Sex differences in the genetics of sarcoidosis across European and African ancestry populations.

Pubmed ID: 37250650

Pubmed Central ID: PMC10213734

Journal: Frontiers in medicine

Publication Date: May 11, 2023

Grants: R01 HL120393, U01 HL120393, R01 HL117626, R01 HL113326, P30 GM110766, U54 GM104938, HHSN268201800001C, HHSN268201600032C

Authors: Iannuzzi MC, Rybicki BA, Xiong Y, Schreiber S, Ellinghaus D, Garman L, Montgomery CG, Pezant N, Kullberg S, Vasila V, Eklund A, Müller-Quernheim J, Grunewald J, Padyukov L, Rivera NV

Cite As: Xiong Y, Kullberg S, Garman L, Pezant N, Ellinghaus D, Vasila V, Eklund A, Rybicki BA, Iannuzzi MC, Schreiber S, Müller-Quernheim J, Montgomery CG, Grunewald J, Padyukov L, Rivera NV. Sex differences in the genetics of sarcoidosis across European and African ancestry populations. Front Med (Lausanne) 2023 May 11;10:1132799. doi: 10.3389/fmed.2023.1132799. eCollection 2023.

Studies:

Abstract

BACKGROUND: Sex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two clinical sarcoidosis phenotypes: Löfgren's syndrome (LS) and non-Löfgren's syndrome (non-LS). METHODS: A meta-analysis of genome-wide association studies was conducted on Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden (<i>n</i> = 3,843), Germany (<i>n</i> = 3,342), and the United States (<i>n</i> = 2,918), followed by an SNP lookup in the UK Biobank (UKB, <i>n</i> = 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in the sex groups. The association test was based on logistic regression using the additive model in LS and non-LS sex groups independently. Additionally, gene-based analysis, gene expression, expression quantitative trait loci (eQTL) mapping, and pathway analysis were performed to discover functionally relevant mechanisms related to sarcoidosis and biological sex. RESULTS: We identified sex-dependent genetic variations in LS and non-LS sex groups. Genetic findings in LS sex groups were explicitly located in the extended Major Histocompatibility Complex (xMHC). In non-LS, genetic differences in the sex groups were primarily located in the MHC class II subregion and <i>ANXA11</i>. Gene-based analysis and eQTL enrichment revealed distinct sex-specific gene expression patterns in various tissues and immune cell types. In LS sex groups, a pathway map related to antigen presentation machinery by IFN-gamma. In non-LS, pathway maps related to immune response lectin-induced complement pathway in males and related to maturation and migration of dendritic cells in skin sensitization in females were identified. CONCLUSION: Our findings provide new evidence for a sex bias underlying sarcoidosis genetic architecture, particularly in clinical phenotypes LS and non-LS. Biological sex likely plays a role in disease mechanisms in sarcoidosis.