The CIDEA Gene V115F Polymorphism Is Associated With Obesity in Swedish Subjects

Abstract

The cell death-inducing DFFA (DNA fragmentation factor-␣)-like effector A (CIDEA) gene is implicated as an important regulator of body weight in mice and humans and is therefore a candidate gene for human obesity. Here, we characterize common CIDEA gene polymorphisms and investigate them for association with obesity in two independent Swedish samples; the first comprised 981 women and the second 582 men. Both samples display a large variation in BMI. The only detected coding polymorphism encodes an exon 4 V115F amino acid substitution, which is associated with BMI in both sexes (P ‫؍‬ 0.021 for women, P ‫؍‬ 0.023 for men, and P ‫؍‬ 0.0015 for joint analysis). These results support a role for CIDEA alleles in human obesity. CIDEAdeficient mice display higher metabolic rate, and the gene cross-talks with tumor necrosis factor-␣ (TNF-␣) in fat cells. We hypothesize that CIDEA alleles regulate human obesity through impact on basal metabolic rate and adipocyte TNF-␣ signaling. Diabetes 54:3032-3034, 2005

Obesity and polymorphisms in genes regulating human adipose tissue

“…One such identified obesity candidate gene is CIDEA. 4,5 Of course, there are limits to the usefulness of the microarray approach for identifying adipose genes of importance for obesity. For genes differentially expressed between case and control cohorts, we cannot differentiate between what is primary cause and what is secondary association; one consistent finding is upregulation of inflammatory genes in adipose tissue of obese humans, which intuitively is of greater importance for the metabolic complications of obesity than for obesity per se.…”

“…134,135 Adipose tissue CIDEA levels are reduced in obese humans and one non-synonymous SNP has been associated with obesity in female and male Swedes. 5,135 Insulin signalling in adipocytes Insulin stimulates the build-up of lipid stores in adipose tissue and an insulin gene variable number of tandem repeat is associated with juvenile obesity, implying a role for genes participating in insulin signalling in genetic susceptibility to obesity. 15,136 Polymorphisms in the insulin receptor (INSR) or insulin receptor substrate genes do not seem to affect human adiposity.…”

Characterization of the human CIDEA promoter in fat cells

“…6 In vitro-differentiated human adipocytes were transfected with reporter constructs containing three different haplotypes. However, we observed no difference in luciferase activity among the constructs (Figure 2b).…”

“…Moreover, a single nucleotide polymorphism (SNP) in exon 4 of CIDEA, C19787G-T, resulting in a V115F amino acid substitution, is associated with body mass index (BMI) in a Swedish cohort of both genders. 6 CIDEA mRNA is downregulated by TNF-a, a cytokine overexpressed in obesity. It is not known whether this is mediated through direct effects on transcription or post-transcriptional mechanisms, for example decreased mRNA stability.…”

“…7 In this study, we characterized the human CIDEA promoter in human fat cells and 3T3-L1 cells and studied the effect of TNF-a on promoter activity. Furthermore, several SNPs in the 5 0 flanking region of human CIDEA have recently been described 6 and we assessed the effect of the three most common haplotypes in this region on the transcriptional regulation of CIDEA.…”