Patient ancestry significantly contributes to molecular heterogeneity of systemic lupus erythematosus

Abstract

Gene expression signatures can stratify patients with heterogeneous diseases, such as Systemic Lupus Erythematosus (SLE), yet understanding the contributions of ancestral background to this heterogeneity is not well elucidated. We hypothesized that ancestry would significantly influence gene expression signatures and measured 34 gene modules in 1566 SLE patients of african (AA), european (EA) or native american (NAA) ancestry to determine the impact of ancestry on gene expression. Healthy subject ancestry-specific gene expression provided the transcriptomic background upon which the SLE patient signatures were built. Although standard therapy affected every gene signature, and significantly increased myeloid cell signatures, logistic regression analysis determined that ancestral background significantly changed 23/34 gene signatures. Additionally, the strongest association to gene expression changes was autoantibodies and this also had etiology in ancestry; the AA predisposition to have both RNP and dsDNA autoantibodies compared to EA predisposition to have only anti-dsDNA. A machine learning approach was used to determine a gene signature characteristic to distinguish AA SLE and was most influenced by genes characteristic of the perturbed B cell axis in AA SLE patients.

New insights into the role of antinuclear antibodies in systemic lupus erythematosus

“…These expression patterns imply differences in induction mechanisms, as well as in production by various B cell populations, and can also reflect the influence of race and ethnicity in patients. Thus, data suggest that patients with African ancestry are more likely to express anti-Sm and anti-RNP antibodies than those with European ancestry 49 . In view of the important immunological effects of anti-RBP antibodies, the severe disease manifestations that are commonly observed in patients with African ancestry (such as nephritis) might relate to their overall serological pattern, which comprises antibodies that recognize nucleosomes, as well as anti-RBP antibodies that are specific for SLE (such as anti-Sm antibodies) and those that can be expressed in other diseases (such as anti-RNP antibodies) [50][51][52][53] .…”

“…Although initial studies on cytokine induction by immune complexes implicated anti-DNA antibodies as an important factor 80 , subsequent research has shown that immune complexes with anti-RBP antibodies can stimulate type I interferon production and might actually be the main promoters of this pathway 49 . The differing results of these studies probably reflect the demographics of the patient populations studied, as the increased expression of anti-RBP antibodies in patients with African ancestry can affect the assessment of pathogenicity [86][87][88] .…”

Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus

“…As there is considerable transcriptomic heterogeneity among lupus patients 20 , 21 , we sought to examine expression of genes controlling metabolism at the individual patient level, and, therefore, employed gene set variation analysis (GSVA) 22 (Supplemental Data S3 ). Generally, lupus tissues exhibited lower GSVA scores indicative of metabolic pathways, whereas controls had higher metabolism GSVA scores (Fig.…”

The Autoantigen Repertoire and the Microbial RNP World

“…Recent work has also demonstrated that U1 snRNP immune complexes can activate a separate component of the innate immune system, the NLRP3 inflammasome [81]. Notably, autoantibodies to RNA-associated autoantigens are more enriched in immune complexes than autoantibodies to DNA-containing complexes [82], and are more strongly linked to activation of the type I interferon pathway in patients with SLE [83,84].…”