1 Department of Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden
2 Department of Biosciences, Clinical Research Center, Karolinska Institute, Stockholm, Sweden
3 Department of Medicine, Kuopio University Hospital, Kuopio, Finland
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ABSTRACT |
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The cell deathinducing DFFA (DNA fragmentation factor-)-like effector A (CIDEA) gene has been implicated as an important regulator of body weight in mice and humans and is therefore a candidate gene for human obesity. Several factors support that CIDEA is involved in the regulation of body weight. CIDEA-null mice are resistant to diet-induced obesity and diabetes and display higher metabolic rate and lipolysis in brown adipose tissue than their wild-type littermates (1). In obese women undergoing weight reduction through low-calorie diet, mRNA for CIDEA is the highest upregulated in subcutaneous adipose tissue among 8,000 investigated genes (2). Furthermore, CIDEA mRNA is downregulated in subcutaneous adipose tissue of obese subjects (3).
Obesity is the strongest risk factor for the development of type 2 diabetes, and there is a marked parallel increase in the prevalence of these two disorders in most countries. Although a genetic impact on common obesity is established, underlying susceptibility genes are largely unknown. The CIDEA gene is encoded on human chromosome 18p11.21. This region is established among Caucasians as a susceptibility locus for type 2 diabetes in connection with obesity (4). In addition, Chagnon et al. (5) has reported linkage and association of polymorphisms in the melanocortin receptor 5 (MC5R) gene on chromosome 18p11.2 with BMI. As far as we know, there is no publication of CIDEA gene polymorphisms and the gene promoter has not been characterized.
Based on the above, we consider CIDEA a strong candidate gene for obesity and here characterize common gene polymorphisms and analyze them for association with obesity in two Swedish samples.
By sequencing exons and surrounding regions of the CIDEA gene in 24 obese women and 2.2 kb upstream of exon 1 in 48 subjects, we detected 16 single nucleotide polymorphisms (SNPs) (Fig. 1). The only detected coding SNP, C19787GT, encodes an exon 4 V115F amino acid substitution. This polymorphism is located in a nonconserved region of the protein (Fig. 1). Since the targets for CIDEA action are unknown and overexpression of CIDEA leads to marked apoptosis (6), it is currently difficult to elucidate the consequence of this amino acid substitution. In addition, we detected seven common and two rare (allele frequency <5% in sequenced women) SNPs in the 5' region as well as three common and three rare SNPs in introns (Fig. 1).
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Using SNPHAP and attached programs, the CIDEA gene SNPs were estimated to define eight haplotypes with frequency >2% (Table 2) that comprised two haploblocks (Fig. 1). In the joint analysis of women and men, no haplotype was associated with obesity (results not shown).
The most important result of this study is the nominal association between BMI and the CIDEA V115F genotype in independent samples of Swedish women and men. Although these results will not remain significant if multiple testing of different loci is taken into account, the relevance of CIDEA gene alleles for obesity is supported by the similar phenotypic associations observed in two independent samples. Because the obese/nonobese phenotype is defined by BMI, it is not necessary to correct for multiple testing regarding these two investigated phenotypes. In addition, previous results with CIDEA in knock-out mice, human obesity, and humans undergoing weight reduction make the CIDEA gene, and in particular the only identified nonsynonomous SNP, a priori a strong candidate for common obesity (13). This should reduce the need for multiple comparison corrections. In addition, when the two materials are combined, the P value will still be significant when multiple comparisons are taken into account. We believe it is valid to combine the female and male cohorts because our results do not support a sex-specific effect on CIDEA. We consider the observed association of CIDEA V115F genotype with BMI, although preliminary, interesting and important to follow up. CIDEA-deficient mice display higher metabolic rate (1). In human fat cells, the gene cross talks with tumor necrosis factor- (TNF-
), which is an established candidate gene for obesity and influences lipolysis (3). We hypothesize that CIDEA alleles regulate human obesity through impact on basal metabolic rate, TNF-
signaling, and lipid metabolism in adipocytes.
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RESEARCH DESIGN AND METHODS |
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Two independently sampled datasets of adult subjects were used to investigate CIDEA impact on obesity. The major sample comprised 434 nonobese (aged 40 ± 10 years, BMI 24 ± 3 kg/m2) and 547 obese (aged 41 ± 11 years, BMI 39 ± 5 kg/m2) women. The second sample comprised 230 nonobese (aged 43 ± 15 years, BMI 24 ± 2 kg/m2) and 352 obese (aged 47 ± 11 years, BMI 40 ± 5 kg/m2) men. Obese men had higher waist circumference (129 ± 12 vs. 115 ± 12 cm), serum insulin (26 ± 16 vs. 17 ± 10 mU/l), and plasma triglycerides (2.2 ± 1.6 vs. 1.7 ± 0.9 mmol/l) than obese women. All individuals were recruited in Stockholm, Sweden, and were of Nordic origin for at least two generations. The obese subset included 77 women and 125 men with diagnosed hypertension, 32 women and 55 men with type 2 diabetes, and 3 women and 15 men with dyslipidemia. Otherwise, the subjects were healthy according to self-report and free of medication. Women and men were separately consecutively recruited in order to study candidate genes for obesity in men and women, respectively. Individuals came to the laboratory in the morning after an overnight fast for determination of body height and weight as well as waist circumference using standardized procedures. A venous blood sample was obtained for extraction of DNA. The study was approved by the committee on ethics at Karolinska Institute. It was explained in detail to each subject, and his/her informed consent was obtained.
The DNA samples were genotyped using Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (SEQUENOM, San Diego, CA) as described (7). Linkage disquilibrium between adjacent markers and haplotypes was estimated using SNPHAP and attached programs (available at http://archimedes.well.ox.ac.uk/pise/snphap-simple.html).
Subjects were grouped according to the World Health Organization definition of obesity (obese, BMI >30 kg/m2; and nonobese, BMI 30 kg/m2). Frequencies of genotypes, alleles, and haplotypes in obese and lean groups were analyzed by Fishers exact test. Analyses in men that were extensions of nominal significant associations obtained in women were considered one-sided hypotheses; we therefore display one-sided P values. The nonparametric Kruskal-Wallis and the parametric ANCOVA with age as a covariate were used to compare BMI between genotypes. Data are presented as means ± SD unless otherwise indicated.
Address correspondence and reprint requests to Peter Arner, Professor, MD, Department of Medicine, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. E-mail: peter.arner{at}medhs.ki.se
Received for publication March 29, 2005 and accepted in revised form June 27, 2005
CIDEA, cell deathinducing DFFA (DNA fragmentation factor-)-like effector A; SNP, single nucleotide polymorphism; TNF-
, tumor necrosis factor-
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