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Variation in the FABP2 promoter alters transcriptional activity and is associated with body composition and plasma lipid levels

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Abstract

The fatty acid-binding proteins (FABPs) are cytoplasmic proteins involved in intracellular fatty acid transport and metabolism. FABP2, the intestinal-type FABP, is expressed exclusively in enterocytes in the small intestine. In previous studies of an Ala54Thr substitution in FABP2, the Thr-allele showed association with increased lipid oxidation, elevated plasma lipids, and impaired insulin sensitivity. We screened roughly 1 kb 5' of the FABP2 initiation codon and identified three insertion/deletion polymorphisms and four single nucleotide polymorphisms (SNPs). Three of the SNPs were in complete linkage disequilibrium with the three insertion/deletion polymorphisms, defining exactly two haplotypes (FABP2p-ID). We tested the hypothesis that this variation alters gene expression by transfecting Caco-2 cells with pGL3-Basic constructs containing opposite FABP2p-ID haplotypes. Luciferase assays showed a statistically significant two-fold increase in gene expression of the pGL3-insertion construct over the pGL3-deletion construct (P<0.001; n=5). We also tested for association between three FABP2 variants and measurements of body composition, plasma lipids, and insulin sensitivity in non-diabetic control subjects from the San Luis Valley Diabetes Study (n=714). The only informative variant, FABP2p-ID, was statistically significantly associated with body mass index (P=0.042) and marginally associated with fat mass (P=0.084), cholesterol (P=0.066), and HOMA IR (a derived measure of insulin resistance; P=0.062) in the entire cohort. Similar associations were seen only in non-Hispanics when the analysis was stratified by ethnicity. Within the non-Hispanic subgroup, the effects of FABP2p-ID on plasma lipids were sex-specific. These results suggest that genetic variation in the 5' region of FABP2 affects transcriptional activity, presumably leading to alterations in body composition and lipid processing.

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Acknowledgements

This work was supported by NIH grants DK-46204, DK-30747, and CRC-RR00051. The authors thank the residents of the San Luis Valley, Colo., for participating in this study and convey special thanks to Donna Kudla and Susana Montoya for technical assistance.

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Authors and Affiliations

  1. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pa., USA

    Coleen M. Damcott, Eleanor Feingold, Susan P. Moffett, M. Michael Barmada & Robert E. Ferrell

  2. Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colo., USA

    Julie A. Marshall & Richard F. Hamman

  3. Department of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, 660 W. Redwood Street, Baltimore, MD 21201, USA

    Coleen M. Damcott

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  1. Coleen M. Damcott
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  2. Eleanor Feingold
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  3. Susan P. Moffett
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  4. M. Michael Barmada
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  5. Julie A. Marshall
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  6. Richard F. Hamman
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  7. Robert E. Ferrell
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Correspondence to Coleen M. Damcott.

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Damcott, C.M., Feingold, E., Moffett, S.P. et al. Variation in the FABP2 promoter alters transcriptional activity and is associated with body composition and plasma lipid levels. Hum Genet 112, 610–616 (2003). https://doi.org/10.1007/s00439-003-0937-1

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  • DOI: https://doi.org/10.1007/s00439-003-0937-1

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