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2011 | 58 | 2 | 179-186
Article title

Hepatocyte nuclear factor 4 alpha P2 promoter variants associate with insulin resistance

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This study aimed to investigate the associations of hepatocyte nuclear factor 4 (HNF4) alpha single nucleotide polymorphisms (SNPs) and haplotype with insulin resistance and metabolic syndrome parameters. Nine SNPs spanning the HNF4 alpha P2 promoter (rs4810424, rs1884613 and rs1884614) and coding region (rs2144908, rs6031551, rs6031552, rs1885088, rs1028583 and rs3818247) were genotyped in 160 subjects without diabetes or metabolic syndrome. The HNF4 alpha P2 promoter SNPs rs4810424, rs1884613 and rs1884614 were associated with insulin resistance (p = 0.017; 0.037; 0.024) and body mass index (BMI) (p = 0.03; 0.035; 0.039). The intron 1D SNP rs2144908 was associated with high-density lipoprotein cholesterol (HDLc) (p = 0.020) and the intron 9 SNP rs3818247 showed association with systolic (p = 0.02) and diastolic (p = 0.034) blood pressure. HNF4 alpha common haplotype CCCGTC associated with higher insulin resistance (p = 0.022), fasting blood glucose (FBG) (p = 0.035) and lower HDLc (p = 0.001). In conclusion, subjects with HNF4 alpha P2 variants and haplotypes have been shown to have a higher insulin resistance and are therefore at a higher risk for developing type 2 diabetes mellitus.
Physical description
  • UKM Medical Molecular Biology Institute (UMBI), University Kebangsaan, Malaysia
  • UKM Medical Molecular Biology Institute (UMBI), University Kebangsaan, Malaysia
  • Institute of Biological Sciences, University of Malaya, Malaysia
  • UKM Medical Molecular Biology Institute (UMBI), University Kebangsaan, Malaysia
  • Amed S, Daneman D, Mahmud FH, Hamilton J (2010) Type 2 diabetes in children and adolescents. Expert Rev Cardiovasc Ther 8: 393-406.
  • Andrulionyte L, Laukkanen O, Chiasson JL, Laakso M (2006) Single nucleotide polymorphisms of the HNF4alpha gene are associated with the conversion to type 2 diabetes mellitus: the STOP-NIDDM trial. J Mol Med 84: 701-708.
  • Bolotin E, Liao H, Ta TC, Yang C, Hwang-Verslues W, Evans JR, Jiang T, Sladek FM (2010) Integrated approach for the identification of human hepatocyte nuclear factor 4alpha target genes using protein binding microarrays. Hepatology 51: 642-653.
  • Bonnycastle LL, Willer CJ, Conneely KN, Jackson AU, Burrill CP, Watanabe RM, Chines PS, Narisu N, Scott LJ, Enloe ST, Swift AJ, Duren WL, Stringham HM, Erdos MR, Riebow NL, Buchanan TA, Valle TT, Tuomilehto J, Bergman RN, Mohlke KL, Boehnke M, Collins FS (2006) Common variants in maturity-onset diabetes of the young genes contribute to risk of type 2 diabetes in Finns. Diabetes 55: 2534-2540.
  • Cali AM, Caprio S (2008) Prediabetes and type 2 diabetes in youth: an emerging epidemic disease? Curr Opin Endocrinol Diabetes Obes 15: 123-127.
  • Gonzalez FJ (2008) Regulation of hepatocyte nuclear factor 4 alpha-mediated transcription. Drug Metab Pharmacokinet 23: 2-7.
  • Haffner SM, Mykkanen L, Festa A, Burke JP, Stern MP (2000) Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the prediabetic state. Circulation 101: 975-980.
  • Hansen SK, Rose CS, Glumer C, Drivsholm T, Borch-Johnsen K, Jorgensen T, Pedersen O, Hansen T (2005) Variation near the hepatocyte nuclear factor (HNF)-4alpha gene associates with type 2 diabetes in the Danish population. Diabetologia 48: 452-458.
  • Holmkvist J, Almgren P, Lyssenko V, Lindgren CM, Eriksson KF, Isomaa B, Tuomi T, Nilsson P, Groop L (2008) Common variants in maturity-onset diabetes of the young genes and future risk of type 2 diabetes. Diabetes 57: 1738-1744.
  • Holst-Schumacher I, Nunez-Rivas H, Monge-Rojas R, Barrantes-Santamaria M (2009) Components of the metabolic syndrome among a sample of overweight and obese Costa Rican school children. Food Nutr Bull 30: 161-170.
  • Leclercq IA, Da Silva Morais A, Schroyen B, Van Hul N, Geerts A (2007) Insulin resistance in hepatocytes and sinusoidal liver cells: mechanisms and consequences. J Hepatol 47: 142-156.
  • Lehman DM, Richardson DK, Jenkinson CP, Hunt KJ, Dyer TD, Leach RJ, Arya R, Abboud HE, Blangero J, Duggirala R, Stern MP (2007) P2 promoter variants of the hepatocyte nuclear factor 4alpha gene are associated with type 2 diabetes in Mexican Americans. Diabetes 56: 513-517.
  • Love-Gregory LD, Wasson J, Ma J, Jin CH, Glaser B, Suarez BK, Permutt MA (2004) 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 53: 1134-1140.
  • Nathan BM (2007) The increase of type 2 diabetes mellitus in children. Minn Med 90: 39-43.
  • Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, Murray HL, Volkert TL, Schreiber J, Rolfe PA, Gifford DK, Fraenkel E, Bell GI, Young RA (2004) Control of pancreas and liver gene expression by HNF transcription factors. Science 303: 1378-1381.
  • Parviz F, Matullo C, Garrison WD, Savatski L, Adamson JW, Ning G, Kaestner KH, Rossi JM, Zaret KS, Duncan SA (2003) Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 34: 292-296.
  • Phillips J, Phillips PJ (2009) Children get type 2 diabetes too. Aust Fam Physician 38: 699-703.
  • Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D, Spiegelman BM (2003) Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 423: 550-555.
  • Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ, Spiegelman BM (2003) Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. Proc Natl Acad Sci USA 100: 4012-4017.
  • Rhee J, Ge H, Yang W, Fan M, Handschin C, Cooper M, Lin J, Li C, Spiegelman BM (2006) Partnership of PGC-1alpha and HNF4alpha in the regulation of lipoprotein metabolism. J Biol Chem 281: 14683-14690.
  • Sesti G (2006) Pathophysiology of insulin resistance. Best Pract Res Clin Endocrinol Metab 20: 665-679.
  • Silander K, Mohlke KL, Scott LJ, Peck EC, Hollstein P, Skol AD, Jackson AU, Deloukas P, Hunt S, Stavrides G, Chines PS, Erdos MR, Narisu N, Conneely KN, Li C, Fingerlin TE, Dhanjal SK, Valle TT, Bergman RN, Tuomilehto J, Watanabe RM, Boehnke M, Collins FS (2004) Genetic variation near the hepatocyte nuclear factor-4 alpha gene predicts susceptibility to type 2 diabetes. Diabetes 53: 1141-1149.
  • Stoffel M, Duncan SA (1997) The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. Proc Natl Acad Sci USA 94: 13209-13214.
  • Wang H, Maechler P, Antinozzi PA, Hagenfeldt KA, Wollheim CB (2000) Hepatocyte nuclear factor 4alpha regulates the expression of pancreatic beta-cell genes implicated in glucose metabolism and nutrient-induced insulin secretion. J Biol Chem 275: 35953-35959.
  • Wanic K, Malecki MT, Wolkow PP, Klupa T, Skupien J, Bobrek J, Kozek E, Krolewski AS, Sieradzki J (2006) Polymorphisms in the gene encoding hepatocyte nuclear factor-4alpha and susceptibility to type 2 diabetes in a Polish population. Diabetes Metab 32: 86-88.
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