C. S. Rose

Variations of the interleukin-6 promoter are associated with features of the metabolic syndrome in Caucasian Danes.

Aims/hypothesisThe cytokine interleukin 6 (IL-6) is an essential regulator of the acute phase response associated with insulin-resistant states including type 2 diabetes and obesity. Three polymorphisms at positions −597, −572, and −174 of the IL6 promoter have been reported to influence IL6 transcription. The aim of this study was to investigate whether the IL6 promoter polymorphisms were associated with features of the WHO-defined metabolic syndrome and related quantitative traits in 7,553 Caucasian Danes.MethodsUsing analysis of PCR-generated primer extension products by mass spectrometry we examined −597 G/A, −572 G/C, and −174 G/C IL6 variants in the population-based Inter99 study cohort of middle-aged people (n=6,164) and in a group of type 2 diabetic patients (n=1,389).ResultsThe −174 G/C and −597 G/A polymorphisms were in strong linkage disequilibrium (R2=0.95). In the Inter99 cohort the −174 G-allele was associated with insulin resistance (p<0.02) and dyslipidaemia (p<0.007) whereas the C-allele of the −572 polymorphism was associated with increased serum insulin release during an OGTT (p<0.0005). Composite genotype or haplotype analyses of all 3 IL6 promoter variants showed associations with type 2 diabetes (p<0.002), obesity (p<0.02), and the metabolic syndrome (p<0.01).ConclusionsThe present studies suggest that single-nucleotide polymorphisms and composite genotypes or haplotypes of the IL6 promoter may be associated with several features of the metabolic syndrome in Caucasians.

Large-scale studies of the HphI insulin gene variable-number-of-tandem-repeats polymorphism in relation to Type 2 diabetes mellitus and insulin release

Aims/hypothesisThe class III allele of the variable-number-of-tandem-repeats polymorphism located 5′ of the insulin gene (INS-VNTR) has been associated with Type 2 diabetes and altered birthweight. It has also been suggested, although inconsistently, that the class III allele plays a role in glucose-induced insulin response among NGT individuals.MethodsWe investigated the impact of the class III allele on Type 2 diabetes susceptibility in a case-control study involving 1462 Type 2 diabetic patients and 4931 NGT subjects. We also examined the potential impact of the class III allele in genotype-quantitative trait studies in three Danish study populations containing (i) 358 young healthy subjects; (ii) 4444 middle-aged NGT subjects, 490 subjects with IFG and 678 subjects with IGT; and (iii) 221 NGT subjects, of whom one parent had Type 2 diabetes.ResultsThere was no difference in frequency of the class III allele or in genotype distribution between the 1462 Type 2 diabetic patients and the 4931 NGT subjects. Among the 358 young subjects the class III/III carriers had significantly reduced post-IVGTT acute serum insulin and C-peptide responses (p=0.04 and 0.03 respectively). However, among the 4444 middle-aged subjects we failed to demonstrate any association between the class III allele and post-OGTT serum insulin and C-peptide levels.Conclusions/interpretationThe class III allele of the INS-VNTR does not confer susceptibility to Type 2 diabetes or consistent alterations in glucose-induced insulin release in the examined populations, which consisted of Danish Caucasians.

A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone

CONTEXT RTHα is a recently discovered resistance to thyroid hormone (RTH) due to mutation of THRA, the gene encoding TRα1, the thyroid hormone receptor. It has been described in a few patients with growth retardation, short stature, and a low free T4/free T3 (FT4/FT3) ratio. OBJECTIVE A 27-year-old patient presenting with dwarfism and a low FT4/FT3 ratio was investigated. DESIGN Clinical, biochemical, and radiological data were collected. Whole exome sequencing was performed in the patient and her relatives. RESULTS The patient exhibited congenital macrocytic anemia and severe bone malformation with growth retardation, dwarfism, clavicular agenesis, and abnormalities of the fingers, toes, and elbow joints. In adulthood, she presented with active behavior, chronic motor diarrhea, and hypercalcemia. Treatment with T3 led to heart rate acceleration, worsening of diarrhea, and TSH suppression. Low resting energy expenditure normalized on T3. rT3, SHBG, and IGF-1 remained normal. A de novo monoallelic missense mutation in THRA was discovered, the N359Y amino acid substitution (c.1075A>T), which affected both the TRα1 and the non-receptor isoform TRα2. The mutant TRα1 had a decrease in transcriptional activity related to decreased T3 binding and a dominant-negative effect on the wild-type receptor. CONCLUSIONS This patient presents a new phenotype including more significant bone abnormalities, lower TSH, and higher FT3 levels, without certainty of all her symptoms with the TRα1(N359Y) mutation. This case suggests that patients with a low FT4/FT3 ratio should be screened for THRA mutations, even if clinical and biological features differ from previous reported cases of RTHα.

Studies of relationships between the GLUT10 Ala206Thr polymorphism and impaired insulin secretion

Aims  This study aimed to investigate if the previously observed association between the GLUT10 Ala206Thr polymorphism and variation in fasting and oral glucose‐induced serum insulin concentrations could be replicated in a large‐scale population‐based cohort of Danish whites.