Sex differences in the genetics of sarcoidosis across European and African ancestry populations
Year: 2023
Type: article
Abstract: Background: Sex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two sarcoidosis clinical phenotypes: Löfgren's syndrome (LS) and non- Löfgren's syndrome (non-LS).Methods: A meta-analysis of genome-wide association studies was conducted in Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden (n = 3,843), Germany (n = 3,342), and the United States (n = 2,918), followed by replication look-up in the UK Biobank (n = 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in males and females in each cohort, respectively. The association test was based on logistic regression using the additive model in LS and non-LS independently. Additionally, gene-based analysis, expression quantitative trait loci (eQTL) assessments, and enrichment analysis were performed to discover functionally relevant mechanisms related to biological sex. Results: In LS sarcoidosis, we identified various sex-dependent genetic variations (798 SNPs in males and 703 SNPs in females). Genetic findings in sex groups were explicitly located in the extended major histocompatibility complex. In non-LS, we detected 16 SNPs in males and 38 in females, primarily localized to the MHC class II region. Additionally, the ANXA11 gene, a well-documented locus in sarcoidosis, was associated exclusively with non-LS males. Gene-based, eQTL assessment and enrichment analyses revealed distinct sex-dependent genomic loci and gene expression variation in the sex groups. Conclusions: Our findings provide new evidence of the existence of sex-dependent genetic variations underlying sarcoidosis genetic architecture. These findings suggest a sex bias in molecular mechanisms of sarcoidosis.
Source: Frontiers in Medicine
Institutions: Karolinska Institutet, Karolinska University Hospital, Oklahoma Medical Research Foundation, Christian-Albrechts-Universität zu Kiel, Henry Ford Health, Hofstra University, Staten Island University Hospital, University Hospital Schleswig-Holstein, University of Freiburg, University Medical Center Freiburg
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,838
Funders: Foundation for Sarcoidosis Research, Deutsche Forschungsgemeinschaft, Hjärt-Lungfonden, Karolinska Institutet, Vetenskapsrådet, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences
Awards: G1462704709, G165400314, Rare variants and NHLBI traits in deeply phenotyped cohorts, G232264632, G2694361877, G2816736420, Molecular Mechanisms and Genetics of Autoimmunity COBRE, G3256118428, SARCOIDOSIS GENETIC LINKAGE CONSORTIUM, G353643266, EXC 2167: Präzisionsmedizin für Chronische Entzündungserkrankungen (PMI), Genetic interactions in autoimmune diseases, G387318277, Rare variants and NHLBI traits in deeply phenotyped cohorts, G488439188, G5462759524, G629286870, G7086254578, G712881263, G7166526206, Sarcoidosis: Identification of disease markers and specific antigens, G7654203544, Admixture Mapping of Sarcoidosis Genes in African American, Studies of Rare Genetic Variation in the Isolated Population of Sardinia, Characterization of European American and African American Sarcoidosis via Immunogenetics, G9000130911, Oklahoma Shared Clinical and Translational Resources
OpenAlex ID: W4376279311