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.
Genetic variations and risk of placental abruption: A genome-wide association study and meta-analysis of genome-wide association studies
