Targeted sequencing of DAP1 gene locus in SLE patients and healthy controls

Deep sequencing across DAP1 genomic segment was performed in SLE patients and healthy controls and discovered a low-frequency functional haplotype strongly associated [OR=1.5, p=4.5E-05] with SLE risk in multiple ethnicities. Genomic and RNA sequence analysis show multiple cis-eQTLs embedded in risk haplotype that progressively downregulate DAP1 transcription in immune cells. Decreased DAP1 transcription resulted in reduced DAP1 protein in PBMC, monocytes and LCLs, leading to enhanced autophagic flux in the immune cells expressing the DAP1 risk haplotype. Patients with DAP1-risk allele exhibit significantly higher autoantibody titers and altered expression of immune system, autophagy and apoptosis pathway transcripts, indicating that DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody.