The -250G>A promoter variant in hepatic lipase associates with elevated fasting serum high-density lipoprotein cholesterol modulated by interaction with physical activity in a study of 16,156 Danish subjects.
CONTEXT: Hepatic lipase plays a pivotal role in the metabolism of high-density lipoprotein (HDL) and low-density lipoprotein by involvement in reverse cholesterol transport and the formation of atherogenic small dense low-density lipoprotein. OBJECTIVES: The objective was to investigate the impact of variants in LIPC on metabolic traits and type 2 diabetes in a large sample of Danes. Because behavioral factors influence hepatic lipase activity, we furthermore examined possible gene-environment interactions in the population-based Inter99 study. DESIGN: The LIPC -250G>A (rs2070895) variant was genotyped in the Inter99 study (n = 6070), the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care Denmark screening cohort of individuals with risk factors for undiagnosed type 2 diabetes (n = 8662), and in additional type 2 diabetic patients (n = 1,064) and glucose-tolerant control subjects (n = 360). RESULTS: In the Inter99 study, the A allele of rs2070895 associated with a 0.057 mmol/liter [95% confidence interval (CI) 0.039-0.075] increase in fasting serum HDL-cholesterol (HDL-c) (P = 8 x 10(-10)) supported by association in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care study [0.038 mmol/liter per allele (95% CI 0.024-0.053); P = 2 x 10(-7)). The allelic effect on HDL-c was modulated by interaction with self-reported physical activity (P(interaction) = 0.002) because vigorous physically active homozygous A-allele carriers had a 0.30 mmol/liter (95% CI 0.22-0.37) increase in HDL-c compared with homozygous G-allele carriers. CONCLUSIONS: We validate the association of LIPC promoter variation with fasting serum HDL-c and present data supporting an interaction with physical activity implying an increased effect on HDL-c in vigorous physically active subjects carrying the -250 A allele. This interaction may have potential implications for public health and disease prevention.
Objective: To investigate the association between serum TSH, total T4 and various patient characteristics when hypothyroidism is diagnosed in a population, and to study how age, sex and serum T4 levels influenced pituitary TSH response. Design: A computer-based register linked to laboratory databases prospectively identified all patients with new, biochemically overt hypothyroidism (n = 685) in an open cohort in Denmark. The diagnosis was verified in each patient, and disease was classified into nosological type. Serum TSH and total T4 were recorded at the time of diagnosis in untreated patients with spontaneous autoimmune hypothyroidism (n = 578). Main outcome: In untreated primary, spontaneous autoimmune hypothyroidism, we observed a four fold difference in average serum TSH levels between the youngest (0-20 years: TSH = 100 mU/l) and the oldest (80+ years: TSH = 24.4 mU/l) group of patients. No age dependent variation was observed in serum total T4. Log TSH showed an inverse linear correlation with age. An inverse linear correlation was present between log TSH and total T4 in both young and old patients, but for all total T4 values we observed lower median serum TSH values in elderly patients. Conclusions: For the same degree of thyroid failure, the serum TSH is lower among the elderly. This is most likely caused by a decrease in the hypothalamic/pituitary response to low serum T4. A certain increase in serum TSH may indicate more severe hypothyroidism in an old than in a young patient, and longer time may be needed after thyroid hormone withdrawal before elderly patients with thyroid cancer reach sufficiently high TSH values to allow for an effective radio-iodine treatment.
OBJECTIVE: The gene encoding the alpha2 Heremans-Schmid glycoprotein (AHSG) is a credible biological and positional candidate gene for type 2 diabetes and the metabolic syndrome, and previous attempts to relate AHSG variation with type 2 diabetes and obesity in Swedish and French Caucasians have been largely successful. We related seven frequent AHSG tag single nucleotide polymorphisms to a range of metabolic traits, including type 2 diabetes, obesity, and dyslipidemia. RESEARCH DESIGN AND METHODS: The polymorphisms were genotyped in 7,683 white Danish subjects using Taqman allelic discrimination or chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, providing a statistical power of >99% to replicate previous findings. Data were analyzed in case-control and haplotype settings, and quantitative metabolic traits were examined for association. Moreover, epistatic effects between AHSG variants and insulin receptor substrate-1 (IRS1) and beta-2-adrenergic receptor polymorphisms were investigated. RESULTS: The -469T>G (rs2077119) and IVS6+98C>T (rs2518136) polymorphisms were associated with type 2 diabetes (P = 0.007 and P = 0.006, respectively, or P(corr) = 0.04 and P(corr) = 0.03, respectively, following correction for multiple hypothesis testing), and in a combined analysis of the present and a previous study -469T>G remained significant (odds ratio 0.90 [95% CI 0.84-0.97]; P = 0.007). Furthermore, two AHSG haplotypes were associated with dyslipidemia (P = 0.003 and P(corr) = 0.009). Thr248Met (rs4917) tended to associate with lower fasting and post-oral glucose tolerance test serum insulin release (P = 0.02, P(corr) = 0.1 for fasting and P = 0.04, P(corr) = 0.2 for area under the insulin curve) and improved insulin sensitivity estimated by the homeostasis model assessment of insulin resistance (9.0 vs. 8.6 mmol x l(-1) x pmol(-1) x l(-1); P = 0.01, P(corr) = 0.06). Indications of epistatic effects of AHSG variants with the IRS1 Gly971Arg polymorphism were observed for fasting serum triglyceride concentrations. CONCLUSIONS: Based on present and previous findings, common variation in AHSG may contribute to the interindividual variation in metabolic traits.
OBJECTIVES: To evaluate the effect of multifactorial fall prevention in community-dwelling people aged 65 and older in Denmark. DESIGN: Randomized, controlled clinical trial. SETTING: Geriatric outpatient clinic at Glostrup University Hospital. PARTICIPANTS: Three hundred ninety-two elderly people, mean age 74, 73.7%women, who had visited the emergency department or had been hospitalized due to a fall. INTERVENTION: Identification of general medical, cardiovascular, and physical risk factors for falls and individual intervention in the intervention group. Participants in the control group received usual care. MEASUREMENTS: Falls were registered prospectively in falls diaries, with monthly telephone calls for collection of data. Outcomes were fall rates and proportion of participants with falls, frequent falls, and injurious falls in 12 months. RESULTS: Groups were comparable at baseline. Followup exceeded 90.0%. A total of 422 falls were registered in the intervention group, 398 in the control group. Intention-to-treat analysis revealed no effect of the intervention on fall rates (relative risk=1.06, 95%confidence interval (CI)=0.75 -1.51), proportion with falls (odds ratio (OR)=1.20, 95% CI 0.81-1.79), frequent falls (OR=0.97, 95% CI=0.60-1.56), or injurious falls (OR=0.97, 95% CI=0.57-1.62). CONCLUSION: A program of multifactorial fall prevention aimed at elderly Danish people experiencing at least one injurious fall was not effective in preventing further falls.
BACKGROUND: Deficiency of folate has been associated with several disorders characterized by enhanced activation of the cellular immune system (non-allergic th1 type immune response). Whether folate status is also associated with atopic disease (allergic th2 type immune response) is unknown. We aimed at examining the association between atopy and markers of impaired folate metabolism, i.e. MTHFR(C677T) genotype, plasma total homocysteine, and dietary intakes of methionine, folates, and vitamins B12, B6, and B2. METHODS: Cross-sectional population-based study of 1,671 male and female residents of Copenhagen County, Denmark, aged 30-60 years participating in a health examination during 1999-2001. Atopy was defined as positive levels of specific IgE against a panel of inhalant allergens. MTHFR(C677T) genotype was determined by PCR followed by restriction fragment length polymorphism analyses. Total homocysteine was measured by fluorescent polarization immunoassay. Dietary vitamin intakes were estimated from a semi-quantitative food frequency questionnaire. RESULTS: The prevalence of atopy was associated with MTHFR(C677T) genotype. TT individuals had a significantly higher risk of atopy compared with CC/CT individuals [odds ratio 1.76, 95% confidence interval (95% CI) 1.19-2.60]. Additionally, gene-diet interaction effects were identified. Dietary markers were negatively associated with risk of atopy in persons with the TT genotype. Total homocysteine was not related to atopy (odds ratio per 5 mumol/l = 1.12, 95% CI 0.98-1.29). CONCLUSIONS: The results suggest that an impaired folate metabolism may be causally related to the development of atopy.
BACKGROUND: Neuromedin U (NMU) is an anorexic neuropeptide expressed in the hypothalamus. Mice lacking the NmU gene are hyperphagic and obese, whereas mice overexpressing Nmu are hypophagic and lean. OBJECTIVE: Our objective was to investigate whether variants in NMU are associated with human obesity. DESIGN: The coding region of NMU was analyzed for variants in obese Czech children and obese Danish adults. Identified missense variants were investigated for cosegregation with obesity in families or association with obesity in the general population. SETTING: The study was performed at Steno Diabetes Center, Denmark, and Department of Pediatrics, Charles University, Czech Republic. SUBJECTS AND METHODS: A total of 289 Czech children and adolescents with early-onset obesity and 84 Danish obese adults were analyzed for variants in NMU. A NMU Ala19Glu polymorphism was genotyped in 5851 Danish subjects of the Inter99 cohort, and a rare NMU Arg165Trp mutation was sequenced in the proband family and in 53 lean and unrelated Czech subjects. RESULTS: The rare NMU Arg165Trp variant cosegregated with childhood obesity in a Czech family. Homozygous carriers of the Glu allele of the NMU Ala19Glu polymorphism were more common in the overweight and obese subjects; the Glu/Glu frequency was 0.4 (95% confidence interval, 0.2-0.6) among 2586 lean subjects (BMI or= 25 kg/m2) [odds ratio, 2.5 (1.2-5.3); P = 0.01]. CONCLUSION: Amino acid variants in NMU associate with overweight and obesity, suggesting that NMU is involved in energy regulation in humans.
CONTEXT: Iodine-induced hyperthyroidism has been reported in the early phases of almost all iodine fortification programs, depending on prior iodine intake in the population, the amount of fortification, and the rate of change. OBJECTIVE: The aim of the study was to monitor the effect of the Danish iodine fortification program on incidence of hyperthyroidism as measured by the incident use of antithyroid medication. DESIGN: We conducted a register study. Using the unique identification number of all Danes, we linked data from the Register of Medicinal Product Statistics and the Civil Registration register on an individual level. All dispensing of antithyroid medication from 1995 to 2007 was studied. The place of residency was used to divide patients into mildly and moderately iodine-deficient groups. MAIN OUTCOME MEASURE: We measured the incident use of antithyroid medication. RESULTS: In the region with moderate iodine deficiency, the number of incident users of antithyroid medication increased 46% in the first 4 yr of iodine fortification. The use increased the most among the youngest age group (younger than 40 yr) and the oldest age group (older than 75 yr). In the mildly iodine-deficient region, the number of incident users increased only 18%, and only in the youngest age groups (below 40 and 40-59 yr). After 4 yr of fortification, the incidence rates started to fall and reached baseline, for most groups, 6 yr after onset of fortification. CONCLUSIONS: This study shows that iodine fortification induced a temporary, modest increase in the incidence of hyperthyroidism as measured by use of antithyroid medication. A new steady state has not yet evolved.
Association testing of novel type 2 diabetes risk alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity, and obesity in a population-based sample of 4,516 glucose-tolerant middle-aged Danes.
OBJECTIVE: We evaluated the impact on diabetes-related intermediary traits of common novel type 2 diabetes-associated variants in the JAZF1 (rs864745), CDC123/CAMK1D (rs12779790), TSPAN8 (rs7961581), THADA (rs7578597), ADAMTS9 (rs4607103), and NOTCH2 (rs10923931) loci, which were recently identified by meta-analysis of genome-wide association data. RESEARCH DESIGN AND METHODS: We genotyped the six variants in 4,516 middle-aged glucose-tolerant individuals of the population-based Inter99 cohort who were all characterized by an oral glucose tolerance test (OGTT). RESULTS: Homozygous carriers of the minor diabetes risk G-allele of the CDC123/CAMK1D rs12779790 showed an 18% decrease in insulinogenic index (95% CI 10-27%; P = 4 x 10(-5)), an 18% decrease in corrected insulin response (CIR) (8.1-29%; P = 4 x 10(-4)), and a 13% decrease in the ratio of area under the serum-insulin and plasma-glucose curves during an OGTT (AUC-insulin/AUC-glucose) (5.8-20%; P = 4 x 10(-4)). Carriers of the diabetes-associated T-allele of JAZF1 rs864745 had an allele-dependent 3% decrease in BIGTT-AIR (0.9-4.3%; P = 0.003). Furthermore, the diabetes-associated C-allele of TSPAN8 rs7961581 associated with decreased levels of CIR (4.5% [0.5-8.4]; P = 0.03), of AUC-insulin/AUC-glucose ratio (3.9% [1.2-6.7]; P = 0.005), and of the insulinogenic index (5.2% [1.9-8.6]; P = 0.002). No association with traits of insulin release or insulin action was observed for the THADA, ADAMTS9, or NOTCH2 variants. CONCLUSIONS: If replicated, our data suggest that type 2 diabetes at-risk alleles in the JAZF1, CDC123/CAMK1D, and TSPAN8 loci associate with various OGTT-based surrogate measures of insulin release, emphasizing the contribution of abnormal pancreatic beta-cell function in the pathogenesis of type 2 diabetes.
Mental health surveillance in infancy was studied in an existing child health surveillance programme with child psychiatric disorder at 1(1/2) year as the outcome. METHODS: Children considered of concern by community health nurses were cases in a case control study nested in the Copenhagen Child Cohort (CCC 2000). Outcome was mental health status at 1(1/2) year assessed by clinical and standardised strategies, including videotape recordings, parent interviews and the instruments: CBCL 1(1/2)-5, ITSCL, CHAT, Bayley Scales of Infant Development II, PC ERA and PIR-GAS. RESULTS: The positive predictive value of concern in the first 10 months of living was 24% (CI 17.0-31.9), the negative predictive value was 85% (CI 77.9-89.6) and the sensitivity was 56% (CI 42.4-69.0). Concern about development was significantly associated with the child having a neuro-developmental disorder at 1(1/2) year, and concern about mother-child relationship was associated with emotional, behavioural, eating, and sleeping disturbances. CONCLUSIONS: A general health surveillance program seems to have potentials to identify infants at risk for mental health problems provided standardised measures and specific training of the involved health professionals.
INTRODUCTION: The prevention of disorders in social communication and attention is hampered by the lack of effective tools to screen in the first year of living. In Denmark public health nurses perform screening of physical and mental health in all infants, and at the age of 8-10 months a standardised test, BOEL, is performed to screen for hearing loss plus social communication and attention disturbances. METHOD: The predictive value of abnormal reactions at the BOEL test at 8-10 months of age was investigated in a subpopulation of 211 children from the CCCC 2000. Predictions were calculated in relation to outcome concerning psychopathological disturbances in social communication and attention, diagnosed by child psychiatric assessment at 18 months. RESULTS: Communication and attention disturbances at 18 months were predicted by the BOEL test with predictive validity of positive test (PV pos) 29%, and the predictive validity of negative test (PV neg) 95%. The BOEL test was found superior to the general clinical judgement by the public health nurses. CONCLUSION: The infant mental health screening by public health nurses seems to have potential concerning early identification of social communication and attention disturbances by using the BOEL test, but investigations of larger populations and with a longer time of observation are needed.