Association of ACACB polymorphisms with obesity and diabetes

Abstract

Acetyl-CoA carboxylase beta, encoded by the ACAB gene, plays an important role in the oxidation of fatty acids. The aim of this study was to check the hypothesis that allelic variants of ACACB influence the risk of obesity and type 2 diabetes mellitus. Twenty five tagging single nucleotide polymorphisms (SNPs) capturing common variants of the ACACB gene were selected and analyzed in two cohorts including 1695 postmenopausal women of the general population and in 161 women with severe obesity (BMI>35). In vitro binding of transcription factors was explored by electrophoretic mobility shift assays (EMSA). T alleles at the rs2268388 locus were overrepresented in women with severe obesity (18% vs. 10% in controls; OR 1.74 [95% confidence interval 1.30-2.47]), which was statistically significant after multiple-test adjustment (p=0.0004). Likewise, T alleles at the rs2268388 locus and C alleles at the rs2239607 locus were associated with diabetes, in the discovery as well as in the replication cohorts, even after women with severe obesity were excluded (OR 3.6 and 2.8, for TT and CC homozygotes, respectively). Allelic differences in the binding affinity for nuclear proteins were revealed in vitro by EMSA and competition experiments were consistent with the binding of glucorticoid receptor and serum response factor. In conclusion, common polymorphisms of ACACB gene are associated with obesity and, independently, with type 2 diabetes in postmenopausal women, suggesting that the activity of acetyl-CoA carboxylase beta plays an important role in these disorders related to energy metabolism.

Identification of key genes and pathways associated with obesity in children

“…ACACB, one isoform of ACAC, is involved in fatty acid oxidation (36,37). The variants of the ACACB allele are associated with obesity (38). A previous study showed that body fat may act as a mechanism of metabolic adaptation and a signal that downregulated ACACB expression in adipose tissue (39).…”

“…A previous study showed that body fat may act as a mechanism of metabolic adaptation and a signal that downregulated ACACB expression in adipose tissue (39). In addition, rs2268388 polymorphisms of ACACB are associated with severe obesity and ACACB has a significant part in disorders associated with energy metabolism such as obesity (38). Furthermore, ACACB is involved in triglyceride synthesis and triglyceride contents of soleus muscle were greater in obese than in lean individuals (40,41).…”

Genomic structural variations for cardiovascular and metabolic comorbidity

“…At the juncture of lipid synthesis and oxidation pathways, inhibition of this enzyme presents a therapeutic target for metabolic syndrome. ACACB polymorphisms are associated with obesity, diabetes and metabolic syndrome in humans52. The gain in 12q24.11 ( ACACB ) was described in the DGV.…”

A genetic variant in the LDLRpromoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia

“…Preparation of nuclear extracts from sub-confluent HepG2 cell cultures and Electrophoretic Mobility Shift Assays (EMSAs) were done as reported by Riancho et al [26]. The gel bands were analyzed in an ODYSSEY infrared imaging system (Li-Cor Biosciences, Lincoln, NE).…”