Showing papers by "Allan Linneberg published in 2014"

Association between alcohol and cardiovascular disease:Mendelian randomisation analysis based on individual participant data

Abstract: OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes

Abstract: Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes

Abstract: Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (−0.17 s.d., P = 4.6 × 10−4). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.

A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes

Abstract: An association mapping study of type-2-diabetes-related quantitative traits in the Greenlandic population identified a common variant in TBC1D4 that increases plasma glucose levels and serum insulin levels after an oral glucose load and type 2 diabetes risk, with effect sizes several times larger than any previous findings of large-scale genome-wide association studies for these traits. This systematic genetic association study of quantitative traits related to type 2 diabetes (T2D) has identified a nonsense variant in the gene TBC1D4 which is present in 17% of the Greenlandic population, known to be a small founder population with a high incidence of T2D. The gene variant increases the levels of plasma glucose, serum insulin, and dramatically increases T2D risk. It also modestly reduces the concentrations of fasting plasma and fasting serum insulin. This work illustrates the value of founder populations — or of small and historically isolated populations — in maximizing the effectiveness of genetic association studies of this type. The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years1. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (β = 3.8 mmol l−1, P = 2.5 × 10−35) and serum insulin (β = 165 pmol l−1, P = 1.5 × 10−20) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β = −0.18 mmol l−1, P = 1.1 × 10−6) and fasting serum insulin (β = −8.3 pmol l−1, P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10−24). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (β = 0.43 mmol l−1, P = 5.3 × 10−5). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits2,3,4 and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes

Abstract: Unnur Thorsteinsdottir, Kari Stefansson and colleagues identify low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. The newly discovered variants include an intronic variant associated with altered expression of CCND2, two independent missense variants in PAM and a rare frameshift variant in PDX1.

Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort

Abstract: Background: A possible aetiological link between obesity and certain autoimmune diseases (ADs) has been suggested. We investigated the associations between body mass index (BMI, kg/m 2 ) and 43 ADs. Methods: 75 008 women participating in the Danish National Birth Cohort were followed during a median time of 11 years. Diagnoses on ADs were retrieved from the Danish National Patient Register. Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated adjusting for potential confounders (smoking, alcohol, parity and socio-occupational status). Results: During follow-up, 2430 women (3.2%) developed a total of 2607 new-onset ADs. Risk of any autoimmune disease was increased in obese women (HR, 1.27; 95% CI, 1.11 to 1.46) compared with normal weight women (18.5‐� 25kg/m 2 ). Obese women (BMI � 30kg/m 2 ) were at increased risk of sarcoidosis (HR 3.59; 95% CI, 2.31 to 5.57) and type 1 diabetes mellitus (HR 2.67; 95% CI, 1.71 to 4.17). Risk of dermatitis herpetiformis increased by 14% (95% CI, 1% to 30%) per BMI unit. Conversely, risk of celiac disease and Raynaud’s phenomenon decreased by 7% (95% CI, 1% to 13%) and 12% (95% CI, 4% to 19%) per BMI unit, respectively. Further associations between BMI and risk of psoriasis, rheumatoid arthritis and Crohn’s disease were suggested. Conclusions: BMI was found to be associated with several Ads. This was most pronounced between obesity and risk of sarcoidosis and and risk of type 1 diabetes mellitus. These novel findings need confirmation and the possible role of adipose tissue-derived immunological changes in the development of autoimmune reactions needs consideration.

Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Abstract: Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium

Abstract: Objectives: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. Design: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. Participants: Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). Primary outcome measures: Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. Results: The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. Conclusions: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.

Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Abstract: Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10−8) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68–2.81, P = 8.1×10−8), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26–1.82, P = 2.9×10−6), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66–0.89, P = 6.5×10−4). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22–1.54, P = 1.2×10−7 and OR: 1.25, 95% CI 1.12–1.39, P = 6.2×10−5). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18–2.10, P = 1.9×10−3). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

Cohort Profile: The Health2006 cohort, Research Centre for Prevention and Health

Abstract: Research Centre for Prevention and Health, Copenhagen University Hospital Glostrup, The Capital Region of Denmark, Denmark, National Allergy Research Centre, Department of Dermato-Allergology, Copenhagen University Hospital Gentofte, Denmark, Danish Research Centre for Chemical Sensitivities, Gentofte University Hospital, University of Copenhagen, Copenhagen, Denmark, Hagedorn Research Institute and Steno Diabetes Centre, Gentofte, Denmark, The Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark and Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark

IgE antibodies to alpha‐gal in the general adult population: relationship with tick bites, atopy, and cat ownership

Abstract: SummaryBackground The carbohydrate alpha-gal epitope is present in many animal proteins, including those of red meat and animal immunoglobulins, such as cat IgA. Systemic anaphylaxis to the alpha-gal epitope has recently been described. Objective To investigate and compare the prevalence of alpha-gal-specific (s)IgE and its associated factors in the general adult population from two separated (Northern and Southern) European regions (Denmark and Spain, respectively). Methods Cross-sectional study of 2297 and 444 randomly selected adults from 11 municipalities in Denmark and one in Spain. Alpha-gal sIgE was assessed by ImmunoCAP to bovine thyroglobulin. Additional assessments included a panel of skin prick test (SPT) to common aeroallergens and epidemiological factors, including the history of tick bites in the Danish series. Results The prevalence of positive (≥ 0.1 kUA/L) sIgE to alpha-gal was 5.5% and 8.1% in the Danish and Spanish series, respectively. The prevalence of sIgE ≥ 0.35 kUA/L was 1.8% and 2.2% in Denmark and Spain, respectively. Alpha-gal sIgE positivity was associated with pet ownership in both series and, particularly, cat ownership (data available in the Danish series). Alpha-gal sIgE positivity was associated with atopy (SPT positivity) in both series, although it was not associated with SPT positivity to cat or dog dander. Alpha-gal sIgE positivity was strongly associated with a history of tick bites. Conclusions and Clinical Relevance The prevalence of alpha-gal sIgE antibodies in these general adult European populations is similarly low. The presence of alpha-gal sIgE antibodies is associated with a history of tick bites, atopy, and cat ownership.

Prospective Population-Based Study of the Association between Serum 25-Hydroxyvitamin-D Levels and the Incidence of Specific Types of Cancer

Abstract: Background: Observational studies have suggested an inverse association between vitamin D status and cancer. We investigated the prospective associations between vitamin D status and the total and specific type of cancer in three cohorts from the general Danish population. Methods: A total of 12,204 individuals 18 to 71 years old were included. The level of 25-hydroxyvitamin D was measured at baseline, and information about cancer was obtained from the Danish Cancer Registry. Results: During the 11.3-year median follow-up time, there were 1,248 incident cancers. HRs [95% confidence intervals (CI)] per 10 nmol/L higher baseline vitamin D level were: for all cancers (HR = 1.02; 95% CI, 0.99–1.04), all cancers excluding non-melanoma skin cancer, NMSC (HR = 1.00; 95% CI, 0.97–1.03), head and neck cancer (HR = 0.97; 95% CI, 0.84–1.12), colorectal cancer (HR = 0.95; 95% CI, 0.88–1.02), cancer of bronchus and lung (HR = 0.98; 95% CI, 0.91–1.05), breast cancer (HR = 1.02; 95% CI, 0.96–1.09), cancer of the uterus (HR = 1.10; 95% CI, 0.95–1.27), prostate cancer (HR = 1.00; 95% CI, 0.93–1.08), cancer of the urinary organs (HR = 1.01; 95% CI, 0.90–1.14), NMSC (HR = 1.06; 95% CI, 1.02–1.10), and malignant melanoma (HR = 1.06; 95% CI, 0.95–1.17). Conclusions: Apart from a significantly higher risk for NMSC with higher vitamin D status, we found no statistically significant associations between vitamin D status and total or specific cancers. Impact: Our results do not indicate that there is an impact of vitamin D on total cancer incidence. Cancer Epidemiol Biomarkers Prev; 23(7); 1220–9. ©2014 AACR .

Cadherin 5 is regulated by corticosteroids and associated with central serous chorioretinopathy.

Abstract: Central serous chorioretinopathy (CSC) is characterized by leakage of fluid from the choroid into the subretinal space and, consequently, loss of central vision. The disease is triggered by endogenous and exogenous corticosteroid imbalance and psychosocial stress and is much more prevalent in men. We studied the association of genetic variation in 44 genes from stress response and corticosteroid metabolism pathways with the CSC phenotype in two independent cohorts of 400 CSC cases and 1,400 matched controls. The expression of cadherin 5 (CDH5), the major cell–cell adhesion molecule in vascular endothelium, was downregulated by corticosteroids which may increase permeability of choroidal vasculature, leading to fluid leakage under the retina. We found a significant association of four common CDH5 SNPs with CSC in male patients in both cohorts. Two common intronic variants, rs7499886:A>G and rs1073584:C>T, exhibit strongly significant associations with CSC; P = 0.00012; odds ratio (OR) = 1.5; 95%CI [1.2;1.8], and P = 0.0014; OR = 0.70; 95%CI [0.57;0.87], respectively. A common haplotype was present in 25.4% male CSC cases and in 35.8% controls (P = 0.0002; OR = 0.61, 95% CI [0.47–0.79]). We propose that genetically predetermined variation in CDH5, when combined with triggering events such as corticosteroid treatment or severe hormonal imbalance, underlie a substantial proportion of CSC in the male population.

Longitudinal Changes in Leukocyte Telomere Length and Mortality in Humans

Abstract: BACKGROUND Leukocyte telomere length (LTL) ostensibly shortens with age and has been moderately associated with mortality. In humans, these findings have come almost solely from cross-sectional studies. Only recently has LTL shortening within individuals been analyzed in longitudinal studies. Such studies are relevant to establish LTL dynamics as biomarkers of mortality as well as to disentangle the causality of telomeres on aging. METHODS We present a large longitudinal study on LTL and human mortality, where the 10-year change of LTL is analyzed in 1,356 individuals aged 30-70 years. RESULTS We find age, smoking status, and alcohol consumption to be associated with LTL attrition and confirm a strong association with baseline LTL. The latter association might be an epiphenomenon of regression to the mean. We do not find an association of mortality with either absolute LTL or LTL attrition. Further, we show that DNA quality has an impact on TS ratios. CONCLUSIONS This study establishes that certain lifestyle factors influence LTL dynamics. However, it questions the applicability of LTL dynamics as a predictor of mortality. We suggest cautiousness when assessing actual LTL attrition due to the need for high-quality DNA and the phenomena of regression to the mean.

High Levels Of Bed Occupancy Associated With Increased Inpatient And Thirty-Day Hospital Mortality In Denmark

Abstract: High bed occupancy rates have been considered a matter of reduced patient comfort and privacy and an indicator of high productivity for hospitals. Hospitals with bed occupancy rates of above 85 percent are generally considered to have bed shortages. Little attention has been paid to the impact of these shortages on patients’ outcomes. We analyzed all 2.65 million admissions to Danish hospitals’ departments of medicine in the period 1995–2012. We found that high bed occupancy rates were associated with a significant 9 percent increase in rates of in-hospital mortality and thirty-day mortality, compared to low bed occupancy rates. Being admitted to a hospital outside of normal working hours or on a weekend or holiday was also significantly associated with increased mortality. The health risks of bed shortages, including mortality, could be better documented as a priority health issue. Resources should be allocated to researching the causes and effects of bed shortages, with the aim of creating greater inter...

Socioeconomic position and participation in baseline and follow-up visits: the Inter99 study

Abstract: Background:The aim of this paper was to identify the extent of socioeconomic inequality in participation at baseline and follow-up visits.Design:The Inter99 study is a randomized intervention with the aim of investigating the effects of an individualized lifestyle consultation on ischaemic heart disease (IHD). The study comprised 61,301 persons of which 13,016 were assigned to the intervention group. The rest formed the control group. All those in the intervention group were invited to participate in health examinations, risk assessments, and lifestyle consultations. Participants at high risk of IHD were invited to follow-up visits after 1, 3, and 5 years.Methods:Data on five socioeconomic factors were retrieved from nationwide registers. For each socioeconomic factor we estimated the relative risks and relative index of inequality of participation at the baseline visit and among high-risk participants at follow-up visits. In addition, we conducted analyses of trends in socioeconomic inequality in partici...

Vitamin D status, liver enzymes, and incident liver disease and mortality: a general population study.

Abstract: Vitamin D deficiency is common among patients with liver diseases. Both cholestatic and non-cholestatic liver diseases can cause vitamin D deficiency. Whether vitamin D status can also affect liver function is poorly understood. To investigate the association between vitamin D status, liver enzymes, and incident liver disease, we included a total of 2,649 individuals from the Monica10 study conducted in 1993-1994. Vitamin D status as assessed by serum 25-hydroxyvitamin, serum alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transferase (GGT) were measured at baseline. Information on fatal and non-fatal liver disease was obtained from the Danish National Patient Register and The Danish Registry of Causes of Death, respectively. Median follow-up time was 16.5 years, and there were 62 incident cases of fatal and non-fatal liver disease. Multivariable Cox regression analyses with age as underlying time axis and delayed entry showed a statistically significant inverse association between vitamin D status and incident liver disease with a hazard ratio = 0.88 (95 % confidence interval 0.79-0.99) per 10 nmol/l higher vitamin D status at baseline (adjusted for gender, season, alcohol consumption, smoking, physical activity, dietary habits, education, body mass index, and ALT). The risk of having a high level of ALT, AST, or GGT tended to be higher for lower vitamin D levels, although not statistically significant. In this general population study, vitamin D status was inversely associated with incident liver disease. Further studies are needed to determine whether patients in risk of developing impaired liver function should be screened for vitamin D deficiency for preventive purposes.

KCNQ1 Long QT syndrome patients have hyperinsulinemia and symptomatic hypoglycemia

Abstract: Patients with loss-of-function mutations in KCNQ1 have KCNQ1 long QT syndrome (LQTS). KCNQ1 encodes a voltage-gated K(+) channel located in both cardiomyocytes and pancreatic β-cells. Inhibition of KCNQ1 in β-cells increases insulin secretion. Therefore KCNQ1 LQTS patients may exhibit increased insulin secretion. Fourteen patients, from six families, diagnosed with KCNQ1 LQTS were individually matched to two randomly chosen BMI-, age-, and sex-matched control participants and underwent an oral glucose tolerance test (OGTT), a hypoglycemia questionnaire, and continuous glucose monitoring. KCNQ1 mutation carriers showed increased insulin release (area under the curve 45.6 ± 6.3 vs. 26.0 ± 2.8 min ⋅ nmol/L insulin) and β-cell glucose sensitivity and had lower levels of plasma glucose and serum potassium upon oral glucose stimulation and increased hypoglycemic symptoms. Prolonged OGTT in four available patients and matched control subjects revealed hypoglycemia in carriers after 210 min (range 1.4-3.6 vs. 4.1-5.3 mmol/L glucose), and 24-h glucose profiles showed that the patients spent 77 ± 18 min per 24 h in hypoglycemic states (<3.9 mmol/L glucose) with 36 ± 10 min (<2.8 mmol/L glucose) vs. 0 min (<3.9 mmol/L glucose) for the control participants. The phenotype of patients with KCNQ1 LQTS, caused by mutations in KCNQ1, includes, besides long QT, hyperinsulinemia, clinically relevant symptomatic reactive hypoglycemia, and low potassium after an oral glucose challenge, suggesting that KCNQ1 mutations may explain some cases of "essential" reactive hypoglycemia.

Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers

Abstract: We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00 × 10(-10)), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38 × 10(-5)). An interaction test confirmed that these estimates differed from each other (P = 4.95 × 10(-13)). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.

Vascular and lung function related to ultrafine and fine particles exposure assessed by personal and indoor monitoring: a cross-sectional study

Abstract: Exposure to ambient air particulate matter (PM) has been linked to decline in pulmonary function and cardiovascular events possibly through inflammation. Little is known about individual exposure to ultrafine particles (UFP) inside and outside modern homes and associated health-related effects. Associations between vascular and lung function, inflammation markers and exposure in terms of particle number concentration (PNC; d = 10-300 nm) were studied in a cross-sectional design with personal and home indoor monitoring in the Western Copenhagen Area, Denmark. During 48-h, PNC and PM2.5 were monitored in living rooms of 60 homes with 81 non-smoking subjects (30-75 years old), 59 of whom carried personal monitors both when at home and away from home. We measured lung function in terms of the FEV1/FVC ratio, microvascular function (MVF) and pulse amplitude by digital artery tonometry, blood pressure and biomarkers of inflammation including C-reactive protein, and leukocyte counts with subdivision in neutrophils, eosinophils, monocytes, and lymphocytes in blood. PNC from personal and stationary home monitoring showed weak correlation (r = 0.15, p = 0.24). Personal UFP exposure away from home was significantly inversely associated with MVF (1.3% decline per interquartile range, 95% confidence interval: 0.1-2.5%) and pulse amplitude and positively associated with leukocyte and neutrophil counts. The leukocyte and neutrophil counts were also positively and pulse amplitude negatively associated with total personal PNC. Indoor PNC and PM2.5 showed positive association with blood pressure and inverse association with eosinophil counts. The inverse association between personal exposure away from home and MVF is consistent with adverse health effects of UFP from sources outside the home and might be related to increased inflammation indicated by leukocyte counts, whereas UFP from sources in the home could have less effect.

Association between parental socioeconomic position and prevalence of asthma, atopic eczema and hay fever in children.

Abstract: Aim: To determine the prevalence of asthma, atopic eczema and hay fever among children in different age groups and examine the associations with parental socioeconomic position. Methods: A cross-se...

Infancy predictors of hyperkinetic and pervasive developmental disorders at ages 5-7 years: results from the Copenhagen Child Cohort CCC2000.

Abstract: Background Epidemiological studies infancy predictors of mental disorders are scarce. Methods The study is part of a longitudinal birth-cohort study, The Copenhagen Child Cohort CCC2000. Infant mental health and development and mother-infant relations were assessed by community health nurses from birth to age 10 months. Data on the perinatal period were obtained from Danish National Registers. Mental health outcome at age 5–7 years was investigated in 1,585 children who were assessed by the Developmental and Well-Being Assessment (DAWBA) and diagnosed according to the ICD-10. Results Predictors of autism spectrum disorders were problems of oral-motor development OR 5.02 (95% CI: 1.63–15.42) and overall development OR 4.24 (95% CI: 1.35–13.33). A deviant pattern of activity and interests were predictive of autism spectrum disorder, OR 5.34 (95% CI 1.45–19.70) and hyperkinetic disorder, OR 4.71 (95% CI: 1.28–17.39). Hyperkinetic disorder was furthermore predicted by mother-infant relationship problems, OR 8.07 (95% CI: 2.90–22.47). The significant associations between infant developmental problems and autism spectrum disorders persisted in multiple logistic regression analyses controlled for maternal psychological problems and mother-infant relationship problems, OR 3.21 (95% CI: 1.09–9.45). Mother-infant relationship problems remained strongly associated to hyperkinetic disorders in the multivariate analyses controlled for child development problems and maternal psychological problems, OR 5.20 (95% CI: 1.55–17.47). No significant infancy predictors were found regarding emotional and behavioural disorders at age 5–7 years. Conclusion Predictors of autism spectrum/pervasive developmental disorders and hyperkinetic disorders at child age 5–7 years were identified between birth and child age 10 months in community health settings. The study results suggest potential areas of early preventive intervention, which have to be further explored regarding the psychometric qualities of the identification of infants at risk, and concerning methods to handle and intervene towards these children in the general child health surveillance.

Vitamin D Status and Chronic Obstructive Pulmonary Disease: A Prospective General Population Study

Abstract: Objectives Vitamin D deficiency is common among persons with chronic obstructive pulmonary disease (COPD). Whether vitamin D affects the development and deterioration of COPD or is a consequence of the disease lacks clarity. We investigated the association between vitamin D status and prevalent and incident COPD in the general population. Methods We included a total of 12,041 individuals from three general population studies conducted in 1993–94, 1999–2001, and 2006–2008, respectively, with vitamin D measurements. Information on COPD was obtained from the Danish National Patient Register and The Danish Registry of Causes of Death. Results There were 85 prevalent and 463 incident cases of COPD (median follow-up 9.7 years). We found a statistically significant inverse association between vitamin D status and prevalent COPD with odds ratio = 0.89 (95% confidence interval, CI: 0.79, 1.0), but no statistically significant association with incident COPD with a hazard ratio = 0.98 (95% CI: 0.94, 1.0), respectively, per 10 nmol/l higher vitamin D status, when adjusted for possible confounders. Conclusions We found a statistically significant inverse cross-sectional association between vitamin D status and COPD, but no association between vitamin D status and incident COPD.

No association between type 1 diabetes and genetic variation in vitamin D metabolism genes: a Danish study.

Abstract: Background Vitamin D, certain single nucleotide polymorphisms (SNPs) in the vitamin D-receptor (VDR) gene and vitamin D metabolism genes have been associated with type 1 diabetes (T1D). Objective We wanted to examine if the most widely studied SNPs in genes important for production, transport, and action of vitamin D were associated with T1D or to circulating levels of vitamin D 25-hydroxyvitamin D [25(OH)D] in a juvenile Danish population. Methods We genotyped eight SNPs in five vitamin D metabolism genes in 1467 trios. 25(OH)D status were analyzed in 1803 children (907 patients and 896 siblings). Results We did not demonstrate association with T1D for SNPs in the following genes: CYP27B1, VDR, GC, CYP2R1, DHCR7, and CYP24A1. Though, variants in the GC gene were significantly associated with 25(OH)D levels in the joint model. Conclusion Some of the most examined SNPs in vitamin D metabolism genes were not confirmed to be associated with T1D, though 25(OH) levels were associated with variants in the GC gene.

MTHFR C677T genotype and cardiovascular risk in a general population without mandatory folic acid fortification.

Abstract: Purpose Meta-analyses have suggested an effect of MTHFR C677T genotype (rs1801133), a proxy for blood total homocysteine, on cardiovascular disease (CVD) in populations with low population dietary folate. The aim was to examine the association and effect modification by serum folate and vitamin B12 levels between MTHFR and CVD-related outcomes in a general population with no mandatory folic acid fortification policy.

Seroepidemiology of pertussis in a cross-sectional study of an adult general population in Denmark.

Abstract: An increase in pertussis has been observed in several countries over the last decades, especially in adult populations. The seroprevalence of pertussis was determined in a cross-sectional study of the adult population in the Copenhagen area, Denmark, conducted between 2006 and 2008. Specific IgG antibodies against pertussis toxin (PT) were measured in 3440 persons resulting in an age-standardized seroprevalence of 3.0% (95% confidence interval 1.9-4.7) using an IgG anti-PT cut-off of 75 IU/ml. By using antibody decay profiles from longitudinal data the estimated seroincidence was 143/1000 person-years. In contrast, an incidence of 0.03/1000 person-years was estimated from the official data of notified cases during the same period. Of the investigated risk factors, only age and education were significantly associated with pertussis infection. This study indicates that pertussis is highly underestimated in the adult population in Denmark, which has implications for future prevention strategies, including raising the awareness of pertussis.

Filaggrin loss-of-function mutations and incident cancer: a population-based study

Abstract: Summary Background Loss-of-function mutations in the filaggrin gene (FLG) could have opposing effects on cancer risk, as mutations are associated with both 10% higher serum vitamin D levels, which may protect against cancer, and with impaired skin barrier function, which may lead to higher cancer susceptibility. Objectives To investigate the association of the FLG genotype and cancer types in four population-based cohorts. Methods A total of 13 376 individuals were genotyped for FLG mutations. Information on cancer was obtained from the Danish Cancer Registry. Persons with a history of cancer at baseline were excluded from prospective analyses. Results There were 1339 incident cancers (median follow-up 11·4 years). The hazard ratios (HRs) and 95% confidence intervals (CIs) for FLG mutation carriers vs. wild types were: for any cancer (HR 0·95, 95% CI 0·78–1·16), any cancer excluding nonmelanoma skin cancer (NMSC) (HR 1·05, 95% CI 0·84–1·31), head and neck cancer (HR 1·72, 95% CI 0·71–4·15), colorectal cancer (HR 0·82, 95% CI 0·44–1·52), bronchus and lung cancer (HR 1·34, 95% CI 0·77–2·33), breast cancer (HR 0·58, 95% CI 0·30–1·14), uterine cancer (HR 0·42, 95% CI 0·06–3·10), prostate cancer (HR 1·09, 95% CI 0·61–1·94), urinary cancer (HR 1·30, 95% CI 0·51–3·29), malignant melanoma (HR 1·03, 95% CI 0·41–2·58) and NMSC (HR 0·70, 95% CI 0·47–1·05). Among participants aged over 60 years at baseline, we found statistically significant lower risks of all cancers and NMSC among FLG mutation carriers. Conclusions The only significant associations between FLG loss-of-function mutations and cancer were in subgroup analyses.

Differential cross-sectional associations of work- and leisure-time sitting, with cardiorespiratory and muscular fitness among working adults.

Abstract: Objectives Sedentary behavior is increasingly recognized as a risk factor for cardiovascular and metabolic morbidity and mortality. Recent studies suggest that sitting during work and leisure time may affect markers of cardiometabolic health, differently. However, little is known about associations’ between sitting time and cardiorespiratory and muscular fitness among adults. The aim of the present study was to examine associations between work- and leisure-time sitting, and key markers of cardiorespiratory and muscular fitness among working adults. Methods Working adults (N=2544) aged 18–69 from Health2006, a Danish population-based study, were included in this cross-sectional study. Sitting time during work and leisure time along with sociodemographic and behavioral covariates, including physical activity, were self-reported. Participants underwent a health examination with assessment of cardiorespiratory fitness (step test estimated VO 2 Max, systolic and diastolic blood pressure) and muscular fitness (handgrip strength, lower limb extension power). Associations were explored by linear regression. Results Leisure-time sitting time was significantly (P<0.05) and inversely associated with VO 2 Max, systolic blood pressure and handgrip strength among adults <50 years. There were no significant associations between sitting time at work and any of the markers of cardiorespiratory and muscular fitness. Conclusion Work- and leisure-time sitting were differentially associated with cardiorespiratory and muscular fitness among working adults. This suggests that the domain in which sitting time is accrued should be considered when further investigating the relationship between sedentary behaviors and various healthy outcomes. In particular, caution should be exercised when labeling occupational sitting a danger per se for health.