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 antidsDNA. 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.