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DOI: 10.1055/s-0028-1082069
© 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
Publikationsverlauf
received 18.04.2008
first decision 26.05.2008
accepted 02.07.2008
Publikationsdatum:
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.
Key words
peroxisome proliferator activated receptor alpha - obesity - single nucleotide polymorphism - L162V - type 2 diabetes - body fat composition
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
Telefon: +0049/7071/298 05 90
Fax: +0049/7071/295 97 4
eMail: andreas.fritsche@med.uni-tuebingen.de