Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10, 999 controls across 123, 127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P = 2.0 x 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P = 4.8 x 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition

New Access Routes to Undertreated Populations; How Do Problem Substance Users Recruited from An Unemployment office Differ from Drug Detoxification Treatment Inpatients?

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Background: Only a minority of subjects with substance use disorders (SUD) are in addic-tion-specific treatment (treatment gap). A co-operation between an unemployment office and a psychiatric hospital was established for the assessment and counseling of long-term unemployed clients with SUD. We aim at validating whether such a treatment gap exists in that group, and whether clients from an unemployment office differed from a matched group of inpatient detoxi-fication patients with regard to socio-economic characteristics, substance use and treatment history, and prevalence of mental disorders Methods: Unemployment office clients (n=166) with a SUD were assessed using a standardized sociodemographic and clinical interview. They were compared with 83 inpatients from a local detoxification ward, matched for age, sex, and primary addictive disorder (matching ratio 2:1).  Results: Most (75.9%) subjects were males, with an average age of 36.7 years. SUD mostly related to alcohol (63.9%) and cannabis (27.7%). Although most unemployment office clients had a long SUD history, only half of them had ever been in addiction-specific treatment during lifetime, and only one of four during the last year. There were no statistically significant differences between groups regarding age at onset of problematic substance use, proportion of migrants, and prevalence of comorbid mental disorders. The unemployment office sample showed lower levels of education (p< 0.001), job experience (p=0.009), and current employment rates (p< 0.001). Conversely, inpatients showed lower rates of imprisonment (p<0.001), more inpatient de-toxification episodes (p<0.03); and longer abstinence periods (p<0.005).  Conclusions: There was a lifetime and recent treatment gap in the group of long-term unemployed subjects with alcohol and cannabis dependence.. The markedly lower educational attainment, chronic employment problems and higher degree of legal conflict in the client group, as compared with patients in detoxification treatment, might require specific access and treatment options. The co-operation between the psychiatric unit and the unemployment office facilitated access to that group.Peer reviewedFinal Published versio

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

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

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

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