Our aim was to investigate the possible role of the type 2 diabetes susceptibility gene CAPN10 in obesity. A case control study consisting of 235 obese Swedish subjects [body mass index, 40 (35–45) kg/m²] and 235 controls matched for age and gender [body mass index, 22 (21–24) kg/m²], and a transmission disequilibrium test consisting of 116 parents-offspring trios, where the offspring was abdominally obese [waist, 100 (95–110) cm], were performed. CAPN10 mRNA expression was studied in adipose tissue biopsies from 33 of the obese subjects participating in the case control study. The CAPN10 single-nucleotide polymorphism (SNP)-43 was genotyped using PCR followed by NdeI digestion or by allelic discrimination. CAPN10 mRNA levels were quantified using real-time RT-PCR with Cyclophilin A as an internal standard. No significant associations between CAPN10 SNP-43 and obesity were seen, neither in the case control study nor in the transmission disequilibrium test, but obese subjects homozygous for the SNP-43 G allele had significantly elevated triglyceride levels compared with subjects carrying the A allele [1.7 (1.1–2.4) vs. 1.4 (1.0–2.0); P = 0.03]. The CAPN10 mRNA expression in sc fat was significantly reduced in subjects with the SNP-43 G/G genotype compared with carriers of SNP-43 G/A (G/G, 0.33 ± 0.02, vs. G/A, 0.51 ± 0.09; P = 0.048), and a similar trend was observed in visceral fat (G/G, 0.52 ± 0.06, vs. G/A, 0.65 ± 0.10; P = 0.22). Our data suggest that reduced CAPN10 expression may be a risk factor for features associated with the metabolic syndrome in obese subjects, although variation in the gene does not seem to contribute to the risk for developing obesity per se.

The gene encoding calpain-10 (CAPN10) has been identified as a candidate gene for type 2 diabetes. Our aim was to study the impact of genetic (heritability and polymorphisms) and nongenetic (insulin, free fatty acids, and age) factors on CAPN10 mRNA expression in skeletal muscle using two different study designs. Muscle biopsies were obtained before and after hyperinsulinemic-euglycemic clamps from 166 young and elderly monozygotic and dizygotic twins as well as from 15 subjects with normal (NGT) or impaired glucose tolerance (IGT) exposed to an Intralipid infusion. We found hereditary effects on both basal and insulin-exposed CAPN10 mRNA expression. Carriers of the type 2 diabetes–associated single nucleotide polymorphism (SNP)-43 G/G genotype had reduced CAPN10 mRNA levels compared with subjects carrying the SNP-43 A-allele. Age had no significant influence on CAPN10 mRNA levels. Insulin had no significant effect on CAPN10 mRNA levels, neither in the twins nor in the basal state of the Intralipid study. However, after a 24-h infusion of Intralipid, we noted a significant increase in CAPN10 mRNA in response to insulin in subjects with NGT but not in subjects with IGT. In conclusion, we provide evidence that mRNA expression of CAPN10 in skeletal muscle is under genetic control. Glucose-tolerant but not glucose-intolerant individuals upregulate their CAPN10 mRNA levels in response to prolonged exposure to fat.

The transcription factor FOXC2 has been implicated in resistance to diet‐induced obesity and insulin resistance. To investigate the possible role for FOXC2 in obesity and related phenotypes, we performed two association studies for obesity using unrelated case‐control materials by genotyping the FOXC2 C‐512T polymorphism. In the first study (127 obese and 127 normal‐weight nondiabetic subjects matched for age and sex), the C‐allele showed association with obesity, odds ratio 1.74 (1.12 to 2.73; p < 0.01) for the C‐ vs. T‐allele and 1.81 (1.04 to 3.25; p < 0.05) for the C/C and C/T vs. T/T genotype. BMI was higher in carriers of the C/C and C/T genotype in normal weight [adjusted p value (p_adj) = 0.02] but not in obese subjects (p_adj = 0.1). In the replication study (223 obese and 231 nonobese subjects), subjects with the C/C genotype exhibited an increased risk for obesity, odds ratio 2.01 (1.15 to 3.52; p = 0.01). Obese carriers of the C‐allele had lower high‐density lipoprotein‐cholesterol [1.1 (0.9 to 1.3) vs. 1.2 (1.0 to 1.4) mM, p_adj = 0.006] and increased triglyceride levels (1.95 [1.30 to 2.68] vs. 1.60 [1.10 to 2.40] mM, p_adj = 0.02) compared with obese carriers of the T/T genotype. Our data suggest that FOXC2 is a weak but consistent candidate gene for obesity and dyslipidemia.