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

BMC Medical Genomics

Ahmed H Kissebah⁵  Melanie A Carless⁴  John Blangero⁴  Michael Olivier¹  Robert Diasio²  Omar Ali³  Diana Cerjak³  Adam Lee²  Jack W Kent⁴  Yi Zhang⁵ 

[1] Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA;Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA;Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA;Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas 78245, USA;Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA

关键词: Association studies;    Family studies;    Fatty acid binding proteins;    Metabolic syndrome;    Epigenetic regulation;   

Others  :  1098154
DOI  :  10.1186/1755-8794-6-9

 received in 2012-10-08, accepted in 2013-03-06,  发布年份 2013

【 摘 要 】

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 (β_WHR = −0.72; β_LDL-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.

【 授权许可】

   
2013 Zhang et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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Figure 3.

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