Alternative titles; symbols
HGNC Approved Gene Symbol: FABP2
Cytogenetic location: 4q26 Genomic coordinates (GRCh38): 4:119,317,250-119,322,138 (from NCBI)
Intestinal fatty acid-binding protein is an abundant cytosolic protein in small intestine epithelial cells. It may participate in the uptake, intracellular metabolism and/or transport of long chain fatty acids (summary by Sweetser et al., 1987). See also FABP1 (134650), FABP3 (134651), and FABP4 (600434).
Sweetser et al. (1987) cloned the human intestinal fatty acid-binding gene, which encodes a 132-amino acid protein that shares 82% sequence identity with the homologous rat protein.
Sweetser et al. (1987) determined that the FABP2 gene contains 4 exons.
Sparkes et al. (1987) used a human cDNA probe to assign the FABP2 gene to chromosome 4 in somatic cell hybrids. Using the same probe for in situ hybridization studies, they regionalized the assignment to 4q28-q31. The intestinal form of FABP was mapped to mouse chromosome 3 between the amylase and alcohol dehydrogenase-3 loci (Sweetser et al., 1987).
Polymeropoulos et al. (1991) presented data on the polymorphic (TTA)n repeat in the FABP2 gene; the polymorphism can be typed using PCR as described by Weber and May (1989) and Weber et al. (1990).
The Pima Indians of Arizona have the highest reported prevalence of noninsulin-dependent diabetes mellitus (NIDDM; 125853) of any population in the world; more than half of the population over 35 years of age has the disease. Prochazka et al. (1993) found linkage between measures of insulin action in Pimas (fasting insulin concentrations and maximum insulin-stimulated glucose uptake) and a region on chromosome 4q near the FABP2 locus. Since fatty acid metabolism has long been linked to insulin resistance, Baier et al. (1995) analyzed FABP2 as a candidate gene for determining insulin action. They found a polymorphism at codon 54 (see 134640.0001) that identified an alanine-encoding allele (frequency 0.71) and a threonine-encoding allele (frequency 0.29). Pimas who were homozygous or heterozygous for the threonine-encoding allele were found to have a higher mean fasting plasma insulin concentration, a lower mean insulin-stimulated glucose uptake rate, a higher mean insulin response to oral glucose with a mixed meal, and a higher mean fat oxidation rate compared with Pimas who were homozygous for the alanine-encoding allele. Titration microcalorimetry studies with purified recombinant FABP2 protein showed that the threonine-containing protein had a 2-fold greater affinity for long chain fatty acids than the alanine-containing protein. Baier et al. (1995) concluded that the threonine-containing protein may increase absorption and/or processing of dietary fatty acids by the intestine and therefore increase fat oxidation, which has been shown to reduce insulin action.
Hegele et al. (1996) hypothesized that allelic variation in the amino acid sequence of the FABP2 could be related to variation in body mass index (BMI) and associated clinical phenotypes in aboriginal Canadians. They studied 507 adult native Canadians from an isolated community in northern Ontario and found that the frequency of the threonine-54 variant of the FABP2 gene was 0.14 in this sample. The presence of this variant was associated with significant increases in BMI, percent body fat, and fasting plasma triglyceride concentration (P = 0.012, 0.019, and 0.012, respectively). However, the thr54 variant was not associated with the presence of diabetes mellitus. These findings suggested that the FABP2 thr54 variant is associated with differences in fat metabolism in this aboriginal population.
Sipilainen et al. (1997) screened the entire coding region of the FABP2 gene in samples from 40 obese nondiabetic Finnish subjects. They also investigated the effects of the ala54-to-thr polymorphism (A54T; 134640.0001) of this gene on insulin levels and basal metabolic rate in 170 obese subjects. The frequencies of the variants found in exon 4 (GTA-to-GTG) and the 3-prime noncoding region (GCGCA-to-GCACA), as well as the allele frequencies for the variable lengths of the ATT repeat sequence in intron 2, did not differ between the obese subjects and nonobese controls. The frequency of the ala54-to-thr polymorphism did not differ between obese and control subjects (28% vs 29%, respectively). The authors found that obesity is not associated with specific variants in the FABP2 gene and that the ala54-to-thr polymorphism does not influence insulin levels or basal metabolic rate in obese Finns.
To test the hypothesis that the A54T FABP2 polymorphism is associated with impaired lipid metabolism and cardiovascular disease, Carlsson et al. (2000) compared clinical characteristics and a parental history of cardiovascular disease between 213 sib pairs discordant for the polymorphism. Sibs with an excess of the thr54 allele had higher triglyceride and cholesterol concentrations than sibs with the ala54 allele. Parents of offspring with the thr/thr and thr/ala genotypes reported an increased prevalence of stroke compared to parents of offspring with the ala/ala genotype. The authors confirmed the association of the FABP2 thr54 allele with increased concentrations of cholesterol and triglycerides in genotype-discordant sib pairs. They also presented novel evidence that genetic variation in the FABP2 gene may increase susceptibility to stroke.
To assess whether increased intestinal triglyceride input leads to elevated fasting and postprandial triglycerides in type II diabetes (NIDDM), Georgopoulos et al. (2000) studied the A54T polymorphism of FABP2, which is associated with increased intestinal input of triglyceride. Of the 287 diabetic patients screened, 108 (37.6%) were heterozygous and 31 (10.8%) were homozygous for the thr54 allele. Mean fasting plasma triglyceride levels in 80 patients with the wildtype, 57 heterozygous for the thr54 allele, and 18 homozygous for it were 2.0 +/- 0.09, 2.7 +/- 0.20, and 3.8 +/- 0.43 mmol/L, respectively. A linear relationship of mean fasting plasma triglyceride levels between the 3 groups was found. After fat ingestion, the postprandial area under the curve of plasma triglyceride and chylomicrons was higher in 6 patients homozygous for the thr54 allele than in 9 wildtype patients. The authors concluded that their results support the hypothesis that, in type II diabetes, increased intestinal input of triglyceride can lead to elevated fasting and postprandial plasma triglycerides.
In contrast to patients with type II diabetes, those with type I diabetes (IDDM; 222100) are usually normolipidemic as judged by a fasting lipid profile. To assess whether the A54T polymorphism is associated with fasting and postprandial triglyceride elevation or dyslipidemia in type I diabetes, Georgopoulos et al. (2002) screened 181 patients with similar glycemic control as the type II patients. Thirty percent were heterozygous, and 9% were homozygous for the polymorphism, but fasting plasma triglyceride levels did not differ between ala54/ala54, ala54/thr54, and thr54/thr54 subjects. The authors concluded that in contrast to type II, type I diabetes does not interact with the codon 54 polymorphism of the FABP2 gene to cause hypertriglyceridemia/dyslipidemia.
Damcott et al. (2003) presented evidence from association studies in Hispanic and non-Hispanic white individuals living in the geographically isolated San Luis Valley of Colorado that genetic variation in the 5-prime region of FABP2 affects transcriptional activity, presumably leading to alterations in body composition and lipid processing.
Klapper et al. (2008) performed functional studies of the 6 SNPs in the FABP2 promoter region that define the so-called A and B haplotypes. Using electrophoretic mobility shift and transfection assays, they demonstrated that the 2- to 3-fold lower transcriptional activity of haplotype B compared to haplotype A was determined by the -80insT SNP (rs5861422) via transcription factors GATA5 (611496) and GATA6 (601656), which showed lower binding affinity to FABP with the -80insT allele compared to FABP lacking the -80insT allele.
Baier et al. (1995) found an association between insulin resistance and homozygosity or heterozygosity for the threonine-encoding allele among Pima Indians in Arizona.
Sipilainen et al. (1997) found that this polymorphism did not influence insulin levels or basal metabolic rate in obese Finns.
Carlsson et al. (2000) confirmed the association of the FABP2 thr54 allele with increased concentrations of cholesterol and triglycerides in genotype-discordant sib pairs and presented novel evidence that genetic variation in the FABP2 gene may increase susceptibility to stroke.
Georgopoulos et al. (2000) studied the ala54-to-thr (A54T) polymorphism of FABP2, which is associated with increased intestinal input of triglyceride, and concluded that their results support the hypothesis that, in type II diabetes (125853), increased intestinal input of triglyceride can lead to elevated fasting and postprandial plasma triglycerides.
Georgopoulos et al. (2002) concluded that in contrast to type II, type I diabetes (IDDM; 222100) does not interact with the codon 54 polymorphism of the FABP2 gene to cause hypertriglyceridemia/dyslipidemia.
Lara-Castro et al. (2005) examined the association between the A54T variant in the FABP2 gene and levels of visceral and subcutaneous abdominal fat in a group of 223 premenopausal women, 103 of whom were African-American and 120 Caucasian. The frequency of the 54T allele did not differ significantly by ethnic group. After adjusting for total body fat, total abdominal adipose tissue and subcutaneous abdominal fat were significantly lower in carriers of either 1 or 2 copies of the mutant thr allele (P less than 0.01). There was no association between total fat mass or visceral abdominal fat and the FABP2 polymorphism. Separate analyses by ethnic group showed that the association between the polymorphism and total abdominal fat and subcutaneous abdominal fat was observed in Caucasian (P less than 0.01), but not in African-American, women.
Formanack and Baier (2004) analyzed the promoter region of the FABP2 gene and identified 7 variations that were in complete concordance with each other and with the A54T variant in Pima Indians, but not in Caucasian subjects. The authors suggested that the phenotypic associations previously attributed to the A54T substitution, which alters binding characteristics of the protein, may instead be due to promoter variation, which alters expression levels.
Baier, L. J., Sacchettini, J. C., Knowler, W. C., Eads, J., Paolisso, G., Tataranni, P. A., Mochizuki, H., Bennett, P. H., Bogardus, C., Prochazka, M. 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. 95: 1281-1287, 1995. [PubMed: 7883976] [Full Text: https://doi.org/10.1172/JCI117778]
Carlsson, M., Orho-Melander, M., Hedenbro, J., Almgren, P., Groop, L. C. The T54 allele of the intestinal fatty acid-binding protein 2 is associated with a parental history of stroke. J. Clin. Endocr. Metab. 85: 2801-2804, 2000. [PubMed: 10946885] [Full Text: https://doi.org/10.1210/jcem.85.8.6751]
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. 112: 610-616, 2003. [PubMed: 12634920] [Full Text: https://doi.org/10.1007/s00439-003-0937-1]
Formanack, M. L., Baier, L. J. Variation in the FABP2 promoter affects gene expression: implications for prior association studies. Diabetologia 47: 349-351, 2004. [PubMed: 14666368] [Full Text: https://doi.org/10.1007/s00125-003-1289-z]
Georgopoulos, A., Aras, O., Noutsou, M., Tsai, M. Y. Unlike type 2 diabetes, type 1 does not interact with the codon 54 polymorphism of the fatty acid binding protein 2 gene. J. Clin. Endocr. Metab. 87: 3735-3739, 2002. [PubMed: 12161503] [Full Text: https://doi.org/10.1210/jcem.87.8.8728]
Georgopoulos, A., Aras, O., Tsai, M. Y. Codon-54 polymorphism of the fatty acid-binding protein 2 gene is associated with elevation of fasting and postprandial triglyceride in type 2 diabetes. J. Clin. Endocr. Metab. 85: 3155-3160, 2000. [PubMed: 10999802] [Full Text: https://doi.org/10.1210/jcem.85.9.6791]
Hegele, R. A., Harris, S. B., Hanley, A. J. G., Sadikian, S., Connelly, P. W., Zinman, B. Genetic variation of intestinal fatty acid-binding protein associated with variation in body mass in aboriginal Canadians. J. Clin. Endocr. Metab. 81: 4334-4337, 1996. [PubMed: 8954037] [Full Text: https://doi.org/10.1210/jcem.81.12.8954037]
Klapper, M., Bohme, M., Nitz, I., Doring, F. Type 2 diabetes-associated fatty acid binding protein 2 promoter haplotypes are differentially regulated by GATA factors. Hum. Mutat. 29: 142-149, 2008. [PubMed: 17960769] [Full Text: https://doi.org/10.1002/humu.20618]
Lara-Castro, C., Hunter, G. R., Lovejoy, J. C., Gower, B. A., Fernandez, J. R. Association of the intestinal fatty acid-binding protein ala(54)thr polymorphism and abdominal adipose tissue in African American and Caucasian women. J. Clin. Endocr. Metab. 90: 1196-1201, 2005. [PubMed: 15572430] [Full Text: https://doi.org/10.1210/jc.2004-0676]
Polymeropoulos, M. H., Rath, D. S., Xiao, H., Merril, C. R. Trinucleotide repeat polymorphism at the human intestinal fatty acid binding protein gene (FABP2). Nucleic Acids Res. 18: 7198 only, 1991.
Prochazka, M., Lillioja, S., Tait, J. F., Knowler, W. C., Mott, D. M., Spraul, M., Bennett, P. H., Bogardus, C. Linkage of chromosomal markers on 4q with a putative gene determining maximal insulin action in Pima Indians. Diabetes 42: 514-519, 1993. [PubMed: 8454101] [Full Text: https://doi.org/10.2337/diab.42.4.514]
Sipilainen, R., Uusitupa, M., Heikkinen, S., Rissanen, A., Laakso, M. Variants in the human intestinal fatty acid binding protein 2 gene in obese subjects. J. Clin. Endocr. Metab. 82: 2629-2632, 1997. [PubMed: 9253345] [Full Text: https://doi.org/10.1210/jcem.82.8.4179]
Sparkes, R. S., Mohandas, T., Heinzmann, C., Gordon, J. I., Klisak, I., Zollman, S., Sweetser, D. A., Ragunathan, L., Winokur, S., Lusis, A. J. Human fatty acid binding protein assignments intestinal to 4q28-4q31 and liver to 2p11. (Abstract) Cytogenet. Cell Genet. 46: 697 only, 1987.
Sweetser, D. A., Birkenmeier, E. H., Klisak, I. J., Zollman, S., Sparkes, R. S., Mohandas, T., Lusis, A. J., Gordon, J. I. The human and rodent intestinal fatty acid binding protein genes: a comparative analysis of their structure, expression, and linkage relationships. J. Biol. Chem. 262: 16060-16071, 1987. [PubMed: 2824476] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(18)47696-X]
Weber, J. L., Kwitek, A. E., May, P. E., Polymeropoulos, M. Dinucleotide repeat polymorphism at the D12S43 locus. Nucleic Acids Res. 18: 4637 only, 1990. [PubMed: 2388861]
Weber, J. L., May, P. E. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am. J. Hum. Genet. 44: 388-396, 1989. [PubMed: 2916582]