Recently, two G-->A polymorphisms at positions -308 and -238, in the promoter of the tumor necrosis factor alpha (TNF-alpha) gene, have been identified. These variants have, in different ethnic groups, been linked to estimates of insulin resistance and obesity. The objective of the present study was to investigate whether these genetic variants of TNF-alpha were associated with features of the insulin resistance syndrome or alterations in birth weight in two Danish study populations comprising 380 unrelated young healthy subjects and 249 glucose-tolerant relatives of type 2 diabetic patients, respectively. All study participants underwent an iv glucose tolerance test with the addition of tolbutamide after 20 min. In addition, a number of biochemical and anthropometric measures were performed on each subject. The subjects were genotyped for the polymorphisms by applying PCR restriction fragment length polymorphism. Neither of the variants was related to altered insulin sensitivity index or other features of the insulin resistance syndrome (body mass index, waist to hip ratio, fat mass, fasting serum lipids or fasting serum insulin or C-peptide). Birth weight and the ponderal index were also not associated with the polymorphisms. In conclusion, although the study was carried out on sufficiently large study samples, the study does not support a major role of the -308 or -238 substitutions of the TNF-alpha gene in the pathogenesis of insulin resistance or altered birth weight among Danish Caucasian subjects.
Kir6.2 is an inwardly rectifying potassium channel that is expressed in pancreatic beta-cells and cardiac and skeletal muscle. Expressed together with the high-affinity sulphonylurea receptor, it reconstitutes a sulphonylurea- and also ATP-sensitive potassium channel resembling the native beta-cell channel. The objective of this study was to search for mutations in the Kir6.2 gene that might be associated with NIDDM or related to altered insulin secretion, insulin action, or glucose metabolism in healthy subjects. Using polymerase chain reaction-single-strand conformation polymorphism analysis (PCR-SSCP) on genomic DNA from 69 Danish NIDDM patients and 66 matched control subjects, we report the finding of three missense polymorphisms in otherwise conserved codons and three silent polymorphisms in the gene encoding Kir6.2: codon 23 (GAG/AAG), Glu-->Lys; codon 190 (GCT/GCC), Ala-->Ala; codon 267 (CTC/CTG), Leu-->Leu; codon 270 (CTG/GTG), Leu-->Val; codon 337 (ATC/GTC), Ile-->Val; codon 381 (AAG/AAA), Lys-->Lys. The codon 23 and codon 337 amino acid polymorphisms were always coupled. The allelic frequencies of the polymorphisms were similar in NIDDM patients and control subjects. The amino acid polymorphisms were not associated with altered insulin secretion after intravenous glucose or tolbutamide injections or with altered glucose effectiveness in a phenotype study of 346 young healthy subjects. However, carriers of the maximal load of amino acid variants, the compound homozygous codon 23/337 and heterozygous codon 270, had on average a 62% higher insulin sensitivity index (P = 0.006), compared with noncarriers. We conclude that a combination of common Kir6.2 amino acid variants may contribute to the genetic background behind the large variation of the insulin sensitivity index in the general population.
To identify whether a genetic variation (rs1800857; IVS1-5T>C) in the neuropeptide cholecystokinin-A receptor (CCKAR) gene is a risk factor in the pathogenesis of schizophrenia.
The variation was analysed in a case-control design comprising 508 patients with schizophrenia and 1619 control subjects. A possible functional impact of this variant on CCKAR protein synthesis through alterations in splicing was analysed in an exon-trapping assay.
In males only, the risk variant, IVS1-5C, was associated with a significantly increased risk of schizophrenia. Carrying one risk allele was associated with an increased risk of 1.74 (Odds Ratio, OR) and homozygosity (CC) was associated with an OR of 3.19. The variation had no impact on protein synthesis of CCKAR.
This is the first report associating the CCKAR gene variant with schizophrenia specifically in men. Our study strengthens the conclusion that a CCKAR dysfunction could be involved in the aetiology of schizophrenia.
Associations between a 45 bp 3'untranslated insertion polymorphism in the uncoupling protein 2 (UCP2) gene and both body mass index (BMI) and sleeping metabolic rate have previously been reported. We investigated the impact of this polymorphism on BMI and long-term body weight changes.
The allelic frequency of the UCP2 insertion variant was determined in a cohort of 744 obese Danish Caucasian men who had a BMI of at least 31 kg/m2 at the draft-board examinations and a randomly selected control cohort consisting of 872 draftees. Follow-up measurements of BMI were done on average 26 years after the draft-board examinations.
The prevalence of the insertion allele was 30.4% (95% confidence interval: 28.0-32.8%) among the obese and 29.6% (27.4-31.8%) in the control group (p = 0.6). In a lean group selected as the 354 subjects with a BMI less than 25 kg/m2 at 46 years of age from the control group, the frequency of insertion allele was 29.0% (27.2-30.8%) (p = 0.5 compared with the obese cohort). The BMI at the ages of 20 and 46 years did not differ between genotypes either in the obese or the control group. Similarly, the changes in BMI/year between examinations at 20 and 46 years of age did not differ between genotypes in either group.
In a large group of Danish Caucasian men we found no association between a 3'untranslated insertion polymorphism in the UCP2 gene and obesity. Neither did we identify a relation between this variant and BMI changes during adult age.
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 1, DIKU Building, Room 1.1.N121, DK-2100 Copenhagen, Denmark. Kristoffer.Burgdorf@sund.ku.dk
Genome-wide association studies have identified novel WHR and BMI susceptibility loci. The aim of this study was to elucidate if any of these loci had an effect on quantitative measures of glucose homeostasis, including estimates of insulin release and insulin sensitivity in an epidemiological setting.
By applying an additive genetic model, 14 WHR-associated gene variants and 18 BMI-associated variants were investigated for their relationships with glucose-related metabolic traits in treatment-naive individuals from the population-based Inter99 study sample (n?=?6,039).
Of the variants associated with BMI, the QPCTL rs2287019 C allele was associated with an increased insulinogenic index of 7.4% per risk allele (p?=?4.0?×?10?7) and increased disposition index of 5.6% (p?=?6.4?×?10?5). The LRP1B rs2890652 C allele was associated with insulin resistance, showing a 3.3% increase (p?=?0.0011) using the HOMA-insulin resistance (HOMA-IR) index and a 2.2% reduction (p?=?0.0014) with the Matsuda index. Of the variants associated with WHR, LYPLAL1/SLC30A10 rs4846567 G allele carriers showed a 5.2% lower HOMA-IR (p?=?0.00086) in women, indicating improved insulin sensitivity. Female carriers of the VEGFA rs6905288 A allele were insulin resistant, with a 3.7% increase in HOMA-IR (p?=?0.00036) and 4.0% decrease in Matsuda index (p?=?2?×?10?4).
Our correlative findings from analysing single-locus data suggest that some variation in validated BMI and WHR loci are associated with either increased or decreased insulin sensitivity and thereby potentially with metabolically healthy or metabolically unhealthy subsets of obesity. The results call for testing in larger study samples and for further physiological exploration of the possible metabolic implications of these loci.
During its "Heart-week" in Feb. 1975, the Danish Heart Foundation drew the attention of the public to the importance of blood pressure measurements as a vital part of health control and prevention. In all, 24 thousand men and women attending supermarkets in Copenhagen took advantage of an offer to have their BP checked. 23% of the screened, who had systolic BP greater than or equal to age+110 (and this sum exceeded 145) and/or diastolic BP greater than or equal to 100 mmHg for all ages, were advised to contact a general practitioner for further evaluation. The campaign showed that it is possible to measure BP and obtain reliable results in an easy, quick, inexpensive and unorthodox way accepted by a public accustomed to free medical care.
Human papillomavirus and hormonal contraceptives may be risk factors for cervical precancer and malignant breast tumours.
Standardised incidence ratios (SIRs) of malignant breast tumours during 1970-2008 were estimated separately for women with prior squamous and glandular cervical precancer.
Women with squamous precancer and women with glandular precancer in the cervix had a significantly higher risk of malignant breast tumours than the general female population (SIR, 95% confidence interval: 1.10, 1.05-1.14 and 1.52, 1.11-2.08, respectively).
Shared risk factors or screening attendance may explain the excess risk of malignant breast tumours among women with a history of cervical precancer.
To test the assumption that knowledge, attitudes, and skills (KAS) in geriatrics are learned via exposure to elderly patients in nongeriatric clerkships. In the developed world, the proportion of adults > or = 65 years old will soon surpass the proportion of children
We tested the hypothesis that individuals heterozygous for the common cystic fibrosis delta F508 mutation are at risk of obstructive pulmonary disease. We studied a cross-sectional sample from the general population of Copenhagen, aged 20 years and older. We performed spirometry to measure FEV1 and FVC, and genotyped blood samples from 9141 individuals. We identified 250 carriers of the delta F508 mutation (2.7%; 95% CI: 2.5%-3.1%). Nine precent of carriers reported having asthma compared with 6% of non-carriers (chi 2: p = 0.04). Furthermore, among individuals with airway obstruction, the percentage of predicted FEV1 and FVC were significantly lower in participants heterozygous for delta F508 than in non-carriers (49% vs. 58%, p = 0.004 and 70% vs. 82%, p