Download PDF
Horm Metab Res 2006; 38(5): 300-307
DOI: 10.1055/s-2006-925405
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Association Between Functional FABP2 Promoter Haplotype and Type 2 Diabetes

Y.  Li1 , E.  Fisher2 , M.  Klapper1 , H.  Boeing2 , A.  Pfeiffer2 , J.  Hampe3 , S.  Schreiber3 , B.  Burwinkel4 , J.  Schrezenmeir5 , F.  Döring1
  • 1 Molecular Nutrition, Christian-Albrechts University, Kiel, Germany
  • 2 Departments of Epidemiology (E.F. and H.B.) and Clinical Nutrition (AF), German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany
  • 3 Institute for Clinical Molecular Biology, Christian-Albrechts University, Kiel, Germany
  • 4 Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany
  • 5 Institute for Physiology and Biochemistry of Nutrition, Federal Research Centre for Nutrition and Food, Kiel, Germany
Further Information

Publication History

Received 22 August 2005

Accepted after revision 22 November 2005

Publication Date:
23 May 2006 (online)

Also available at
    Permissions and Reprints

Abstract

Fatty acid-binding protein 2 (FABP2) is a cytosolic protein expressed exclusively in epithelial cells of the small intestine. Some, albeit not conclusive, evidence indicates that the Thr-allele of FABP2 Ala54Thr polymorphism is associated with type 2 diabetes. More recently, common FABP2 promoter polymorphisms have shown association with postprandial increase of triglycerides, body composition and plasma lipid levels. Therefore, we reasoned that variants in the FABP2 promoter may also predispose to type 2 diabetes mellitus. In our Caucasian study population, we found three SNPs and three insertion-deletion polymorphisms that are in complete linkage disequilibrium defining promoter haplotype A and B within 1kb 5’ of the FABP2 initiation codon. Haplotype calculations indicated that the FABP2 promoter and Ala54Thr variants were strongly linked. Functional analysis of promoter fragments demonstrated that haplotype difference is caused by polymorphisms within 260 bp downstream of the FABP2 initiation codon. Using a prospective case-control study nested within the EPIC-Potsdam cohort of 192 incident type 2 diabetes cases and 384 sex-/age-matched controls, male subjects carrying the FABP2 haplotype B allele showed significantly decreased risk of type 2 diabetes when adjusted for BMI (OR = 0.50, 95 % CI = 0.28 - 0.87, p < 0.05) and additional covariates (OR = 0.42, 95 % CI 0.22 - 0.81, p < 0.01). Further adjustment for the Ala54Thr polymorphism revealed an OR of 0.18 (95 % CI 0.06 - 0.49, p < 0.001). Similarly, Ala/Ala homozygote males carrying the promoter haplotype B had decreased risk (0.33, 0.11 - 0.94, p < 0.05) of type 2 diabetes after stratification for the Ala54Thr polymorphism. FABP2 promoter haplotypes or genotype combinations defined by the promoter and Ala54Thr polymorphism were not associated with BMI, body fat, leptin, HbA1c, total cholesterol or HDL. In conclusion, our findings suggest that the functional FABP2 promoter haplotype may contribute to type 2 diabetes in a sex-specific manner.

Key words

Fatty acid-binding protein - polymorphism - case-control study - SEAP assay

References

  • 1 Bernlohr D A, Simpson M A, Hertzel A V, Banaszak L J. Intracellular lipid-binding proteins and their genes.  Annu Rev Nutr. 1997;  17 277-303
    CrossrefPubMedGoogle Scholar
  • 2 Baier L J, Bogardus C, Sacchettini J C. A polymorphism in the human intestinal fatty acid-binding protein alters fatty acid transport across Caco-2 cells.  J Biol Chem. 1996;  271 10 892-10 896
    PubMedGoogle Scholar
  • 3 Vassileva G, Huwyler L, Poirier K, Agellon L B, Toth M J. The intestinal fatty acid-binding protein is not essential for dietary fat absorption in mice.  Faseb J. 2000;  14 2040-2046
    CrossrefPubMedGoogle Scholar
  • 4 Prochazka M, Lillioja S, Tait J F, Knowler W C, Mott D M, Spraul M, Bennett P H. et al . Linkage of chromosomal markers on 4q with a putative gene determining maximal insulin action in Pima Indians.  Diabetes. 1993;  42 514-519
    PubMedGoogle Scholar
  • 5 Baier L J, Sacchettini J C, Knowler W C, Eads J, Paolisso G, Tataranni P A, Mochizuki H. et al . An amino acid substitution in the human intestinal fatty acid-binding protein is associated with increased fatty acid binding, increased fat oxidation, and insulin resistance.  J Clin Invest. 1995;  95 1281-1287
    PubMedGoogle Scholar
  • 6 Agren J J, Valve R, Vidgren H, Laakso M, Uusitupa M. Postprandial lipemic response is modified by the polymorphism at codon 54 of the fatty acid-binding protein 2 gene.  Arterioscler Thromb Vasc Biol. 1998;  18 1606-1610
    PubMedGoogle Scholar
  • 7 Chiu K C, Chuang L M, Yoon C. The A54T polymorphism at the intestinal fatty acid-binding protein 2 is associated with insulin resistance in glucose tolerant Caucasians.  BMC Genet. 2001;  2 7
    CrossrefPubMedGoogle Scholar
  • 8 Galluzzi J R, Cupples L A, Meigs J B, Wilson P W, Schaefer E J, Ordovas J M. Association of the Ala54-Thr polymorphism in the intestinal fatty acid-binding protein with 2-h postchallenge insulin levels in the Framingham Offspring Study.  Diabetes Care. 2001;  24 1161-1166
    PubMedGoogle Scholar
  • 9 Galluzzi J R, Cupples L A, Otvos J D, Wilson P W, Schaefer E J, Ordovas J M. Association of the A/T54 polymorphism in the intestinal fatty acid-binding protein with variations in plasma lipids in the Framingham Offspring Study.  Atherosclerosis. 2001;  159 417-424
    CrossrefPubMedGoogle Scholar
  • 10 Pihlajamaki J, Rissanen J, Heikkinen S, Karjalainen L, Laakso M. Codon 54 polymorphism of the human intestinal fatty acid-binding protein 2 gene is associated with dyslipidemias but not with insulin resistance in patients with familial combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 1997;  17 1039-1044
    PubMedGoogle Scholar
  • 11 Yamada K, Yuan X, Ishiyama S, Koyama K, Ichikawa F, Koyanagi A, Koyama W. et al . Association between Ala54Thr substitution of the fatty acid-binding protein 2 gene with insulin resistance and intra-abdominal fat thickness in Japanese men.  Diabetologia. 1997;  40 706-710
    CrossrefPubMedGoogle Scholar
  • 12 Lei H H, Coresh J, Shuldiner A R, Boerwinkle E, Brancati F L. Variants of the insulin receptor substrate-1 and fatty acid-binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in African-Americans: the Atherosclerosis Risk in Communities Study.  Diabetes. 1999;  48 1868-1872
    PubMedGoogle Scholar
  • 13 Tahvanainen E, Molin M, Vainio S, Tiret L, Nicaud V, Farinaro E, Masana L. et al . Intestinal fatty acid-binding protein polymorphism at codon 54 is not associated with postprandial responses to fat and glucose tolerance tests in healthy young Europeans. Results from EARS II participants.  Atherosclerosis. 2000;  152 317-325
    CrossrefPubMedGoogle Scholar
  • 14 Erkkila A T, Lindi V, Lehto S, Pyorala K, Laakso M, Uusitupa M I. Variation in the fatty acid-binding protein 2 gene is not associated with markers of metabolic syndrome in patients with coronary heart disease.  Nutr Metab Cardiovasc Dis. 2002;  12 53-59
    PubMedGoogle Scholar
  • 15 Hayakawa T, Nagai Y, Nohara E, Yamashita H, Takamura T, Abe T, Nomura G. et al . Variation of the fatty acid-binding protein 2 gene is not associated with obesity and insulin resistance in Japanese subjects.  Metabolism. 1999;  48 655-657
    CrossrefPubMedGoogle Scholar
  • 16 Damcott C M, Feingold E, Moffett S P, Barmada M M, Marshall J A, Hamman R F, Ferrell R E. Variation in the FABP2 promoter alters transcriptional activity and is associated with body composition and plasma lipid levels.  Hum Genet. 2003;  112 610-616
    PubMedGoogle Scholar
  • 17 Formanack M L, Baier L J. Variation in the FABP2 promoter affects gene expression: implications for prior association studies.  Diabetologia. 2004;  47 349-351
    CrossrefPubMedGoogle Scholar
  • 18 Geschonke K, Klempt M, Lynch N, Schreiber S, Fenselau S, Schrezenmeir J. Detection of a promoter polymorphism in the gene of intestinal fatty acid-binding protein (I-FABP).  Ann N Y Acad Sci. 2002;  967 548-553
    PubMedGoogle Scholar
  • 19 Boeing H, Korfmann A, Bergmann M M. Recruitment procedures of EPIC-Germany. European Investigation into Cancer and Nutrition.  Ann Nutr Metab. 1999;  43 205-215
    PubMedGoogle Scholar
  • 20 Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann M M, Ristow M, Boeing H. et al . Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC) Potsdam Study.  Diabetes. 2003;  52 812-817
    CrossrefPubMedGoogle Scholar
  • 21 Nakanishi S, Yamane K, Kamei N, Okubo M, Kohno N. The effect of polymorphism in the intestinal fatty acid-binding protein 2 gene on fat metabolism is associated with gender and obesity amongst non-diabetic Japanese-Americans.  Diabetes Obes Metab. 2004;  6 45-49
    CrossrefPubMedGoogle Scholar
  • 22 Wyszynski D F, Panhuysen C I. Parental sex effect in families with alcoholism.  Genet Epidemiol. 1999;  17 Suppl 1 S409-413
    PubMedGoogle Scholar
  • 23 Henle G, Deinhardt F, Rodriguez J. The development of polyoma virus in mouse embryo cells as revealed by fluorescent antibody staining.  Virology. 1959;  8 388-391
    CrossrefPubMedGoogle Scholar
  • 24 Lavappa K S. Survey of ATCC stocks of human cell lines for HeLa contamination.  In Vitro. 1978;  14 469-475
    PubMedGoogle Scholar
  • 25 Lavappa K S, Macy M L, Shannon J E. Examination of ATCC stocks for HeLa marker chromosomes in human cell lines.  Nature. 1976;  259 211-213
    PubMedGoogle Scholar
  • 26 Mochizuki K, Suruga K, Yagi E, Takase S, Goda T. The expression of PPAR-associated genes is modulated through postnatal development of PPAR subtypes in the small intestine.  Biochim Biophys Acta. 2001;  1531 68-76
    PubMedGoogle Scholar
  • 27 Dworatzek P D, Hegele R A, Wolever T M. Postprandial lipemia in subjects with the threonine 54 variant of the fatty acid-binding protein 2 gene is dependent on the type of fat ingested.  Am J Clin Nutr. 2004;  79 1110-1117
    PubMedGoogle Scholar
  • 28 Brubaker P L, Anini Y. Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2.  Can J Physiol Pharmacol. 2003;  81 1005-1012
    CrossrefPubMedGoogle Scholar
  • 29 Korczynska J, Stelmanska E, Swierczynski J. Differential effect of long-term food restriction on fatty acid synthase and leptin gene expression in rat white adipose tissue.  Horm Metab Res. 2003;  35 593-597
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Marion-Latard F, Crampes F, Zakaroff-Girard A, DeGlisezinski I, Harant I, Stich V, Thalamas C, Reviere D, Lafontan M, Berlan M. Post-exercise increase of lipid oxidation after a moderate exercise bout in untrained healthy obese men.  Horm Metab Res. 2003;  35 97-103
    Article in Thieme ConnectPubMedGoogle Scholar

Frank Döring

Molecular Nutrition

University of Kiel · Hermann-Weigmann-Strasse 1 · 24103 Kiel · Germany

Fax: +49 (0) 431-6092472

Email: doering@molmat.uni-kiel.de

      >