Background/Purpose: SLE occurs more frequently in females than males, with relative prevalence 9-10:1. While the impact of hormones on immune function may contribute to the female predominance of SLE, recent interest has focused on the immune functions conferred by the two X chromosomes in women. To identify unique mechanisms that may result in SLE in males, we generated RNA transcript data from male and female subjects with SLE or from healthy individuals.

Methods: Female and male SLE patients were characterized in detail based on demographic, clinical and laboratory features. Multiple correspondence analysis of 95 parameters was used to optimally match 15 female and 15 male SLE patients, along with healthy donors. A PBMC sample for RNAseq analysis was selected for each patient at the time of their lowest level of disease activity. RNA sequencing was performed and data analyzed using principal component analysis (PCA) and determination of differentially expressed gene transcripts.

Results: PCA distribution of RNAseq data showed male SLE patients distinct from healthy males and female SLE patients. As observed for the overall SLE population, type I interferon-stimulated genes dominate transcripts differentially expressed between SLE males and healthy males, with SLE males also showing higher expression of NFkB pathway genes and pro-inflammatory cytokines/chemokines compared with healthy males. Among the differentially expressed genes, 4 Y chromosome-encoded transcripts (TXLNGY, ENSG00000267793, BCORP1 and KDM5D) were significantly decreased in SLE males compared with healthy males and 1 Y chromosome-encoded gene (EIF1AY) was increased in SLE males. Of those, KDM5D, also called SMCY, encoding lysine demethylase 5D, is of particular interest as it mediates the removal of methyl groups from histone lysine residues at the K4 position and regulates both promoters and enhancers throughout the genome. Remarkably, review of the Y chromosome location of those differentially expressed genes revealed that all 5 genes share a portion of a genomic locus (termed AZFb) in the male-specific region of Y that is associated with microdeletions and male infertility.

Conclusion: Males with SLE demonstrate altered expression of several genes occupying a common Y chromosome locus, along with increased expression of NFkB and pro-inflammatory cytokine genes. Among the Y chromosome-encoded transcripts decreased in male SLE, KDM5D, a histone demethylase, warrants further investigation. KDM5D is expressed in multiple cell types and may contribute to impaired epigenetic regulation and activation of inflammation-related pathways throughout the genome. Our data suggest that males with SLE may be enriched in genomic Y chromosome variants that contribute to altered immune function.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/altered-gene-expression-in-male-sle-is-mapped-to-a-male-specific-y-chromosome-locus-associated-with-microdeletions/