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. 2011;6(8):e23860.
doi: 10.1371/journal.pone.0023860. Epub 2011 Aug 26.

The effect of ACACB cis-variants on gene expression and metabolic traits

Lijun Ma  1 , Ashis K Mondal, Mariana Murea, Neeraj K Sharma, Anke Tönjes, Kurt A Langberg, Swapan K Das, Paul W Franks, Peter Kovacs, Peter A Antinozzi, Michael Stumvoll, John S Parks, Steven C Elbein, Barry I Freedman
Affiliations

The effect of ACACB cis-variants on gene expression and metabolic traits

Lijun Ma et al. PLoS One. 2011.

Abstract

Background: Acetyl Coenzyme A carboxylase β (ACACB) is the rate-limiting enzyme in fatty acid oxidation, and continuous fatty acid oxidation in Acacb knock-out mice increases insulin sensitivity. Systematic human studies have not been performed to evaluate whether ACACB variants regulate gene expression and insulin sensitivity in skeletal muscle and adipose tissues. We sought to determine whether ACACB transcribed variants were associated with ACACB gene expression and insulin sensitivity in non-diabetic African American (AA) and European American (EA) adults.

Methods: ACACB transcribed single nucleotide polymorphisms (SNPs) were genotyped in 105 EAs and 46 AAs whose body mass index (BMI), lipid profiles and ACACB gene expression in subcutaneous adipose and skeletal muscle had been measured. Allelic expression imbalance (AEI) was assessed in lymphoblast cell lines from heterozygous subjects in an additional EA sample (n = 95). Selected SNPs were further examined for association with insulin sensitivity in a cohort of 417 EAs and 153 AAs.

Results: ACACB transcribed SNP rs2075260 (A/G) was associated with adipose ACACB messenger RNA expression in EAs and AAs (p = 3.8×10(-5), dominant model in meta-analysis, Stouffer method), with the (A) allele representing lower gene expression in adipose and higher insulin sensitivity in EAs (p = 0.04). In EAs, adipose ACACB expression was negatively associated with age and sex-adjusted BMI (r = -0.35, p = 0.0002).

Conclusions: Common variants within the ACACB locus appear to regulate adipose gene expression in humans. Body fat (represented by BMI) may further regulate adipose ACACB gene expression in the EA population.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Linkage Disequilibrium (LD) plot of studied ACACB SNPs.
1a: Linkage Disequilibrium (LD) plot of studied ACACB SNPs in European Americans. 1b. Linkage Disequilibrium (LD) plot of studied ACACB SNPs in African Americans.
Figure 2
Figure 2. Adipose ACACB expression vs. rs2075260 in European Americans (EA) and African Americans (AA).
Data are presented as least squares mean±SE after controlling age, sex, and BMI. * The ends of the error bar are the only two data points of ACACB expression values (adjusted for age, sex, and BMI) for this genotypic group. P values were adjusted for age, sex, and BMI. Fisher and Stouffer's methods were used for meta-analysis.
Figure 3
Figure 3. Allelic Expression of G of rs2075260 in both genomic and cDNAs of Utah EA lymphoblast cell lines (n = 18).
Figure 4
Figure 4. Insulin sensitivity by genotype of rs2075260 in European Americans.
Data are presented as least squares mean±SE after controlling age, sex, BMI, cohort, and sibship. Additive P-value was adjusted for age, sex, BMI, cohort, and sibship (GEE model).
Figure 5
Figure 5. Adipose ACACB expression vs. adjusted BMI.
Figure 5a Adipose ACACB expression vs. adjusted BMI in EA. Figure 5b Adipose ACACB expression vs. adjusted BMI in AA.
See this image and copyright information in PMC

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