Association Between Functional FABP2 Promoter Haplotype and Type 2 Diabetes

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, HbA (1c), 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.

Visualization of Sex-Dimorphic Changes in the Intestinal Transcriptome of <b><i>Fabp2</i></b> Gene-Ablated Mice

“…In this regard, Fabp2 –/– mice represent a model of extreme attenuation of FABP2 gene promoter function. Similar polymorphisms have also been found in other human populations [36,37,38,39]. The FABP2 ‘promoter B’ variant [38] which shares the same deletion found in the Pima Indian FABP2 T54 gene promoter was found to be associated with both the A54 and T54 alleles in a German cohort [37], and individuals from this cohort who are homozygous for both the promoter B and T54 alleles exhibit increased postprandial lipemia and lower insulin sensitivity [37].…”

“…The FABP2 ‘promoter B’ variant [38] which shares the same deletion found in the Pima Indian FABP2 T54 gene promoter was found to be associated with both the A54 and T54 alleles in a German cohort [37], and individuals from this cohort who are homozygous for both the promoter B and T54 alleles exhibit increased postprandial lipemia and lower insulin sensitivity [37]. However, the interplay between FABP2 promoter B and A54 and T54 alleles requires further clarification since the FABP2 promoter B was found to be associated with reduced risk of type 2 diabetes in male subjects of another German cohort [38]. …”

Functional analysis of promoter variants in the microsomal triglyceride transfer protein (MTTP) gene

“…All amplifications were performed for 30 cycles at 951C for 45 seconds, a touchdown from 581C to 541C for 30 seconds, and 721C for 1 minute in a buffer containing 2 mM MgSO 4 , 10 mM dNTP, and 0.5 U Pfu polymerase. Cloning procedures were performed using Gateway Technology (Invitrogen, Karlsruhe, Germany), described previously [Li et al, 2006]. attR-sites were inserted into an EcoRV (Promega, Mannheim, Germany) blunt-end site of the reporter plasmid pGL4.10[luc2] encoding Firefly luciferase.…”

Type 2 diabetes-associated fatty acid binding protein 2 promoter haplotypes are differentially regulated by GATA factors

“…More recently, FABP2 promoter haplotypes were associated with postprandial triglyceride levels [Geschonke et al, 2002], body mass index (BMI) [Damcott et al, 2003], and type 2 diabetes . The FABP2 coding and promoter polymorphisms are in strong or complete linkage disequilibrium (D 0 0.6-1.0) [Damcott et al, 2003;Formanack and Baier, 2004;Li et al, 2006]. In accordance with the association studies, male FABP2 knockout mice showed key symptoms of the metabolic syndrome such as increased plasma levels of insulin and triglyceride, increased body weight, and changes in liver histology, possibly resulting from impaired lipid metabolism [Agellon et al, 2006;Vassileva et al, 2000].…”