Abstract
BackgroundSystemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further.ResultsWe perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody.ConclusionsWe demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis.
Highlights
Systemic lupus erythematosus (OMIM 152,700) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies (ANA) and the deposition of immune complexes throughout the body [1,2,3,4,5]
As shown in Additional file 1: Table S1, very weak associations were found between Death-associated protein 1 (DAP1) and Systemic lupus erythematosus (SLE) in an analysis of 1700 SLE patients and 2108 healthy European Americans
These results indicate that a quantitative spectrum of DAP1 transcription levels occurs in the human population with the HAP1 protective allele associated with the highest levels and the haplotype 3 (HAP3) SLE risk allele associated with reduced transcription in macrophages, dendritic cells, ex vivo B cells, lymphoblastoid cell lines (LCLs), and peripheral blood mononuclear cells (PBMCs)
Summary
Systemic lupus erythematosus (OMIM 152,700) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies (ANA) and the deposition of immune complexes throughout the body [1,2,3,4,5]. Three recent meta-analyses of SLE GWAS datasets containing European American, African Americans, Hispanics, and several Asian cohorts identified over 90 risk loci [17,18,19] In each of these studies, roughly 40–50% of the identified loci reached genome-wide significance (p < 5 × 10e−8), with roughly 30% of the rest reaching suggestive levels (p < 5 × 10e−5) and the remainder representing candidate genes (p < 10e−3). Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further
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