Background: A key feature of Systemic Lupus Erythematosus (SLE) is the female predominance, as women present with this disease 9-fold more than men. In addition, the phenotype of the disease in each sex is quite distinct. Hormone impact, genetic distance, differential microbiome and epigenetic mechanisms are thought to be the main reasons for this sex bias. Yet, the details of the pathophysiological mechanisms that lead to the emergence of this trait of the disease are poorly studied.

Objectives: To elucidate the molecular characteristics that differentiate the female from male lupus, using transcriptome analysis on whole blood from a large cohort of SLE patients.

Methods: We mapped through RNA-seq the transcriptomes of 95 female healthy, 11 male healthy, 235 SLE female and 46 SLE male individuals. RNA libraries were prepared using the Illumina Truseq kit. Paired-end 67 bp mRNA-sequencing was performed on the Illumina HiSeq4000. FastQC software assessed quality. Raw reads were aligned to the human (hg38 version) genome using STAR V.2.6 algorithm. Gene quantification was performed using HTSeq. Differential expression analysis of human data was conducted using clusterProfiler package. Enrichment and network analyses were performed using gProfiler2. |log2 Fold Change|> 0.58 and adjusted p-value < 0.05 were utilized as thresholds for list of DEGs.

Results: We curated lists of differentially expressed genes (DEGs) as follows: 1296 DEGs in SLE versus healthy individuals (regardless of gender), 19 DEGs in female versus male healthy individuals and finally 37 DEGs in female versus male SLE individuals. Of note, two genes of interests stand out in the comparison of transcriptomes between SLE female versus SLE male individuals, as NEBL gene (cardiac-muscle specific gene) is downregulated, while RPL10P6 gene (a pseudogene-residing in a neighborhood of enhancer like non-coding RNAs) is expressed higher in SLE females compared to SLE males. Molecular pathways altered specifically on SLE female transcriptomes include the Cohesin Complex (demarcation of the boundaries of active and inactive chromatin) as well as the MLL4 complex (an epigenetic regulator acting as histone methyltransferase). In addition, Xist gene expression is markedly upregulated in SLE females.

Conclusion: According to our findings, chromatin reorganization through epigenetic switches seems to be a major contributor of the SLE sex bias. Though research is still needed towards the genetic component and other epigenetic layers (DNA methylation, non-coding genome), the elucidation of sexual dimorphism in SLE will boost efforts towards personalized therapy.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: None declared.