Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis

Report from the CVOT Summit 2020: new cardiovascular and renal outcomes

The 6th Cardiovascular Outcome Trial (CVOT) Summit “Cardiovascular and Renal Outcomes 2020” was the first to be held virtually on October 29–30, 2020. As in previous years, this summit served as reference meeting for in-depth discussions on the topic of recently completed and presented major outcome trials. This year, focus was placed on the outcomes of VERTIS-CV, EMPEROR-Reduced, DAPA-CKD, and FIDELIO-DKD. Trial implications for diabetes management and the impact on new treatment algorithms were highlighted for diabetologists, cardiologists, endocrinologists, nephrologists, and general practitioners. Discussion evolved from major outcome trials using SGLT-2 inhibitors for treatment and prevention of heart failure and chronic kidney disease in people with and without diabetes, to additional therapy options for chronic kidney disease with a novel mineralocorticoid receptor antagonist. Furthermore, challenges in diabetes management like COVID-19 and obesity, as well as novel treatment strategies and guidelines, were discussed. The 7th Cardiovascular Outcome Trial Summit will be held virtually on November, 18–19, 2021 (http://www.cvot.org)

Insulin Detemir in the Treatment of Type 1 and Type 2 Diabetes

Insulin detemir is a soluble long-acting human insulin analogue at neutral pH with a unique mechanism of action. Following subcutaneous injection, insulin detemir binds to albumin via fatty acid chain, thereby providing slow absorption and a prolonged metabolic effect. Insulin detemir has a less variable pharmacokinetic profile than insulin suspension isophane or insulin ultralente. The use of insulin detemir can reduce the risk of hypoglycemia (especially nocturnal hypoglycemia) in type 1 and type 2 diabetic patients. However, overall glycemic control, as assessed by glycated hemoglobin, is only marginally and not significantly improved compared with usual insulin therapy. The weight gain commonly associated with insulin therapy is rather limited when insulin detemir is used. In our experience, this new insulin analogue is preferably administrated at bedtime but can be proposed twice a day (in the morning and either before the dinner or at bedtime). Detemir is a promising option for basal insulin therapy in type 1 or type 2 diabetic patients

Traffic-related air pollution and hyperactivity/inattention, dyslexia and dyscalculia in adolescents of the German GINIplus and LISAplus birth cohorts

Background Few studies have examined the link between air pollution exposure and behavioural problems and learning disorders during late childhood and adolescence. Objectives To determine whether traffic-related air pollution exposure is associated with hyperactivity/inattention, dyslexia and dyscalculia up to age 15 years using the German GINIplus and LISAplus birth cohorts (recruitment 1995–1999). Methods Hyperactivity/inattention was assessed using the German parent-completed (10 years) and self-completed (15 years) Strengths and Difficulties Questionnaire. Responses were categorized into normal versus borderline/abnormal. Parent-reported dyslexia and dyscalculia (yes/no) at age 10 and 15 years were defined using parent-completed questionnaires. Individual-level annual average estimates of nitrogen dioxide (NO2), particulate matter (PM)10 mass, PM2.5 mass and PM2.5 absorbance concentrations were assigned to each participant's birth, 10 year and 15 year home address. Longitudinal associations between the air pollutants and the neurodevelopmental outcomes were assessed using generalized estimation equations, separately for both study areas, and combined in a random-effects meta-analysis. Odds ratios and 95% confidence intervals are given per interquartile range increase in pollutant concentration. Results The prevalence of abnormal/borderline hyperactivity/inattention scores and parental-reported dyslexia and dyscalculia at 15 years of age was 12.9%, 10.5% and 3.4%, respectively, in the combined population (N = 4745). In the meta- analysis, hyperactivity/inattention was associated with PM2.5 mass estimated to the 10 and 15 year addresses (1.12 [1.01, 1.23] and 1.11 [1.01, 1.22]) and PM2.5 absorbance estimated to the 10 and 15 year addresses (1.14 [1.05, 1.25] and 1.13 [1.04, 1.23], respectively). Conclusions We report associations suggesting a potential link between air pollution exposure and hyperactivity/inattention scores, although these findings require replication

Gene–Environment Interaction Affects Risk of Atopic Eczema: Population and In Vitro Studies

\ua9 2025 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.Background: Multiple environmental and genetic factors play a role in the pathogenesis of atopic eczema (AE). We aimed to investigate gene–environment interactions (G 7 E) to improve understanding of the pathophysiology. Methods: We analysed data from 16 European studies to test for interaction between the 24 most significant AE-associated loci identified from genome-wide association studies and 18 early-life environmental factors. We tested for replication using a further 10 studies and in vitro modeling to independently assess findings. Results: The discovery analysis (including 25,339 individuals) showed suggestive evidence for interaction (p < 0.05) between seven environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking and washing practices) and at least one established variant for AE, 14 interactions in total. In the replication analysis (254,532 individuals) dog exposure 7 rs10214237 (on chromosome 5p13.2 near IL7R) was nominally significant (ORinteraction = 0.91 [0.83–0.99] p = 0.025), with a risk effect of the T allele observed only in those not exposed to dogs. A similar interaction with rs10214237 was observed for siblings in the discovery analysis (ORinteraction = 0.84 [0.75–0.94] p = 0.003), but replication analysis was under-powered (ORinteraction = 1.09 [0.82–1.46]). rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled in vitro showed a differential response according to rs10214237 genotype. Conclusion: Interaction analysis and functional assessment provide preliminary evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via IL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G 7 E studied here implies only weak effects are likely to occur

FADS1 FADS2 Gene Cluster, PUFA Intake and Blood Lipids in Children: Results from the GINIplus and LISAplus Studies

BACKGROUND: Elevated cholesterol levels in children can be a risk factor for cardiovascular diseases in later life. In adults, it has been shown that blood lipid levels are strongly influenced by polymorphisms in the fatty acid desaturase (FADS) gene cluster in addition to nutritional and other exogenous and endogenous determinants. Our aim was to investigate whether lipid levels are determined by the FADS genotype already in children and whether this association interacts with dietary intake of n-3 fatty acids. METHODS: The analysis was based on data of 2006 children from two German prospective birth cohort studies. Total cholesterol, HDL, LDL and triglycerides were measured at 10 years of age. Six single nucleotide polymorphisms (SNPs) of the FADS gene cluster were genotyped. Dietary n-3 fatty acid intake was assessed by food frequency questionnaire. Linear regression modeling was used to assess the association between lipid levels, n-3 fatty acid intake and FADS genotype. RESULTS: Individuals carrying the homozygous minor allele had lower levels of total cholesterol [means ratio (MR) ranging from 0.96 (p = 0.0093) to 0.98 (p = 0.2949), depending on SNPs] and LDL [MR between 0.94 (p = 0.0179) and 0.97 (p = 0.2963)] compared to homozygous major allele carriers. Carriers of the heterozygous allele showed lower HDL levels [β between -0.04 (p = 0.0074) to -0.01 (p = 0.3318)] and higher triglyceride levels [MR ranging from 1.06 (p = 0.0065) to 1.07 (p = 0.0028)] compared to homozygous major allele carriers. A higher n-3 PUFA intake was associated with higher concentrations of total cholesterol, LDL, HDL and lower triglyceride levels, but these associations did not interact with the FADS1 FADS2 genotype. CONCLUSION: Total cholesterol, HDL, LDL and triglyceride concentrations may be influenced by the FADS1 FADS2 genotype already in 10 year old children. Genetically determined blood lipid levels during childhood might differentially predispose individuals to the development of cardiovascular diseases later in life

Physical activity, sedentary behaviour, and childhood asthma: a European collaborative analysis

OBJECTIVES: To investigate the associations of physical activity (PA) and sedentary behaviour in early childhood with asthma and reduced lung function in later childhood within a large collaborative study. DESIGN: Pooling of longitudinal data from collaborating birth cohorts using meta-analysis of separate cohort-specific estimates and analysis of individual participant data of all cohorts combined. SETTING: Children aged 0-18 years from 26 European birth cohorts. PARTICIPANTS: 136 071 individual children from 26 cohorts, with information on PA and/or sedentary behaviour in early childhood and asthma assessment in later childhood. MAIN OUTCOME MEASURE: Questionnaire-based current asthma and lung function measured by spirometry (forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity) at age 6-18 years. RESULTS: Questionnaire-based and accelerometry-based PA and sedentary behaviour at age 3-5 years was not associated with asthma at age 6-18 years (PA in hours/day adjusted OR 1.01, 95% CI 0.98 to 1.04; sedentary behaviour in hours/day adjusted OR 1.03, 95% CI 0.99 to 1.07). PA was not associated with lung function at any age. Analyses of sedentary behaviour and lung function showed inconsistent results. CONCLUSIONS: Reduced PA and increased sedentary behaviour before 6 years of age were not associated with the presence of asthma later in childhood. © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.The authors received no specific funding for this article. Funding information per cohort: ABCD: The ABCD study has been supported by grants from The Netherlands Organisation for Health Research and Development (ZonMW) and The Netherlands Heart Foundation. ABIS: Special thanks to the participating families in the ABIS study, and all staff at Obstetric departments and Well-Baby Clinics. ABIS has been supported by Swedish Research Council (K2005-72X-11242-11A and K2008-69X-20826-01-4) and the Swedish Child Diabetes Foundation (Barndiabetesfonden), JDRF Wallenberg Foundation (K 98-99D-12813-01A), Medical Research Council of Southeast Sweden (FORSS), and the Swedish Council for Working Life and Social Research (FAS2004-1775) and Östgöta Brandstodsbolag. BAMSE: This BAMSE birth cohort was supported by grants from the Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare, Formas, the Swedish Heart-Lung Foundation, the Swedish Asthma and Allergy Research Foundation, Region Stockholm (ALF project, and for cohort and database maintenance), and the European Research Council (TRIBAL, grant agreement 757919). CHOP: The CHOP study reported herein have been carried out with partial financial support from the Commission of the European Community, specific RTD Programme 'Quality of Life and Management of Living Resources', within the European Union's Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition under grant agreement no. 289346, partial financial support from Polish Ministry of Science and Higher Education (2571/7.PR/2012/2), the EU H2020 project PHC-2014-DynaHealth under grant no. 633595 and the European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG-no.322605). COPSAC2000: All funding received by COPSAC is listed on www.copsac.com. The Lundbeck Foundation (Grant no R16-A1694); The Ministry of Health (Grant no 903516); Danish Council for Strategic Research (Grant no 0603-00280B) and The Capital Region Research Foundation have provided core support to the COPSAC research center. DNBC: The Danish National Birth Cohort was established with a significant grant from the Danish National Research Foundation. Additional support was obtained from the Danish Regional Committees, the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Health Foundation and other minor grants. The DNBC Biobank has been supported by the Novo Nordisk Foundation and the Lundbeck Foundation. EDEN: EU FP7 Framework MedAll project, National Institute for Research in Public Health (IRESP TGIR Cohorte Santé 2008 Program); National Agency for Research (ANR non-thematic programme); French Speaking Association for the Study of Diabetes and Metabolism (Alfediam); Mutuelle Générale de l’Éducation Nationale; Nestlé; French National Institute for Health Education (INPES); Paris‐Sud University; French National Istitute for Population Health Surveillance (InVS); French Agency for Environment Security (AFFSET); French Ministry of Health Perinatal Program; Inserm Nutrition Research Program; Institut Fédératif de Recherche and Cohort Program; French Ministry of Research; EURIP and FIRE doctoral school–Programme Bettencourt; Fondation pour la Recherche Médicale (FRM). G21: Generation XXI was supported by the European Regional Development Fund (ERDF) through the Operational Programme Competitiveness and Internationalisation and national funding from the Foundation for Science and Technology (FCT), Portuguese Ministry of Science, Technology and Higher Education under the project 'HIneC: When do health inequalities start? Understanding the impact of childhood social adversity on health trajectories from birth to early adolescence' (POCI-01-0145-FEDER-029567; Reference PTDC/SAU-PUB/29567/2017). It is also supported by the Unidade de Investigação em Epidemiologia–Instituto de Saúde Pública da Universidade do Porto (EPIUnit) (UIDB/04750/2020), Administração Regional de Saúde Norte (Regional Department of Ministry of Health) and Fundação Calouste Gulbenkian; PhD Grant SFRH/BD/108742/2015 (to SS) co-funded by FCT and the Human Capital Operational Programme (POCH/FSE Program); ACS is founded by a FCT Investigator contracts IF/01060/2015. Generation R: The Generation R Study is made possible by financial support from the Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam and The Netherlands Organization for Health Research and Development. The project received funding for projects from the European Union's Horizon 2020 research and innovation programme (LIFECYCLE, grant agreement No 733206, 2016; EUCAN-Connect grant agreement No 824989; ATHLETE, grant agreement No 874583). LD received funding from the European Union's Horizon 2020 cofunded programme ERA-Net on Biomarkers for Nutrition and Health (ERA HDHL) (ALPHABET project (no 696295; 2017), ZonMW The Netherlands (no 529051014; 2017)). GINIplus: The GINIplus study was mainly supported for the first 3 years of the Federal Ministry for Education, Science, Research and Technology (interventional arm) and Helmholtz Zentrum Munich (former GSF) (observational arm). The 4 years, 6 years, 10 years and 15 years follow-up examinations of the GINIplus study were covered from the respective budgets of the five study centres (Helmholtz Zentrum Munich (former GSF), Research Institute at Marien-Hospital Wesel, LMU Munich, TU Munich and from 6 years onwards also from IUF - Leibniz Research-Institute for Environmental Medicine at the University of Düsseldorf) and a grant from the Federal Ministry for Environment (IUF Düsseldorf, FKZ 20462296). Further, the 15-year follow-up examination of the GINIplus study was supported by the Commission of the European Communities, the 7th Framework Program: MeDALL project, and as well by the companies Mead Johnson and Nestlé. The authors thank all the families for their participation in the GINIplus study. Furthermore, we thank all members of the GINIplus Study Group for their excellent work. The GINIplus Study group consists of the following: Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg (Heinrich J, Brüske I, Schulz H, Flexeder C, Zeller C, Standl M, Schnappinger M, Ferland M, Thiering E, Tiesler C); Department of Pediatrics, Marien-Hospital, Wesel (Berdel D, von Berg A); Ludwig-Maximilians-University of Munich, Dr von Hauner Children’s Hospital (Koletzko S); Child and Adolescent Medicine, University Hospital rechts der Isar of the Technical University Munich (Bauer CP, Hoffmann U); IUF- Environmental Health Research Institute, Düsseldorf (Schikowski T, Link E, Klümper C, Krämer U, Sugiri D). HUMIS: HUMIS is supported by the Research Council of Norway (NevroNor, grant number 226402). INMA Asturias: This study was funded by grants from, FIS-FEDER: PI04/2018, PI09/02311, PI13/02429, PI18/00909; Obra Social Cajastur/Fundación Liberbank, and Universidad de Oviedo. We thank Fundación NOE Alimerka. INMA Gipuzkoa: This study was funded by grants from Instituto de Salud Carlos III (FIS-PI06/0867, FIS-PI09/00090, FIS-PI13/02187 include FEDER funds), CIBERESP, Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), and the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). INMA Menorca: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; 97/0588; 00/0021-2; PI061756; PS0901958; PI14/00677 incl. FEDER funds), CIBERESP, Beca de la IV convocatoria de Ayudas a la Investigación en Enfermedades Neurodegenerativas de La Caixa, and EC Contract No. QLK4-CT-2000-00263. INMA Sabadell: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; CPII/00018), CIBERESP, Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR 2009 SGR 501, Fundació La marató de TV3 (090430), EU Commission (261357). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. INMA Valencia: This study was funded by grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (Red INMA G03/176, CB06/02/0041; FIS-FEDER: PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/1213, PI07/0314, PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI17/00663, and 19/1338; Miguel Servet-FEDER CP11/00178, CP15/00025 and CPII16/00051), Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, UGP-15-249, and AICO 2020/285), and Alicia Koplowitz Foundation 2017. KOALA: The KOALA cohort study was cofinanced by Friesland Foods (now FrieslandCampina), Netherlands Asthma Foundation (grant numbers 3.2.07.022 and 3.2.03.48) and Netherlands Heart Foundation (grant number 2014 T037), the Netherlands Organization for Health Research and Development (ZonMw Prevention Program number 1.210-00-090). The funding sources had no role in the study design and the collection, analysis and interpretation of data and the writing of the article and the decision to submit it for publication. Lifeways: The Lifeways study has been funded by the Health Research Board, Ireland, and the Irish Department of Health and Children’s Health Promotion Policy Unit. LISA: The LISA study was mainly supported by grants from the Federal Ministry for Education, Science, Research and Technology and in addition from Helmholtz Zentrum Munich (former GSF), Helmholtz Centre for Environmental Research—UFZ, Leipzig, Research Institute at Marien-Hospital Wesel, Pediatric Practice, Bad Honnef for the first 2 years. The 4 years, 6 years, 10 years and 15 years follow-up examinations of the LISA study were covered from the respective budgets of the involved partners (Helmholtz Zentrum Munich (former GSF), Helmholtz Centre for Environmental Research—UFZ, Leipzig, Research Institute at Marien-Hospital Wesel, Pediatric Practice, Bad Honnef, IUF—Leibniz-Research Institute for Environmental Medicine at the University of Düsseldorf) and in addition by a grant from the Federal Ministry for Environment (IUF Düsseldorf, FKZ 20462296). Further, the 15-year follow-up examination of the LISA study was supported by the Commission of the European Communities, the 7th Framework Program: MeDALL project. The authors thank all the families for their participation in the LISA study. Furthermore, we thank all members of the LISA Study Group for their excellent work. The LISA Study group consists of the following: Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology, Munich (Heinrich J, Schnappinger M, Brüske I, Ferland M, Schulz H, Zeller C, Standl M, Thiering E, Tiesler C, Flexeder C); Department of Pediatrics, Municipal Hospital 'St. Georg', Leipzig (Borte M, Diez U, Dorn C, Braun E); Marien Hospital Wesel, Department of Pediatrics, Wesel (von Berg A, Berdel D, Stiers G, Maas B); Pediatric Practice, Bad Honnef (Schaaf B); Helmholtz Centre of Environmental Research—UFZ, Department of Environmental Immunology/Core Facility Studies, Leipzig (Lehmann I, Bauer M, Röder S, Schilde M, Nowak M, Herberth G, Müller J); Technical University Munich, Department of Pediatrics, Munich (Hoffmann U, Paschke M, Marra S); Clinical Research Group Molecular Dermatology, Department of Dermatology and Allergy, Technische Universität München (TUM), Munich (Ollert M, J. Grosch). LRC: All phases of this study were supported by the Swiss National Science Foundation (grants: SNF 320030_182628, 32003B_162820, PDFMP3 137033, 32003B_162820, 32003B_144068, PZ00P3_147987) and Asthma UK 07/048. LUCKI: This study was supported by Maastricht University and the Public Health Service South Limburg. PIAMA: The Prevention and Incidence of Asthma and Mite Allergy Study has been funded by grants from the Netherlands Organization for Health Research and Development; the Netherlands Organization for Scientific Research; the Lung Foundation of the Netherlands; the Netherlands Ministry of Planning, Housing and the Environment; the Netherlands Ministry of Health, Welfare and Sport; and the National Institute for Public Health and the Environment. SEATON: Medical Research Council, Grant number: 80219, MR/K001035/1; Asthma UK, Grant numbers: 00/011, 02/017. STEPS Study: The Academy of Finland (grant no. 123571 and 121659); the Juho Vainio Foundation; the Foundation for Pediatric Research; the Finnish Medical Foundation. SWS: The SWS was supported by grants from the Medical Research Council (MC_UU_12011/4), Dunhill Medical Trust, British Heart Foundation, Food Standards Agency (contract no N05071), British Lung Foundation. National Institute for Health Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton National Health Service Foundation Trust, the European Union’s Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition (grant 289346) and European Union’s Horizon 2020 research and innovation programme under grant agreement No 733206 (LifeCycle). WHISTLER: The authors (from the WHISTLER birth cohort) received no specific funding for this article. The WHISTLER birth cohort was supported with a grant from the Netherlands Organization for Health Research and Development (grant no. 2001-1-1322) and by an unrestricted grant from GlaxoSmithKline Netherlands