Publications by authors named "Karina Banasik"

44 Publications

Association of Variants Near the Bradykinin Receptor B Gene With Angioedema in Patients Taking ACE Inhibitors.

J Am Coll Cardiol 2021 Aug;78(7):696-709

Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients.

Objectives: The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema.

Methods: A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model.

Results: The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 × 10. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 × 10). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 × 10). We found that carriers of the risk allele had significantly lower systolic (-0.46 mm Hg per T allele; 95% CI: -0.83 to -0.10; P = 0.013) and diastolic (-0.26 mm Hg per T allele; 95% CI: -0.46 to -0.05; P = 0.013) blood pressure.

Conclusions: In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B gene were associated with increased risk for ACE inhibitor-related angioedema.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2021.05.054DOI Listing
August 2021

Impact of COVID-19 Pandemic on Sleep Quality, Stress Level and Health-Related Quality of Life-A Large Prospective Cohort Study on Adult Danes.

Int J Environ Res Public Health 2021 07 17;18(14). Epub 2021 Jul 17.

Department of Clinical Immunology, Zealand University Hospital, 4600 Køge, Denmark.

The everyday lives of Danish inhabitants have been affected by the COVID-19 pandemic, e.g., by social distancing, which was employed by the government in March 2020 to prevent the spread of SARS-CoV-2. Moreover, the pandemic has entailed economic consequences for many people. This study aims to assess changes in physical and mental health-related quality of life (MCS, PCS), in stress levels, and quality of sleep during the COVID-19 pandemic and to identify factors that impact such changes, using a prospective national cohort study including 26,453 participants from the Danish Blood Donor Study who answered a health questionnaire before the pandemic and during the pandemic. Descriptive statistics, multivariable linear and multinomial logistic regression analyses were applied. A worsening of MCS and quality of sleep was found, and an overall decrease in stress levels was observed. PCS was decreased in men and slightly increased in women. The extent of health changes was mainly affected by changes in job situation, type of job, previous use of anti-depressive medication and the participants' level of personal stamina. Thus, living under the unusual circumstances that persisted during the COVID-19 pandemic has had a negative impact on the health of the general population. This may, in time, constitute a public health problem.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph18147610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307688PMC
July 2021

Acute and persistent symptoms in non-hospitalized PCR-confirmed COVID-19 patients.

Sci Rep 2021 06 23;11(1):13153. Epub 2021 Jun 23.

Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.

Reports of persistent symptoms after hospitalization with COVID-19 have raised concern of a "long COVID" syndrome. This study aimed at determining the prevalence of and risk factors for acute and persistent symptoms in non-hospitalized patients with polymerase chain reaction (PCR) confirmed COVID-19. We conducted a cohort study of non-hospitalized participants identified via the Danish Civil Registration System with a SARS-CoV-2-positive PCR-test and available biobank samples. Participants received a digital questionnaire on demographics and COVID-19-related symptoms. Persistent symptoms: symptoms > 4 weeks (in sensitivity analyses > 12 weeks). We included 445 participants, of whom 34% were asymptomatic. Most common acute symptoms were fatigue, headache, and sneezing, while fatigue and reduced smell and taste were most severe. Persistent symptoms, most commonly fatigue and memory and concentration difficulties, were reported by 36% of 198 symptomatic participants with follow-up > 4 weeks. Risk factors for persistent symptoms included female sex (women 44% vs. men 24%, odds ratio 2.7, 95% CI 1.4-5.1, p = 0.003) and BMI (odds ratio 1.1, 95% CI 1.0-1.2, p = 0.001). In conclusion, among non-hospitalized PCR-confirmed COVID-19 patients one third were asymptomatic while one third of symptomatic participants had persistent symptoms illustrating the heterogeneity of disease presentation. These findings should be considered in health care planning and policy making related to COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-92045-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222239PMC
June 2021

Eleven genomic loci affect plasma levels of chronic inflammation marker soluble urokinase-type plasminogen activator receptor.

Commun Biol 2021 06 2;4(1):655. Epub 2021 Jun 2.

Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark.

Soluble urokinase-type plasminogen activator receptor (suPAR) is a chronic inflammation marker associated with the development of a range of diseases, including cancer and cardiovascular disease. The genetics of suPAR remain unexplored but may shed light on the biology of the marker and its connection to outcomes. We report a heritability estimate of 60% for the variation in suPAR and performed a genome-wide association meta-analysis on suPAR levels measured in Iceland (N = 35,559) and in Denmark (N = 12,177). We identified 13 independently genome-wide significant sequence variants associated with suPAR across 11 distinct loci. Associated variants were found in and around genes encoding uPAR (PLAUR), its ligand uPA (PLAU), the kidney-disease-associated gene PLA2R1 as well as genes with relations to glycosylation, glycoprotein biosynthesis, and the immune response. These findings provide new insight into the causes of variation in suPAR plasma levels, which may clarify suPAR's potential role in associated diseases, as well as the underlying mechanisms that give suPAR its prognostic value as a unique marker of chronic inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-021-02144-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172928PMC
June 2021

Combinations of self-reported rhinitis, conjunctivitis, and asthma predicts IgE sensitization in more than 25,000 Danes.

Clin Transl Allergy 2021 Mar;11(1):e12013

Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.

Background: Allergic rhinitis (AR), allergic conjunctivitis (AC), and asthma composing multiple phenotypes and improved understanding of these phenotypes and their respective risk factors are needed.

Objectives: The objective of this study was to define the prevalence of AR, AC, and asthma and their association with allergen-specific immunoglobulin E (sIgE) sensitization in a large cohort of blood donors and identify risk factors.

Methods: From the nationwide population-based Danish Blood Donor Study, 52,976 participants completed an electronic questionnaire including AR, AC, asthma, allergic predisposition, and childhood residence. Of these, 25,257 were additionally tested for sIgE to inhalation allergens (Phadiatop).

Results: The prevalence of sIgE sensitization, AR, AC, and asthma was 30%, 19%, 15%, and 9%, respectively. The youngest birth cohorts had the highest prevalence of sIgE sensitization and symptoms of asthma, AR, and AC, and for asthma, they apparently experienced symptoms at an earlier age. The sIgE sensitization was positively associated with male sex. The sIgE seroprevalence was higher in participants with both AR and AC (ARC) than in participants with either AR or AC. Allergic predisposition and sIgE sensitization increased the risk of the diseases, while farm upbringing was associated with reduced prevalence of ARC, however, only in sIgE sensitized participants.

Conclusion: Birth year, childhood residence, sIgE sensitization, and allergic predisposition were associated with asthma, AR, and AC prevalence. Individuals with self-reported ARC represent a primarily sIgE-positive phenotype, while those with either AR or AC represent more diverse phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/clt2.12013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099331PMC
March 2021

Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.

Gut 2021 Apr 22. Epub 2021 Apr 22.

Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Vienna, Austria.

Objective: Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.

Design: We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.

Results: We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.

Conclusion: HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2020-323868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292596PMC
April 2021

The impact of health-related quality of life and depressive symptoms on blood donor career-Results from the Danish blood donor study.

Transfusion 2021 05 2;61(5):1479-1488. Epub 2021 Mar 2.

Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background: Blood donors report better health-related quality of life (HRQL) than non-donors. Likewise, donors reporting good health are less likely to stop donating and have a higher donation frequency. This is evidence of the healthy donor effect (HDE). This study is the first to investigate the impact of HRQL and depressive symptoms on subsequent donor career.

Study Design And Methods: Prospective cohort study includes 102,065 participants from the Danish Blood Donor Study applying the 12-item short-form health survey (SF-12) measuring a mental (MCS) and a physical component score (PCS) and the Major Depression Inventory (MDI). Poisson and Cox regression models were used to assess the effect of SF-12 and MDI scores on donation frequency and donor cessation. Higher MCS/PCS scores indicate good HRQL, while higher MDI score indicates higher experience of depressive symptoms.

Results: For both sexes, MCS was positively correlated with donation frequency for up to 5 years, and similarly for PCS among women. A negative correlation between MDI score and donation frequency in the year following assessment was observed only among men. No correlation was observed among women. An increase in both MCS and PCS was associated with a lower risk of donation cessation in both sexes, while an increase in MDI score was only associated with an increased risk of donation cessation in men.

Conclusion: MCS, PCS, and MDI score affect donor career. Thus, adjusting for donation frequency may reduce HDE-bias in donor health research. However, because of the small effect sizes, other ways of quantifying HDE may be beneficial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/trf.16336DOI Listing
May 2021

The burden of disease of three food-associated heavy metals in clusters in the Danish population - Towards targeted public health strategies.

Food Chem Toxicol 2021 Apr 18;150:112072. Epub 2021 Feb 18.

Division of Diet, Disease Prevention and Toxicology, National Food Institute, Technical University of Denmark, Denmark. Electronic address:

Lifestyle and sociodemographics are likely to influence dietary patterns, and, as a result, human exposure to chemical contaminants in foods and their associated health impact. We aimed to characterize subgroups of the Danish population based on diet and sociodemographic indicators, and identify those bearing a higher disease burden due to exposure to methylmercury (MeHg), cadmium (Cd) and inorganic arsenic (i-As). We collected dietary, lifestyle, and sociodemographic data on the occurrence of chemical contaminants in foods from Danish surveys. We grouped participants according to similarities in diet, lifestyle, and sociodemographics using Self-Organizing Maps (SOM), and estimated disease burden in disability-adjusted life years (DALY). SOM clustering resulted in 12 population groups with distinct characteristics. Exposure to contaminants varied between clusters and was largely driven by intake of fish, seafood and cereal products. Five clusters had an estimated annual burden >20 DALY/100,000. The cluster with the highest burden had a high proportion of women of childbearing age, with most of the burden attributed to MeHg. Individuals belonging to the top three clusters had higher education and physical activity, were mainly non-smokers and lived in urban areas. Our findings may facilitate the development of preventive strategies targeted to the most affected subgroups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fct.2021.112072DOI Listing
April 2021

A meta-analysis uncovers the first sequence variant conferring risk of Bell's palsy.

Sci Rep 2021 Feb 18;11(1):4188. Epub 2021 Feb 18.

Rigshospitalet, Kobenhavn, Denmark.

Bell's palsy is the most common cause of unilateral facial paralysis and is defined as an idiopathic and acute inability to control movements of the facial muscles on the affected side. While the pathogenesis remains unknown, previous studies have implicated post-viral inflammation and resulting compression of the facial nerve. Reported heritability estimates of 4-14% suggest a genetic component in the etiology and an autosomal dominant inheritance has been proposed. Here, we report findings from a meta-analysis of genome-wide association studies uncovering the first unequivocal association with Bell's palsy (rs9357446-A; P = 6.79 × 10, OR = 1.23; N = 4714, N = 1,011,520). The variant also confers risk of intervertebral disc disorders (P = 2.99 × 10, OR = 1.04) suggesting a common pathogenesis in part or a true pleiotropy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-82736-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893061PMC
February 2021

Genetic insight into sick sinus syndrome.

Eur Heart J 2021 05;42(20):1959-1971

deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 101, Iceland.

Aims: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development.

Methods And Results: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05).

Conclusion: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehaa1108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140484PMC
May 2021

A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis.

Commun Biol 2021 02 3;4(1):156. Epub 2021 Feb 3.

deCODE genetics/Amgen Inc., Reykjavik, Iceland.

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-020-01575-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859200PMC
February 2021

Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study.

Genome Med 2020 12 1;12(1):109. Epub 2020 Dec 1.

NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, UK.

Background: The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D.

Methods: Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts.

Results: We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling.

Conclusions: Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-020-00806-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708171PMC
December 2020

Disease trajectory browser for exploring temporal, population-wide disease progression patterns in 7.2 million Danish patients.

Nat Commun 2020 10 2;11(1):4952. Epub 2020 Oct 2.

Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark.

We present the Danish Disease Trajectory Browser (DTB), a tool for exploring almost 25 years of data from the Danish National Patient Register. In the dataset comprising 7.2 million patients and 122 million admissions, users can identify diagnosis pairs with statistically significant directionality and combine them to linear disease trajectories. Users can search for one or more disease codes (ICD-10 classification) and explore disease progression patterns via an array of functionalities. For example, a set of linear trajectories can be merged into a disease trajectory network displaying the entire multimorbidity spectrum of a disease in a single connected graph. Using data from the Danish Register for Causes of Death mortality is also included. The tool is disease-agnostic across both rare and common diseases and is showcased by exploring multimorbidity in Down syndrome (ICD-10 code Q90) and hypertension (ICD-10 code I10). Finally, we show how search results can be customized and exported from the browser in a format of choice (i.e. JSON, PNG, JPEG and CSV).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18682-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532164PMC
October 2020

Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease.

Genome Med 2020 08 28;12(1):76. Epub 2020 Aug 28.

Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3A, DK-2200, Copenhagen, Denmark.

Background: Congenital heart disease (CHD) occurs in almost 1% of newborn children and is considered a multifactorial disorder. CHD may segregate in families due to significant contribution of genetic factors in the disease etiology. The aim of the study was to identify pathophysiological mechanisms in families segregating CHD.

Methods: We used whole exome sequencing to identify rare genetic variants in ninety consenting participants from 32 Danish families with recurrent CHD. We applied a systems biology approach to identify developmental mechanisms influenced by accumulation of rare variants. We used an independent cohort of 714 CHD cases and 4922 controls for replication and performed functional investigations using zebrafish as in vivo model.

Results: We identified 1785 genes, in which rare alleles were shared between affected individuals within a family. These genes were enriched for known cardiac developmental genes, and 218 of these genes were mutated in more than one family. Our analysis revealed a functional cluster, enriched for proteins with a known participation in calcium signaling. Replication in an independent cohort confirmed increased mutation burden of calcium-signaling genes in CHD patients. Functional investigation of zebrafish orthologues of ITPR1, PLCB2, and ADCY2 verified a role in cardiac development and suggests a combinatorial effect of inactivation of these genes.

Conclusions: The study identifies abnormal calcium signaling as a novel pathophysiological mechanism in human CHD and confirms the complex genetic architecture underlying CHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-020-00772-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453558PMC
August 2020

Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease.

Eur Heart J 2020 07;41(28):2618-2628

Laekning, Medical Clinics, Lágmúli 5, 108 Reykjavik, Iceland.

Aims: To explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols.

Methods And Results: We examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk [odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75-2.31, P = 9.8 × 10-23] compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49-1.59, P = 1.1 × 10-154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10-4).

Conclusions: Genetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehaa531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377579PMC
July 2020

Prevalence and socio-demographic characteristics of persons who have never had a headache among healthy voluntary blood donors - a population-based study.

Cephalalgia 2020 09 20;40(10):1055-1062. Epub 2020 Apr 20.

Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup, Denmark.

Introduction: Headache is an extremely prevalent disorder with a lifetime prevalence of 90-99%. However, a small fraction of people never experiences a headache. Research on people without headache could uncover protective factors in headache, but to our knowledge no study on headache-free individuals has been published. We aim to estimate the prevalence of headache-free individuals among Danish blood donors, and to describe the socio-demographics and health factors of headache-free participants.

Materials And Methods: In all, 38,557 healthy volunteers were recruited as part of the Danish Blood Donor Study. Headache-free participants were identified based on the question "Have you ever experienced a headache of any kind?". Utilising the Danish registries and self-reported questionnaires, we analysed socio-demographic and lifestyle factors using logistic regression adjusted for age and sex.

Results: The prevalence of headache-free individuals was 4.1% (n = 1362) with a female-male ratio of 1:2.2. To be headache free was significantly associated with an employment status as a student, a low level of income and a regular alcohol consumption.

Discussion: The prevalence of headache-free individuals was comparable to population-wide studies of headache. To be headache free was not associated with a high socio-economic status. Further studies on people without headache will hopefully reveal protective factors in headache, and this novel approach might be useful in other very prevalent disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0333102420920653DOI Listing
September 2020

Linking glycemic dysregulation in diabetes to symptoms, comorbidities, and genetics through EHR data mining.

Elife 2019 12 10;8. Epub 2019 Dec 10.

Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.

Diabetes is a diverse and complex disease, with considerable variation in phenotypic manifestation and severity. This variation hampers the study of etiological differences and reduces the statistical power of analyses of associations to genetics, treatment outcomes, and complications. We address these issues through deep, fine-grained phenotypic stratification of a diabetes cohort. Text mining the electronic health records of 14,017 patients, we matched two controlled vocabularies (ICD-10 and a custom vocabulary developed at the clinical center Steno Diabetes Center Copenhagen) to clinical narratives spanning a 19 year period. The two matched vocabularies comprise over 20,000 medical terms describing symptoms, other diagnoses, and lifestyle factors. The cohort is genetically homogeneous (Caucasian diabetes patients from Denmark) so the resulting stratification is not driven by ethnic differences, but rather by inherently dissimilar progression patterns and lifestyle related risk factors. Using unsupervised Markov clustering, we defined 71 clusters of at least 50 individuals within the diabetes spectrum. The clusters display both distinct and shared longitudinal glycemic dysregulation patterns, temporal co-occurrences of comorbidities, and associations to single nucleotide polymorphisms in or near genes relevant for diabetes comorbidities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.44941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904221PMC
December 2019

Linking glycemic dysregulation in diabetes to symptoms, comorbidities, and genetics through EHR data mining.

Elife 2019 12 10;8. Epub 2019 Dec 10.

Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.

Diabetes is a diverse and complex disease, with considerable variation in phenotypic manifestation and severity. This variation hampers the study of etiological differences and reduces the statistical power of analyses of associations to genetics, treatment outcomes, and complications. We address these issues through deep, fine-grained phenotypic stratification of a diabetes cohort. Text mining the electronic health records of 14,017 patients, we matched two controlled vocabularies (ICD-10 and a custom vocabulary developed at the clinical center Steno Diabetes Center Copenhagen) to clinical narratives spanning a 19 year period. The two matched vocabularies comprise over 20,000 medical terms describing symptoms, other diagnoses, and lifestyle factors. The cohort is genetically homogeneous (Caucasian diabetes patients from Denmark) so the resulting stratification is not driven by ethnic differences, but rather by inherently dissimilar progression patterns and lifestyle related risk factors. Using unsupervised Markov clustering, we defined 71 clusters of at least 50 individuals within the diabetes spectrum. The clusters display both distinct and shared longitudinal glycemic dysregulation patterns, temporal co-occurrences of comorbidities, and associations to single nucleotide polymorphisms in or near genes relevant for diabetes comorbidities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.44941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904221PMC
December 2019

DBDS Genomic Cohort, a prospective and comprehensive resource for integrative and temporal analysis of genetic, environmental and lifestyle factors affecting health of blood donors.

BMJ Open 2019 06 9;9(6):e028401. Epub 2019 Jun 9.

Immunology, Rigshospitalet, Kobenhavn, Denmark.

Purpose: To establish a cohort that enables identification of genomic factors that influence human health and empower increased blood donor health and safe blood transfusions. Human health is complex and involves several factors, a major one being the genomic aspect. The genomic era has resulted in many consortia encompassing large samples sizes, which has proven successful for identifying genetic factors associated with specific traits. However, it remains a big challenge to establish large cohorts that facilitate studies of the interaction between genetic factors, environmental and life-style factors as these change over the course of life. A major obstacle to such endeavours is that it is difficult to revisit participants to retrieve additional information and obtain longitudinal, consecutive measurements.

Participants: Blood donors (n=110 000) have given consent to participate in the Danish Blood Donor Study. The study uses the infrastructure of the Danish blood banks.

Findings To Date: The cohort comprises extensive phenotype data and whole genome genotyping data. Further, it is possible to retrieve additional phenotype data from national registries as well as from the donors at future visits, including consecutive measurements.

Future Plans: To provide new knowledge on factors influencing our health and thus provide a platform for studying the influence of genomic factors on human health, in particular the interaction between environmental and genetic factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2018-028401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561431PMC
June 2019

Self-reported restless legs syndrome and involuntary leg movements during sleep are associated with symptoms of attention deficit hyperactivity disorder.

Sleep Med 2019 05 11;57:115-121. Epub 2019 Feb 11.

Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background: Restless legs syndrome (RLS) and attention-deficit hyperactivity disorder (ADHD) are disorders with virtually unknown etiologies. Several studies suggest that these disorders are comorbid. However, previous findings may have been influenced by study participants undergoing medical treatments. Thus, the association between RLS and ADHD needs to be investigated in a large population of individuals, not in continuous medical treatment.

Materials And Methods: This was a cross-sectional study of 25,336 participants enrolled in the Danish Blood Donor Study from May 1, 2015, to February 1, 2017. Study participants completed the Cambridge-Hopkins RLS questionnaire, reported experience of involuntary leg movements during sleep (ILMS), completed the Adult ADHD Self-Report Scale v.1.1 (ASRS), and provided information on sex, age, body mass index, smoking status, alcohol consumption, whole blood donation history, and self-appraised quality of sleep. Associations between RLS and ADHD symptoms, including subtypes, were examined using multivariate linear- and logistic regression analyses.

Results: Of the 25,336 participants with complete data, 1,322 (5.2%) were classified with RLS, and 653 (2.6%) experienced ADHD symptoms. RLS sufferers were more prone to classify with ADHD according to the full ASRS (OR = 3.57, 95% CI: 3.14-4.0), and they were also more likely to experience ADHD-subtype symptoms (inattention, OR = 1.66, 95% CI: 1.43-1.90; hyperactivity-impulsivity, OR = 1.90, 95% CI: 1.66-2.14). Finally, RLS sufferers with ILMS had increased odds for ADHD symptoms compared with RLS sufferers without (OR = 2.15, 95% CI: 1.30-3.55). This was also observed for the hyperactivity-impulsivity subtype (OR = 5.57, 95% CI: 2.14-14.5).

Conclusions: RLS and ADHD are associated and may be comorbid disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sleep.2019.01.039DOI Listing
May 2019

Self-reported restless legs syndrome and involuntary leg movements during sleep are associated with symptoms of attention deficit hyperactivity disorder.

Sleep Med 2019 05 11;57:115-121. Epub 2019 Feb 11.

Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background: Restless legs syndrome (RLS) and attention-deficit hyperactivity disorder (ADHD) are disorders with virtually unknown etiologies. Several studies suggest that these disorders are comorbid. However, previous findings may have been influenced by study participants undergoing medical treatments. Thus, the association between RLS and ADHD needs to be investigated in a large population of individuals, not in continuous medical treatment.

Materials And Methods: This was a cross-sectional study of 25,336 participants enrolled in the Danish Blood Donor Study from May 1, 2015, to February 1, 2017. Study participants completed the Cambridge-Hopkins RLS questionnaire, reported experience of involuntary leg movements during sleep (ILMS), completed the Adult ADHD Self-Report Scale v.1.1 (ASRS), and provided information on sex, age, body mass index, smoking status, alcohol consumption, whole blood donation history, and self-appraised quality of sleep. Associations between RLS and ADHD symptoms, including subtypes, were examined using multivariate linear- and logistic regression analyses.

Results: Of the 25,336 participants with complete data, 1,322 (5.2%) were classified with RLS, and 653 (2.6%) experienced ADHD symptoms. RLS sufferers were more prone to classify with ADHD according to the full ASRS (OR = 3.57, 95% CI: 3.14-4.0), and they were also more likely to experience ADHD-subtype symptoms (inattention, OR = 1.66, 95% CI: 1.43-1.90; hyperactivity-impulsivity, OR = 1.90, 95% CI: 1.66-2.14). Finally, RLS sufferers with ILMS had increased odds for ADHD symptoms compared with RLS sufferers without (OR = 2.15, 95% CI: 1.30-3.55). This was also observed for the hyperactivity-impulsivity subtype (OR = 5.57, 95% CI: 2.14-14.5).

Conclusions: RLS and ADHD are associated and may be comorbid disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sleep.2019.01.039DOI Listing
May 2019

The governance structure for data access in the DIRECT consortium: an innovative medicines initiative (IMI) project.

Life Sci Soc Policy 2018 Sep 4;14(1):20. Epub 2018 Sep 4.

HeLEX Centre, University of Oxford, Ewert House, Banbury Road, Oxford, OX2 7DD, UK.

Biomedical research projects involving multiple partners from public and private sectors require coherent internal governance mechanisms to engender good working relationships. The DIRECT project is an example of such a venture, funded by the Innovative Medicines Initiative Joint Undertaking (IMI JU). This paper describes the data access policy that was developed within DIRECT to support data access and sharing, via the establishment of a 3-tiered Data Access Committee. The process was intended to allow quick access to data, whilst enabling strong oversight of how data were being accessed and by whom, and any subsequent analyses, to contribute to the overall objectives of the consortium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40504-018-0083-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123336PMC
September 2018

Toppar: an interactive browser for viewing association study results.

Bioinformatics 2018 06;34(11):1922-1924

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

Summary: Data integration and visualization help geneticists make sense of large amounts of data. To help facilitate interpretation of genetic association data we developed Toppar, a customizable visualization tool that stores results from association studies and enables browsing over multiple results, by combining features from existing tools and linking to appropriate external databases.

Availability And Implementation: Detailed information on Toppar's features and functionality are on our website http://mccarthy.well.ox.ac.uk/toppar/docs along with instructions on how to download, install and run Toppar. Our online version of Toppar is accessible from the website and can be test-driven using Firefox, Safari or Chrome on sub-sets of publicly available genome-wide association study anthropometric waist and body mass index data (Locke et al., 2015; Shungin et al., 2015) from the Genetic Investigation of ANthropometric Traits consortium.

Contact: [email protected]
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/btx840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972658PMC
June 2018

Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study.

PLoS One 2018 2;13(1):e0189886. Epub 2018 Jan 2.

Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.

Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100). Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05) with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated insulin secretion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189886PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749727PMC
January 2018

A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants.

Diabetes 2017 08 10;66(8):2296-2309. Epub 2017 May 10.

School of Medicine, University of Dundee, Dundee, U.K.

Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the , , , , , , , , , , , and loci. The fasting glucose-raising allele near , a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db16-1452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521867PMC
August 2017

Evaluation of type 2 diabetes genetic risk variants in Chinese adults: findings from 93,000 individuals from the China Kadoorie Biobank.

Diabetologia 2016 07 6;59(7):1446-1457. Epub 2016 Apr 6.

Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.

Aims/hypothesis: Genome-wide association studies (GWAS) have discovered many risk variants for type 2 diabetes. However, estimates of the contributions of risk variants to type 2 diabetes predisposition are often based on highly selected case-control samples, and reliable estimates of population-level effect sizes are missing, especially in non-European populations.

Methods: The individual and cumulative effects of 59 established type 2 diabetes risk loci were measured in a population-based China Kadoorie Biobank (CKB) study of 93,000 Chinese adults, including >7,100 diabetes cases.

Results: Association signals were directionally consistent between CKB and the original discovery GWAS: of 56 variants passing quality control, 48 showed the same direction of effect (binomial test, p = 2.3 × 10(-8)). We observed a consistent overall trend towards lower risk variant effect sizes in CKB than in case-control samples of GWAS meta-analyses (mean 19-22% decrease in log odds, p ≤ 0.0048), likely to reflect correction of both 'winner's curse' and spectrum bias effects. The association with risk of diabetes of a genetic risk score, based on lead variants at 25 loci considered to act through beta cell function, demonstrated significant interactions with several measures of adiposity (BMI, waist circumference [WC], WHR and percentage body fat [PBF]; all p interaction < 1 × 10(-4)), with a greater effect being observed in leaner adults.

Conclusions/interpretation: Our study provides further evidence of shared genetic architecture for type 2 diabetes between Europeans and East Asians. It also indicates that even very large GWAS meta-analyses may be vulnerable to substantial inflation of effect size estimates, compared with those observed in large-scale population-based cohort studies.

Access To Research Materials: Details of how to access China Kadoorie Biobank data and details of the data release schedule are available from www.ckbiobank.org/site/Data+Access .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-016-3920-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4901105PMC
July 2016

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

PLoS Genet 2015 Oct 1;11(10):e1005378. Epub 2015 Oct 1.

HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1005378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591371PMC
October 2015
-->