Exp Clin Endocrinol Diabetes 2009; 117(3): 113-118
DOI: 10.1055/s-0028-1082069
Article

© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

The L162V Polymorphism of the Peroxisome Proliferator Activated Receptor Alpha Gene (PPARA) is not Associated with Type 2 Diabetes, BMI or Body Fat Composition

G. Silbernagel 1 , N. Stefan 1 , M. M. Hoffmann 2 , F. Machicao-Arano 1 , J. Machann 3 , F. Schick 3 , B. R. Winkelmann 4 , B. O. Boehm 5 , H. U. Häring 1 , A. Fritsche 1 , W. März 6 , 7
  • 1Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany
  • 2Division of Clinical Chemistry, Department of Medicine, University of Freiburg, Freiburg, Germany
  • 3Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University of Tübingen, Tübingen, Germany
  • 4Cardiology Group Frankfurt-Sachsenhausen, Frankfurt , Hessen, Germany
  • 5Division of Endocrinology and Diabetes, Department of Internal Medicine, University of Ulm, Ulm, Germany
  • 6Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria
  • 7Synlab Center of Laboratory Diagnostics, Heidelberg
Further Information

Publication History

received 18.04.2008 first decision 26.05.2008

accepted 02.07.2008

Publication Date:
25 August 2008 (online)

Abstract

Background: The L162V single nucleotide polymorphism in PPARA is suggested to play an important role in the pathogenesis of type 2 diabetes, obesity, and body fat composition. However, clinical evidence is controversial.

Objective: Our aim was to investigate the relationships of the L162V SNP with type 2 diabetes, pre-diabetes phenotypes, adiposity, and plasma lipid levels. In addition, we studied the associations of the L162V SNP with body fat composition, intramyocellular lipids, and liver fat content. Furthermore, we examined if the L162V SNP was associated with changes in BMI, insulin secretion, insulin resistance, body fat composition, intramyocellular lipids, and liver fat content in response to lifestyle intervention.

Material and Methods: Data from two large cross sectional studies, the combined TULIP/TUEF cohorts, and the LURIC study were analysed. Prospective data were obtained from TULIP participants who underwent a lifestyle intervention. A total of 4 779 subjects were studied. BMI was measured in all subjects. Type 2 diabetes was diagnosed in a subgroup of the LURIC study. In the TULIP study total body fat, non-visceral adipose tissue, and visceral adipose tissue were measured with magnetic resonance tomography. Liver fat and intramyocellular lipid content were quantified with 1H magnetic resonance spectroscopy. Insulin sensitivity and insulin secretion were estimated from oral glucose tolerance testing.

Results: The L162V SNP was neither associated with type 2 diabetes or BMI nor with body fat composition, intramyocellular lipids or liver fat content.

Conclusions: According to our study, the L162V SNP does not have a strong impact on the pathogenesis of type 2 diabetes or obesity.

References

  • 1 American Diabetes Association. . Diagnosis and classification of diabetes mellitus.  Diabetes Care. 2006;  29 ((Suppl 1)) S43-S48
  • 2 Andrulionyte L, Kuulasmaa T, Chiasson JL, Laakso M. STOP-NIDDM Study Group . Single nucleotide polymorphisms of the peroxisome proliferator-activated receptor-α gene (PPARA) influence the conversion from impaired glucose tolerance to type 2 diabetes: the STOP-NIDDM trial.  Diabetes. 2007;  56 ((4)) 1181-1186
  • 3 Bosse Y, Despres JP, Bouchard C, Perusse L, Vohl MC. The peroxisome proliferator-activated receptor alpha L162V mutation is associated with reduced adiposity.  Obes Res. 2003;  11 ((7)) 809-816
  • 4 Evans D, Aberle J, Wendt D, Wolf A, Beisiegel U, Mann WA. A polymorphism, L162V, in the peroxisome proliferator-activated receptor alpha (PPARalpha) gene is associated with lower body mass index in patients with non-insulin-dependent diabetes mellitus.  J Mol Med. 2001;  79 198-204
  • 5 Faul MM, Grese TA. Selective RXR modulators for the treatment of type II diabetes.  Curr Opin Drug Discov Devel. 2002;  5 ((6)) 974-985
  • 6 Flavell DM, Ireland H, Stephens JW, Hawe E, Acharya J, Mather H, Hurel SJ, Humphries SE. Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes.  Diabetes. 2005;  54 ((2)) 582-586
  • 7 Flavell DM, Jamshidi Y, Hawe E, Pineda Torra I, Taskinen MR, Frick MH, Nieminen MS, Kesäniemi YA, Pasternack A, Staels B, Miller G, Humphries SE, Talmud PJ, Syvänne M. Peroxisome proliferator-activated receptor alpha gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease.  Circulation. 2002;  105 ((12)) 1440-1445
  • 8 Flavell DM, Pineda Torra I, Jamshidi Y, Evans D, Diamond JR, Elkeles RS, Bujac SR, Miller G, Talmud PJ, Staels B, Humphries SE. Variation in the PPARalpha gene is associated with altered function in vitro and plasma lipid concentrations in Type II diabetic subjects.  Diabetologia. 2000;  43 ((5)) 673-680
  • 9 Gouni-Berthold I, Giannakidou E, Müller-Wieland D, Faust M, Kotzka J, Berthold HK, Krone W. Association between the PPARalpha L162V polymorphism, plasma lipoprotein levels, and atherosclerotic disease in patients with diabetes mellitus type 2 and in nondiabetic controls.  Am Heart J. 2004;  147 ((6)) 1117-1124
  • 10 Lalloyer F, Vandewalle B, Percevault F, Torpier G, Kerr-Conte J, Oosterveer M, Paumelle R, Fruchart JC, Kuipers F, Pattou F, Fiévet C, Staels B. Peroxisome proliferator-activated receptor α improves pancreatic adaptation to insulin resistance in obese mice and reduces lipotoxicity in human islets.  Diabetes. 2006;  55 1605-1613
  • 11 Lefebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles of PPARalpha in energy metabolism and vascular homeostasis.  J Clin Invest. 2006;  116 571-580
  • 12 Love-Gregory LD, Wasson J, Ma J, Jin CH, Glaser B, Suarez BK, Permutt MA. A common polymorphism in the upstream promoter region of the hepatocyte nuclear factor-4 alpha gene on chromosome 20q is associated with type 2 diabetes and appears to contribute to the evidence for linkage in an ashkenazi jewish population.  Diabetes. 2004;  53 ((4)) 1134-1140
  • 13 Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.  Diabetes Care. 1999;  22 ((9)) 1462-1470
  • 14 Muller YL, Bogardus C, Pedersen O, Baier L. A Gly482Ser missense mutation in the peroxisome proliferator-activated receptor gamma coactivator-1 is associated with altered lipid oxidation and early insulin secretion in Pima Indians.  Diabetes. 2003;  52 ((3)) 895-898
  • 15 Nelson TL, Fingerlin TE, Moss L, Barmada MM, Ferrell RE, Norris JM. The peroxisome proliferator-activated receptor gamma coactivator-1 alpha gene (PGC-1alpha) is not associated with type 2 diabetes mellitus or body mass index among Hispanic and non Hispanic Whites from Colorado.  Exp Clin Endocrinol Diabetes. 2007;  115 ((4)) 268-275
  • 16 Robitaille J, Brouillette C, Houde A, Lemieux S, Pérusse L, Tchernof A, Gaudet D, Vohl MC. Association between the PPARalpha-L162V polymorphism and components of the metabolic syndrome.  J Hum Genet. 2004;  49 ((9)) 482-489
  • 17 Sapone A, Peters JM, Sakai S, Tomita S, Papiha SS, Dai R, Friedman FK, Gonzalez FJ. The human peroxisome proliferator-activated receptor alpha gene: identification and functional characterization of two natural allelic variants.  Pharmacogenetics. 2000;  10 ((4)) 321-333
  • 18 Schäfer SA, Müssig K, Stefan N, Häring HU, Fritsche A, Balletshofer BM. Plasma homocysteine concentrations in young individuals at increased risk of type 2 diabetes are associated with subtle differences in glomerular filtration rate but not with insulin resistance.  Exp Clin Endocrinol Diabetes. 2006;  114 ((6)) 306-309
  • 19 Shin MJ, Kanaya AM, Krauss RM. Polymorphisms in the peroxisome proliferator activated receptor alpha gene are associated with levels of apolipoprotein CIII and triglyceride in African-Americans but not Caucasians.  Atherosclerosis. 2008;  198 ((2)) 313-319
  • 20 Stefan N, Machicao F, Staiger H, Machann J, Schick F, Tschritter O, Spieth C, Weigert C, Fritsche A, Stumvoll M, Häring HU. Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat.  Diabetologia. 2005;  48 ((11)) 2282-2291
  • 21 Stefan N, Thamer C, Staiger H, Machicao F, Machann J, Schick F, Venter C, Niess A, Laakso M, Fritsche A, Häring HU. Genetic variations in PPARD and PPARGC1A determine mitochondrial function and change in aerobic physical fitness and insulin sensitivity during lifestyle intervention.  J Clin Endocrinol Metab. 2007;  92 ((5)) 1827-1833
  • 22 Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Järvinen H, Haeften T Van, Renn W, Gerich J. Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity.  Diabetes Care. 2000;  23 ((3)) 295-301
  • 23 Tai ES, Demissie S, Cupples LA, Corella D, Wilson PW, Schaefer EJ, Ordovas JM. Association between the PPARA L162V polymorphism and plasma lipid levels: the Framingham Offspring Study.  Arterioscler Thromb Vasc Biol. 2002;  22 ((5)) 805-810
  • 24 Tordjman K, Bernal-Mizrachi C, Zemany L, Weng S, Feng C, Zhang F, Leone TC, Coleman T, Kelly DP, Semenkovich CF. PPARalpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice.  J Clin Invest. 2001;  107 ((8)) 1025-1034
  • 25 Uthurralt J, Gordish-Dressman H, Bradbury M, Tesi-Rocha C, Devaney J, Harmon B, Reeves EK, Brandoli C, Hansen BC, Seip RL, Thompson PD, Price TB, Angelopoulos TJ, Clarkson PM, Moyna NM, Pescatello LS, Visich PS, Zoeller RF, Gordon PM, Hoffman EP. PPARalpha L162V underlies variation in serum triglycerides and subcutaneous fat volume in young males.  BMC Med Genet. 2007;  8 55
  • 26 Vohl MC, Lepage P, Gaudet D, Brewer CG, Bétard C, Perron P, Houde G, Cellier C, Faith JM, Després JP, Morgan K, Hudson TJ. Molecular scanning of the human PPARa gene: association of the L162V mutation with hyperapobetalipoproteinemia.  J Lipid Res. 2000;  41 ((6)) 945-952
  • 27 Winkelmann BR, Marz W, Boehm BO, Zotz R, Hager J, Hellstern P, Senges J. LURIC Study Group (LUdwigshafen RIsk and Cardiovascular Health) . Rationale and design of the LURIC study – a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovacular disease.  Pharmacogenomics. 2001;  2 ((1Suppl 1)) S1-S73

Correspondence

Prof. Dr. A. Fritsche

Division of Endocrinology, Diabetology, Nephrology,

Vascular Disease, and Clinical Chemistry

Department of Internal Medicine

University of Tübingen

Ottfried Müller Straße 10

72076 Tübingen

Germany

Phone: +0049/7071/298 05 90

Fax: +0049/7071/295 97 4

Email: andreas.fritsche@med.uni-tuebingen.de

    >