Exp Clin Endocrinol Diabetes 2007; 115(4): 268-275
DOI: 10.1055/s-2007-960495
Article

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

The Peroxisome Proliferator-activated Receptor Gamma Coactivator-1 Alpha Gene (PGC-1α) is Not Associated with Type 2 Diabetes Mellitus or Body Mass Index Among Hispanic and Non Hispanic Whites from Colorado

T. L. Nelson 1 , 2 , T. E. Fingerlin 2 , L. Moss 2 , M. M. Barmada 3 , R. E. Ferrell 3 , J. M. Norris 2
  • 1Department of Health and Exercise Science, Colorado State University, Fort Collins, CO
  • 2Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Denver, CO
  • 3Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
Further Information

Publication History

received 28. 7. 2006 first decision 6. 11. 2006

accepted 29. 11. 2006

Publication Date:
03 May 2007 (online)

Abstract

The objective of the study was to test for an association between type 2 diabetes mellitus (T2DM) and body mass index (BMI) and three single nucleotide polymorphisms (SNP)s in the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) gene. We were also interested in whether these associations differed by tertiles of diet, physical activity or presence of polymorphisms in the peroxisome proliferator-activated receptor gamma (PPAR-γ) gene among Hispanics and Non-Hispanic Whites (NHW) from Colorado. We studied 216 Hispanic pedigrees (1850 nuclear families) and 236 NHW pedigrees (1240 families) from the San Luis Valley and Denver. We genotyped the Gly482Ser, Thr528Thr and Thr612Met polymorphisms in the PGC-1α gene and the Pro12Ala polymorphism of the PPAR-γ gene. Historical physical activity (average METS/week) as well as average dietary intake over the past year was assessed by self-report. Data were analyzed using the Family Based Association Test (FBAT) as well as generalized estimating equations (GEE). We did not find any significant association between three SNPs in the PGC-1α gene and T2DM in Hispanics or NHW; however, using FBAT, we found the common Thr612Thr allele of the PGC-1α gene to be associated with T2DM among Hispanic subjects carrying the rare Pro12Ala allele of the PPAR-γ gene (p=.003). We found similar associations when we considered a haplotype containing that allele (p=.002). However, the results of the GEE analysis did not confirm these findings: odds ratio (OR)=1.68, 95% CI (0.5, 5.2) suggesting these results may due to chance. BMI also did not show any consistent associations with the PGC-1α gene. In conclusion, we did not find an association between the PGC-1α gene and T2DM or BMI and there were no consistent interactions with diet, physical activity or the Pro12Ala polymorphism of the PPAR-γ gene.

References

  • 1 Andruliontye L, Zacharova J, Chiasson JL, Laasko M. STOP-NIDDM Study Group . Common polymorphisms of the PPAR-gamma2 (Pro12Ala) and PGC-1alpha (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial.  Diabetologia. 2004;  47 ((12)) 2176-2184
  • 2 Auwerx J. PPAR gamma, the ultimate thrifty gene.  Diabetologia. 1999;  42 1033-1049
  • 3 Baar K. Involvement of PPAR gamma co-activator-1, nuclear respiratory factors 1 and 2, and PPAR alpha in the adaptive response to endurance exercise.  Proc Nutr Soc. 2004;  63 ((2)) 269-273
  • 4 Barroso I, Luan J, Sandhu MS, Franks PW, Crowley V, Schafer AJ, O'Rahilly S, Wareham NJ. Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes.  Diabetologia. 2006;  49 ((3)) 501-505
  • 5 Bartsocas CS, Leslie RD. Genetics of diabetes mellitus.  Am J Med Genet. 2002;  115 ((1)) 1-3
  • 6 Block G, Hartman AM, Dresser CM, Carroll MD, Gannon J, Gardner L. A data-based approach to diet questionnaire design and testing.  Am J Epidemiol. 1986;  124 453-469
  • 7 Block G, Woods M, Potosky A, Clifford D. Validation of a self-administered diet history questionnaire using multiple diet records.  J Clin Epidemiol. 1990;  43 1327-1335
  • 8 Bray GA, Bouchard C, James WPT. (Eds.) Handbook of Obesity. New York: Marcel Dekker 1998
  • 9 CDC .Centers for Disease Control and Prevention, National Diabetes Surveillance System. National Center for Chronic Disease Prevention and Health Promotion, Division of Adult and Community Health, data from the Behavioral Risk Factor Surveillance System. 2004
  • 10 Cole SA, Mitchell BD, Hsueh WC, Pineda P, Beamer PA, Shuldiner AR, Comuzzie AG, Blangero J, Hixson JE. The Pro12Ala variant of peroxisome proliferator-activated receptor-gamma2 (PPAR-g2) is associated with measures of obesity in Mexican Americans.  In J of Obes. 2000;  24 522-524
  • 11 Coulter AA, Beardon CM, Liu X, Koza RA, Kozak LP. Dietary fat interacts with QTLs controlling induction of PGC-1 alpha and UCP1 during conversion of white to brown fat.  Physiol Genomics. 2003;  14 ((2)) 139-147
  • 12 Damcott CM, Moffett SP, Feingold E, Barmada MM, Marshal JA, Hamman RF, Ferrell RE. Genetic variation in fatty acid-binding protein-4 and peroxisome proliferator-activated receptor gamma interactively influence insulin sensitivity and body composition in males.  Metabolism. 2004;  53 ((3)) 303-309
  • 13 Deeb S, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J. A Pro12Ala substitution in PPARg2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity.  Nature Gen. 1998;  20 284-287
  • 14 Doucet E, Almeras N, White MD, Despres JP, Bouchard C, Tremblay A. Dietary fat composition and human adiposity.  Eur J Clin Nutr. 1998;  52 2-6
  • 15 Ek J, Andersen G, Urhammer SA, Gaede PH, Drivsholm T, Borch-Johnsen K, Hansen T, Pedersen O. Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to type II diabetes mellitus.  Diabetologia. 2001;  44 2220-2226
  • 16 Ek J, Anderson G, Urhammer SA, Hansen L, Carstensen B, Borch-Johnsen K, Drivsholm T, Berglund L, Hansen T, Lithell H, Pedersen O. Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene in relation to insulin sensitivity among glucose tolerant Caucasians.  Diabetologia. 2001;  44 1170-1176
  • 17 Elbein SC. The genetics of human non-insulin-dependent (type 2) diabetes mellitus.  J Nutr. 1997;  127 1891S-1896S
  • 18 Esterbauer H, Oberkofler H, Linnemayr V, Iglseder B, Hedegger M, Wolfsgruber P, Paulweber B, Fastner B, Krempler F, Patsch W. Peroxisome proliferator-activated receptor-γ coactivator-1 gene locus: Associations with obesity indices in middle-aged women.  Diabetes. 2002;  51 1281-1286
  • 19 Evans D, de Heer J, Hagemann C, Wendt D, Wolf A, Beisiegel U, Mann WA. Association between the P12A and c1431t polymorphisms in the peroxisome proliferator activated-receptor gamma (PPARgamma) gene and type 2 diabetes.  Exp Clin Endocrinol Diabetes. 2001;  109 151-154
  • 20 Franks PW, Luan J, Browne PO, Harding AH, Rahilly SO, Chatterjee VKK, Wareham NJ. Does peroxisome proliferator-activated receptor g genotype (Pro12Ala) modify the association of physical activity and dietary fat with fasting insulin level?.  Metabolism. 2004;  53 ((1)) 11-16
  • 21 Hara K, Tobe K, Okada T, Kadowaki H, Akanuma Y, Ito C, Kimura S, Kadowaki T. A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes.  Diabetologia. 2002;  45 740-743
  • 22 Hill JO, Wyatt HR. Role of physical activity in preventing and treating obesity.  J Appl Physiol. 2005;  99 ((2)) 765-770
  • 23 Horvath S, Xu X, Laird NM. The family based association test method: strategies for studying general genotype-phenotype associations.  Eur J Hum Genet. 2001;  9 301-306
  • 24 Kao WH, Coresh J, Shuldiner AR, Boerwinkle ES, Bray MS, Brancati FL. Pro12Ala of the Peroxisome Proliferator-Activated Receptor-2 Gene Is Associated With Lower Serum Insulin Levels in Non-obese African Americans.  Diabetes. 2003;  52 1568-1572
  • 25 Kliewer SA, Xu HE, Lambert MH, Willson TM. Peroxisome proliferator-activated receptors: From genes to physiology.  Recent Prog Horm Res. 2001;  56 239-263
  • 26 Kriska AM, Knowler WC, LaPorte RE, Drash AL, Wing RR, Blair SN, Bennett PH, Kuller LH. Development of a questionnaire to examine the relationship of physical activity and diabetes in Pima Indians.  Diabetes Care. 1990;  13 401-411
  • 27 Lacquemant C, Chikri M, Boutin P, Samson C, Froguel P. No association between the G482S polymorphism of the proliferator-activated receptor-gamma coactivator-1 (PGC-1) gene and type II diabetes in French Caucasians.  Diabetologia. 2002;  45 602-603
  • 28 Lake SL, Blacker D, Laird NM. Family-based tests of association in the presence of linkage.  Am J Hum Genet. 2000;  67 ((6)) 1515-1525
  • 29 Larrouy D, Vidal H, Andreeli F, Laville M, Langin D. Cloning and mRNA tissue distribution of human PPAR-gamma coactivator-1.  In J of Obes. 1999;  23 1327-1332
  • 30 Li S, Chen W, Srinivasan SR, Boerwinkle E, Berenson GS. The peroxisome proliferator-activated receptor -gamma 2 gene polymorphism (Pro12Ala) beneficially influences insulin resistance and its tracking from childhood to adulthood: The Bogalusa Heart Study.  Diabetes. 2003;  52 1265-1269
  • 31 Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators.  Cell Metabolism. 2005;  1 361-370
  • 32 Lindi VI, Uusitupa MIJ, Lindstrom J, Louheranta A, Eriksson JG, Valle TT, Hamalainen H, Ilannne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Tuomilehto J. Association of the Pro12Ala polymorphism in the PPAR-g gene with 3-year incidence of type 2 diabetes and body weight change in the Finnish Diabetes Prevention Study.  Diabetes. 2002;  51 2581-2586
  • 33 Luan J, Browne PO, Harding AH, Halsall DJ, O'Rahilly S, Krishna VK, Wareham NJ. Evidence for gene-nutrient interaction at the PPAR g locus.  Diabetes. 2001;  50 686-689
  • 34 Lynch J, Helmrich SP, Lakka TA, Kaplan GA, Cohen RD, Salonen R, Salonen JT. Moderately intense physical activities and high levels of cardiorespiratory fitness reduce the risk of non-insulin-dependent diabetes mellitus in middle-aged men.  Arch Intern Med. 1996;  156 ((12)) 307-314
  • 35 Manco M, Calvani M, Mingrone G. Effects of dietary fatty acids on insulin sensitivity and secretion.  Diab Obes Metab. 2004;  6 ((6)) 402-413
  • 36 Masud S, Ye S. Effect of the peroxisome proliferator activated receptor-gamma gene Pro12Ala variant on body mass index: a meta-analysis.  J Med Genet. 2003;  40 773-780
  • 37 Mayer-Davis EJ, Vitolins MZ, Carmichael SL, Hemphill S, Tsaroucha G, Rushing J, Levin S. Validity and reproducibility of a food frequency interview in a Multi-Cultural Epidemiology Study.  Ann Epidemiol. 1999;  9 ((5)) 314-324
  • 38 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
  • 39 O'Connell JR, Weeks DE. PedCheck: a program for identification of genotype incompatibilities in linkage analysis.  Am J Hum Genet. 1998;  63 259-266
  • 40 Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, Lin J, Xiao JZ, Cao HB, Liu PA, Jiang XG, Jiang XY, Wang JP, Zheng H, Zhang H, Bennett PH, Howard BV. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study.  Diab Care. 1997;  20 ((4)) 537-544
  • 41 Pihlajamaki J, Kinnunen M, Ruotsalainen E, Salmenniemi U, Vauhkonen I, Kuulasmaa T, Kainulainen S, Laakso M. Haplotypes of PPARGC1A are associated with glucose tolerance, body mass index and insulin sensitivity in offspring of patients with type 2 diabetes.  Diabetologia. 2005;  48 ((7)) 1331-1334
  • 42 Rabinowitz D, Laird N. A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information.  Hum Hered. 2000;  50 211-223
  • 43 Ridderstrale M, Johansson LE, Rastam L, Lindbland U. Increased risk of obesity associated with the variant allele of the PPARGC1A Gly482Ser polymorphism in physically inactive elderly men.  Diabetologia. 2006;  49 496-500
  • 44 Robitaille J, Despres JP, Perusse L, Vohl MC. The PPAR-gamma P12A polymorphism modulates the relationship between dietary fat intake and components of the metabolic syndrome: results from the Quebec Family Study.  Clin Genet. 2003;  63 109-116
  • 45 Sparks LM, Xie H, Koza RA, Mynatt R, Hulver MW, Bray GA, Smith SR. A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle.  Diabetes. 2005;  54 ((7)) 1926-1933
  • 46 Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: The insulin gene region and insulin dependent diabetes mellitus (IDDM).  Am J Hum Genet. 1993;  52 506-516
  • 47 Stumvoll M, Fritsche A, t'Hart LM, Machann J, Thamer C, Tschritter O, Van Haeften TW, Jacob S, Dekker JM, Maassen JA, Machicao F, Schick F, Heine RJ, Haring H. The Gly482Ser variant in the peroxisome proliferator-activated receptor gamma coactivator-1 is not associated with diabetes-related traits in non-diabetic German and Dutch populations.  Exp Clin Endocrinol Diabetes. 2004;  112 253-257
  • 48 Stumvoll M, Stefan N, Fritsche A, Madaus A, Tschritter O, Koch M, Machicao F, Haring H. Interaction effects between common polymorphisms in PPARgamma2 and insulin receptor substrate 1 (Gly972Arg) on insulin sensitivity.  J Mol Med. 2002;  80 33-38
  • 49 van Dam RM, Willett WC, Rimm EB, Stampfer MJ, Hu FB. Dietary fat and meat intake in relation to risk of type 2 diabetes in men.  Diabetes Care. 2002;  25 ((3)) 417-424
  • 50 WHO. World Health Organization .Obesity: Preventing and managing the global epidemic. Geneva: WHO Division of Noncommunicable Diseases 1998

Correspondence

T. L. Nelson

Colorado State University

Department of Health and Exercise Science

223 Moby

Fort Collins

CO 80523

Phone: 970/491 63 20

Fax: 970/491 04 45

Email: tnelson@cahs.colostate.edu

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