title: Fatty acid binding protein 3 (fabp3) is associated with insulin, lipids and cardiovascular phenotypes of the metabolic syndrome through epigenetic modifications in a Northern European family population.
abstract: BACKGROUND
  Fatty acid-binding proteins (FABPs) play regulatory roles at the nexus of lipid metabolism and signaling. Dyslipidemia in clinical manifestation frequently co-occurs with obesity, insulin resistance and hypertension in the Metabolic Syndrome (MetS). Animal studies have suggested FABPs play regulatory roles in expressing MetS phenotypes. In our family cohort of Northern European descent, transcript levels in peripheral white blood cells (PWBCs) of a key FABPs, FABP3, is correlated with the MetS leading components. However, evidence supporting the functions of FABPs in humans using genetic approaches has been scarce, suggesting FABPs may be under epigenetic regulation. The objective of this study was to test the hypothesis that CpG methylation status of a key regulator of lipid homeostasis, FABP3, is a quantitative trait associated with status of MetS phenotypes in humans.
  
  
  METHODS
  We used a mass-spec based quantitative method, EpiTYPER®, to profile a CpG island that extends from the promoter to the first exon of the FABP3 gene in our family-based cohort of Northern European descent (n=517). We then conducted statistical analysis of the quantitative relationship of CpG methylation and MetS measures following the variance-component association model. Heritability of each methylation and the effect of age and sex on CpG methylation were also assessed in our families.
  
  
  RESULTS
  We find that methylation levels of individual CpG units and the regional average are heritable and significantly influenced by age and sex. Regional methylation was strongly associated with plasma total cholesterol (p=0.00028) and suggestively associated with LDL-cholesterol (p=0.00495). Methylation at individual units was significantly associated with insulin sensitivity, lipid particle sizing and diastolic blood pressure (p<0.0028, corrected for multiple testing for each trait). Peripheral white blood cell (PWBC) expression of FABP3 in a separate group of subjects (n=128) negatively correlated with adverse profiles of metabolism (βWHR=-0.72; βLDL-c=-0.53) while positively correlated with plasma adiponectin (β=0.24). Further, we show that differential methylation of FABP3 affects binding activity with nuclear proteins from heart tissue. This region that we found under methylation regulation overlaps with a region actively modified by histone codes in the newly available ENCODE data.
  
  
  CONCLUSIONS
  Our findings suggest that DNA methylation of FABP3 strongly influences MetS, and this may have important implications for cardiovascular disease.
authors.affiliation: TOPS Obesity and Metabolic Research Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. szhang@mcw.edu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jack W
authors.initials: JW
authors.lastname: Kent
authors.forename: Adam
authors.initials: A
authors.lastname: Lee
authors.forename: Diana
authors.initials: D
authors.lastname: Cerjak
authors.forename: Omar
authors.initials: O
authors.lastname: Ali
authors.forename: Robert
authors.initials: R
authors.lastname: Diasio
authors.forename: Michael
authors.initials: M
authors.lastname: Olivier
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Carless
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Kissebah
mesh_terms: D052242:Adiponectin / Q000097:blood; D000328:Adult; D001794:Blood Pressure; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005091:Exons; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D010316:Particle Size; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011485:Protein Binding
chemical_list: D052242:Adiponectin; D008078:Cholesterol, LDL; C493408:FABP3 protein, human; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D007328:Insulin; D008055:Lipids; D002784:Cholesterol