 

  2. Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010;7:195–203.

    Article  PubMed  Google Scholar 

  3. Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–1419.

    Article  PubMed  CAS  Google Scholar 

  4. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–873.

    Article  PubMed  CAS  Google Scholar 

  5. Hui JM, Kench JG, Chitturi S, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology. 2003;38:420–427.

    Article  PubMed  Google Scholar 

  6. Bernard S, Touzet S, Personne I, et al. Association between microsomal triglyceride transfer protein gene polymorphism and the biological features of liver steatosis in patients with type II diabetes. Diabetologia. 2000;43:995–999.

    Article  PubMed  CAS  Google Scholar 

  7. Namikawa C, Shu-Ping Z, Vyselaar JR, et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol. 2004;40:781–786.

    Article  PubMed  CAS  Google Scholar 

  8. Gambino R, Cassader M, Pagano G, et al. Polymorphism in microsomal triglyceride transfer protein: a link between liver disease and atherogenic postprandial lipid profile in NASH? Hepatology. 2007;45:1097–1107.

    Article  PubMed  CAS  Google Scholar 

  9. Valenti L, Fracanzani AL, Dongiovanni P, et al. Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology. 2002;122:274–280.

    Article  PubMed  CAS  Google Scholar 

  10. Miele L, Beale G, Patman G, et al. The kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology. 2008;135:282–291.e1.

    Article  PubMed  CAS  Google Scholar 

  11. Yoneda M, Hotta K, Nozaki Y, et al. Association between PPARGC1A polymorphisms and the occurrence of nonalcoholic fatty liver disease (NAFLD). BMC Gastroenterol. 2008;8:27.

    Article  PubMed  Google Scholar 

  12. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–1465.

    Article  PubMed  CAS  Google Scholar 

  13. Kotronen A, Johansson LE, Johansson LM, et al. A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia. 2009;52:1056–1060.

    Article  PubMed  CAS  Google Scholar 

  14. Sookoian S, Castano GO, Burgueno AL, et al. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res. 2009;50:2111–2116.

    Article  PubMed  CAS  Google Scholar 

  15. Valenti L, Al-Serri A, Daly AK, et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51:1209–1217.

    Article  PubMed  CAS  Google Scholar 

  16. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–152.

    PubMed  CAS  Google Scholar 

  17. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:370–379.

    Article  PubMed  CAS  Google Scholar 

  18. Cheung O, Sanyal AJ. Abnormalities of lipid metabolism in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:351–359.

    Article  PubMed  CAS  Google Scholar 

  19. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2: a lipid-activated transcription factor. Cell. 1994;79:1147–1156.

    Article  PubMed  CAS  Google Scholar 

  20. Deeb SS, Fajas L, Nemoto M, et al. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998;20:284–287.

    Article  PubMed  CAS  Google Scholar 

  21. Sharma AM, Staels B. Review: peroxisome proliferator-activated receptor gamma and adipose tissue: understanding obesity-related changes in regulation of lipid and glucose metabolism. J Clin Endocrinol Metab. 2007;92:386–395.

    Article  PubMed  CAS  Google Scholar 

  22. Sugii S, Olson P, Sears DD, et al. PPAR{gamma} activation in adipocytes is sufficient for systemic insulin sensitization. Proc Natl Acad Sci USA. 2009;106:22504–22509.

    Article  PubMed  CAS  Google Scholar 

  23. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–1685.

    Article  PubMed  CAS  Google Scholar 

  24. Yen CJ, Beamer BA, Negri C, et al. Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation. Biochem Biophys Res Commun. 1997;241:270–274.

    Article  PubMed  CAS  Google Scholar 

  25. Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000;26:76–80.

    Article  PubMed  CAS  Google Scholar 

  26. Doney A, Fischer B, Frew D, et al. Haplotype analysis of the PPARgamma Pro12Ala and C1431T variants reveals opposing associations with body weight. BMC Genet. 2002;3:21.

    Article  PubMed  Google Scholar 

  27. Doney AS, Fischer B, Cecil JE, et al. Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to type 2 diabetes. Diabetologia. 2004;47:555–558.

    Article  PubMed  CAS  Google Scholar 

  28. Morini E, Tassi V, Capponi D, et al. Interaction between PPARgamma2 variants and gender on the modulation of body weight. Obesity (Silver Spring). 2008;16:1467–1470.

    Article  CAS  Google Scholar 

  29. Hui Y, Yu-Yuan L, Yu-Qiang N, et al. Effect of peroxisome proliferator-activated receptors-gamma and co-activator-1alpha genetic polymorphisms on plasma adiponectin levels and susceptibility of non-alcoholic fatty liver disease in Chinese people. Liver Int. 2008;28:385–392.

    Article  PubMed  Google Scholar 

  30. Dongiovanni P, Rametta R, Fracanzani AL, et al. Lack of association between peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms and progressive liver damage in patients with non-alcoholic fatty liver disease: a case control study. BMC Gastroenterol. 2010;10:102.

    Article  PubMed  Google Scholar 

  31. Rey JW, Noetel A, Hardt A, et al. Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma2 in patients with fatty liver diseases. World J Gastroenterol. 2010;16:5830–5837.

    Article  PubMed  CAS  Google Scholar 

  32. Gupta AC, Chaudhory AK, Sukriti C, et al. Peroxisome proliferators-activated receptor gamma2 Pro12Ala variant is associated with body mass index in non-alcoholic fatty liver disease patients. Hepatol Int. 2010;5:575–580.

    Article  PubMed  CAS  Google Scholar 

  33. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321.

    Article  PubMed  Google Scholar 

  34. Shi SR, Datar R, Liu C, et al. DNA extraction from archival formalin-fixed, paraffin-embedded tissues: heat-induced retrieval in alkaline solution. Histochem Cell Biol. 2004;122:211–218.

    Article  PubMed  CAS  Google Scholar 

  35. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, et al. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003;38:1008–1017.

    PubMed  CAS  Google Scholar 

  36. Sanyal AJ, Mofrad PS, Contos MJ, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2004;2:1107–1115.

    Article  PubMed  CAS  Google Scholar 

  37. Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39:188–196.

    Article  PubMed  CAS  Google Scholar 

  38. Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–2307.

    Article  PubMed  CAS  Google Scholar 

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Conflict of interest

The authors have no financial relationship to disclose and no conflict of interest.

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin, 9200 W. Wisconsin Ave., Milwaukee, WI, 53212, USA

    Samer Gawrieh

  2. Zablocki VA Medical Center, Milwaukee, WI, USA

    Samer Gawrieh

  3. Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, USA

    Miranda C. Marion & Carl D. Langefeld

  4. Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA

    Richard Komorowski

  5. Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA

    James Wallace

  6. Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

    Michael Charlton

  7. Division of Endocrinology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    Ahmed Kissebah

  8. Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA

    Ahmed Kissebah & Michael Olivier

  9. Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, WI, USA

    Michael Olivier

  10. Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA

    Michael Olivier

Authors
  1. Samer Gawrieh
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  2. Miranda C. Marion
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  3. Richard Komorowski
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  4. James Wallace
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  6. Ahmed Kissebah
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  7. Carl D. Langefeld
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  8. Michael Olivier
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Correspondence to Samer Gawrieh.

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Gawrieh, S., Marion, M.C., Komorowski, R. et al. Genetic Variation in the Peroxisome Proliferator Activated Receptor-Gamma Gene Is Associated with Histologically Advanced NAFLD. Dig Dis Sci 57, 952–957 (2012). https://doi.org/10.1007/s10620-011-1994-2

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  • DOI: https://doi.org/10.1007/s10620-011-1994-2

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