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An age-dependent diet-modified effect of the PPARγ Pro12Ala polymorphism in children

      Abstract

      Variation in the peroxisome proliferator–activated receptor γ gene alters the risk for adiposity in adults, with evidence of interaction with diet. We investigated the age-related association between the Pro12Ala variant (rs1801282) and diet in obesity-related traits in children. The Pro12Ala variant was assayed in 2102 young children aged 1 to 6 years and in 794 periadolescent children aged 10 to 12 years of Greek origin. In both cohorts, no differences were found in obesity traits between the Ala allele carriers and Pro/Pro homozygotes. Sex-stratified analysis showed that, in periadolescent boys, Ala carriers exhibited lower measures of skinfolds (triceps: 16.9 ± 6.9 vs 19.4 ± 7.9 mm, P = .01; subscapular: 9.6 ± 4.5 vs 11.2 ± 5.4 mm, P = .02). On the other hand, young girls who were Ala carriers presented higher measures of triceps skinfold thickness (10.5 ± 3.0 vs 9.9 ± 2.8 mm, P = .04). Nominal gene-diet interactions were revealed in periadolescents for saturated fatty acid (SFA) intake and skinfolds (P for interaction = .05). In Pro/Pro homozygous young girls, SFA and total fat (TF) intake was positively associated with higher body mass index (BMI) (P = .01), waist circumference (P = .02), and skinfold thickness (triceps-SFA: P = 10−5, triceps-TF: P = 10−9, subscapular-SFA: P = 10−6, subscapular-TF: P = 10−4). For Pro/Pro homozygotes, unsaturated fat intake was inversely associated with BMI (P = .04) in young girls, and with BMI (P = .03), waist circumference (P = .03), and triceps (P = .02) in periadolescent boys. Our results suggest that adiposity in children is influenced by the Pro12Ala polymorphism in a sex-specific and age-dependent manner. We also demonstrate evidence of an age-dependent gene-diet (SFA, TF) interaction, suggesting that the type of fat intake modifies the effect of the Pro12 allele on obesity-related measures.
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      References

        • Cali A.M.
        • Caprio S.
        Obesity in children and adolescents.
        J Clin Endocrinol Metab. 2008; 93: S31-S36
        • Willett W.C.
        • Leibel R.L.
        Dietary fat is not a major determinant of body fat.
        Am J Med. 2002; 113: 47S-59S
        • Astrup A.
        Dietary fat is a major player in obesity—but not the only one.
        Obes Rev. 2002; 3: 57-58
        • Piers L.S.
        • Walker K.Z.
        • Stoney R.M.
        • Soares M.J.
        • O'Dea K.
        The influence of the type of dietary fat on postprandial fat oxidation rates: monounsaturated (olive oil) vs saturated fat (cream).
        Int J Obes Relat Metab Disord. 2002; 26: 814-821
        • Paniagua J.A.
        • Gallego de la Sacristana A.
        • Romero I.
        • Vidal-Puig A.
        • Latre J.M.
        • Sanchez E.
        • et al.
        Monounsaturated fat-rich diet prevents central body fat distribution and decreases postprandial adiponectin expression induced by a carbohydrate-rich diet in insulin-resistant subjects.
        Diabetes Care. 2007; 30: 1717-1723
        • Moussavi N.
        • Gavino V.
        • Receveur O.
        Is obesity related to the type of dietary fatty acids? An ecological study.
        Public Health Nutr. 2008; 11: 1149-1155
        • Heikkinen S.
        • Auwerx J.
        • Argmann C.A.
        PPARgamma in human and mouse physiology.
        Biochim Biophys Acta. 2007; 1771: 999-1013
        • Argmann C.A.
        • Cock T.A.
        • Auwerx J.
        Peroxisome proliferator–activated receptor gamma: the more the merrier?.
        Eur J Clin Invest. 2005; 35 (discussion 80): 82-92
        • Barak Y.
        • Nelson M.C.
        • Ong E.S.
        • Jones Y.Z.
        • Ruiz-Lozano P.
        • Chien K.R.
        • et al.
        PPAR gamma is required for placental, cardiac, and adipose tissue development.
        Mol Cell. 1999; 4: 585-595
        • Scacchi R.
        • Pinto A.
        • Rickards O.
        • Pacella A.
        • De Stefano G.F.
        • Cannella C.
        • et al.
        An analysis of peroxisome proliferator–activated receptor gamma (PPAR-gamma 2) Pro12Ala polymorphism distribution and prevalence of type 2 diabetes mellitus (T2DM) in world populations in relation to dietary habits.
        Nutr Metab Cardiovasc Dis. 2007; 17: 632-641
        • Altshuler D.
        • Hirschhorn J.N.
        • Klannemark M.
        • Lindgren C.M.
        • Vohl M.C.
        • Nemesh J.
        • et al.
        The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes.
        Nat Genet. 2000; 26: 76-80
        • Mori H.
        • Ikegami H.
        • Kawaguchi Y.
        • Seino S.
        • Yokoi N.
        • Takeda J.
        • et al.
        The Pro12 –>Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes.
        Diabetes. 2001; 50: 891-894
        • Buzzetti R.
        • Petrone A.
        • Caiazzo A.M.
        • Alemanno I.
        • Zavarella S.
        • Capizzi M.
        • et al.
        PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity in childhood obesity.
        Pediatr Res. 2005; 57: 138-140
        • Buzzetti R.
        • Petrone A.
        • Ribaudo M.C.
        • Alemanno I.
        • Zavarella S.
        • Mein C.A.
        • et al.
        The common PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity.
        Eur J Hum Genet. 2004; 12: 1050-1054
        • Lee B.C.
        • Doo H.K.
        • Ahn S.Y.
        • Byun S.H.
        • Kim S.I.
        • Park H.K.
        • et al.
        Peroxisome proliferator–activated receptor–gamma Pro12Ala polymorphism is associated with the susceptibility to ischemic stroke in Taeeumin classified by Sasang medicine.
        Neurol Res. 2007; 29: S32-S37
        • Dedoussis G.V.
        • Theodoraki E.V.
        • Manios Y.
        • Yiannakouris N.
        • Panagiotakos D.
        • Papoutsakis C.
        • et al.
        The Pro12Ala polymorphism in PPARgamma2 gene affects lipid parameters in Greek primary school children: a case of gene-to-gender interaction.
        Am J Med Sci. 2007; 333: 10-15
        • Maeda A.
        • Gohda T.
        • Funabiki K.
        • Horikoshi S.
        • Tomino Y.
        Peroxisome proliferator–activated receptor gamma gene polymorphism is associated with serum triglyceride levels and body mass index in Japanese type 2 diabetic patients.
        J Clin Lab Anal. 2004; 18: 317-321
        • Barbieri M.
        • Rizzo M.R.
        • Papa M.
        • Acampora R.
        • De Angelis L.
        • Olivieri F.
        • et al.
        Role of interaction between variants in the PPARG and interleukin-6 genes on obesity related metabolic risk factors.
        Exp Gerontol. 2005; 40: 599-604
        • Danawati C.W.
        • Nagata M.
        • Moriyama H.
        • Hara K.
        • Yasuda H.
        • Nakayama M.
        • et al.
        A possible association of Pro12Ala polymorphism in peroxisome proliferator–activated receptor gamma2 gene with obesity in native Javanese in Indonesia.
        Diabetes Metab Res Rev. 2005; 21: 465-469
        • Vaccaro O.
        • Lapice E.
        • Monticelli A.
        • Giacchetti M.
        • Castaldo I.
        • Galasso R.
        • et al.
        Pro12Ala polymorphism of the PPARgamma2 locus modulates the relationship between energy intake and body weight in type 2 diabetic patients.
        Diabetes Care. 2007; 30: 1156-1161
        • Luan J.
        • Browne P.O.
        • Harding A.H.
        • Halsall D.J.
        • O'Rahilly S.
        • Chatterjee V.K.
        • et al.
        Evidence for gene-nutrient interaction at the PPARgamma locus.
        Diabetes. 2001; 50: 686-689
        • Pisabarro R.E.
        • Sanguinetti C.
        • Stoll M.
        • Prendez D.
        High incidence of type 2 diabetes in peroxisome proliferator–activated receptor gamma2 Pro12Ala carriers exposed to a high chronic intake of trans fatty acids and saturated fatty acids.
        Diabetes Care. 2004; 27: 2251-2252
        • Lefebvre A.M.
        • Laville M.
        • Vega N.
        • Riou J.P.
        • van Gaal L.
        • Auwerx J.
        • et al.
        Depot-specific differences in adipose tissue gene expression in lean and obese subjects.
        Diabetes. 1998; 47: 98-103
        • Memisoglu A.
        • Hu F.B.
        • Hankinson S.E.
        • Manson J.E.
        • De Vivo I.
        • Willett W.C.
        • et al.
        Interaction between a peroxisome proliferator–activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass.
        Hum Mol Genet. 2003; 12: 2923-2929
        • Cecil J.E.
        • Fischer B.
        • Doney A.S.
        • Hetherington M.
        • Watt P.
        • Wrieden W.
        • et al.
        The Pro12Ala and C-681G variants of the PPARG locus are associated with opposing growth phenotypes in young schoolchildren.
        Diabetologia. 2005; 48: 1496-1502
        • Scaglioni S.
        • Verduci E.
        • Salvioni M.
        • Biondi M.L.
        • Radaelli G.
        • Agostoni C.
        • et al.
        PPAR-gamma2 Pro12Ala variant, insulin resistance and plasma long-chain polyunsaturated fatty acids in childhood obesity.
        Pediatr Res. 2006; 60: 485-489
        • Chen L.
        • Velasco Mondragon H.E.
        • Lazcano-Ponce E.
        • Collins A.
        • Shugart Y.Y.
        Effect of the peroxisome proliferators–activated receptor (PPAR) gamma 3 gene on BMI in 1,210 school students from Morelos, Mexico.
        Pac Symp Biocomput. 2006; : 467-477
        • Lagou V.
        • Scott R.A.
        • Manios Y.
        • Chen T.L.
        • Wang G.
        • Grammatikaki E.
        • et al.
        Impact of peroxisome proliferator–activated receptors gamma and delta on adiposity in toddlers and preschoolers in the GENESIS Study.
        Obesity (Silver Spring). 2008; 16: 913-918
        • Lasky-Su J.
        • Lyon H.N.
        • Emilsson V.
        • Heid I.M.
        • Molony C.
        • Raby B.A.
        • et al.
        On the replication of genetic associations: timing can be everything!.
        Am J Hum Genet. 2008; 82: 849-858
        • Papoutsakis C.
        • Vidra N.V.
        • Hatzopoulou I.
        • Tzirkalli M.
        • Farmaki A.E.
        • Evagelidaki E.
        • et al.
        The Gene-Diet Attica investigation on childhood obesity (GENDAI): overview of the study design.
        Clin Chem Lab Med. 2007; 45: 309-315
        • Manios Y.
        Design and descriptive results of the “Growth, Exercise and Nutrition Epidemiological Study In preSchoolers”: the GENESIS study.
        BMC Public Health. 2006; 6: 32
        • Frank G.C.
        • Berenson G.S.
        • Schilling P.E.
        • Moore M.C.
        Adapting the 24-hr. recall for epidemiologic studies of school children.
        J Am Diet Assoc. 1977; 71: 26-31
        • Kafatos A.
        • Verhagen H.
        • Moschandreas J.
        • Apostolaki I.
        • Van Westerop J.J.
        Mediterranean diet of Crete: foods and nutrient content.
        J Am Diet Assoc. 2000; 100: 1487-1493
        • Sallis J.F.
        • Strikmiller P.K.
        • Harsha D.W.
        • Feldman H.A.
        • Ehlinger S.
        • Stone E.J.
        • et al.
        Validation of interviewer- and self-administered physical activity checklists for fifth grade students.
        Med Sci Sports Exerc. 1996; 28: 840-851
        • Manios Y.K.A.
        • Markakis G.
        Physical activity in 6-year-old children: validation of two proxy reports.
        Pediatr Exerc Sci. 1998; 10: 13
        • Tanner J.M.
        The measurement of maturity.
        Trans Eur Orthod Soc. 1975; : 45-60
        • Bonat S.
        • Pathomvanich A.
        • Keil M.F.
        • Field A.E.
        • Yanovski J.A.
        Self-assessment of pubertal stage in overweight children.
        Pediatrics. 2002; 110: 743-747
        • Duke P.M.
        • Litt I.F.
        • Gross R.T.
        Adolescents' self-assessment of sexual maturation.
        Pediatrics. 1980; 66: 918-920
        • Cole T.J.
        • Bellizzi M.C.
        • Flegal K.M.
        • Dietz W.H.
        Establishing a standard definition for child overweight and obesity worldwide: international survey.
        BMJ. 2000; 320: 1240-1243
        • Miller S.A.
        • Dykes D.D.
        • Polesky H.F.
        A simple salting out procedure for extracting DNA from human nucleated cells.
        Nucleic Acids Res. 1988; 16: 1215
        • Deeb S.S.
        • Fajas L.
        • Nemoto M.
        • Pihlajamaki J.
        • Mykkanen L.
        • Kuusisto J.
        • 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
        • Ylonen S.K.
        • Salminen I.
        • Lyssenko V.
        • Virtanen S.M.
        • Groop L.
        • Aro A.
        • et al.
        The Pro12Ala polymorphism of the PPAR-gamma2 gene affects associations of fish intake and marine n-3 fatty acids with glucose metabolism.
        Eur J Clin Nutr. 2008; 62: 1432-1439