Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component and etiology characterized by chronic inflammation and autoantibody production. The purpose of this study was to ascertain copy number variation (CNV) in SLE using a case-control design in an admixed Brazilian population. The whole-genome detection of CNV was performed using Cytoscan HD array in SLE patients and healthy controls. The best CNV candidates were then evaluated by quantitative real-time PCR in a larger cohort or validated using droplet digital PCR. Logistic regression models adjusted for sex and ancestry covariates was applied to evaluate the association between CNV with SLE susceptibility. The data showed a synergistic effect between the FCGR3B and ADAM3A loci with the presence of deletions in both loci significantly increasing the risk to SLE (5.9-fold) compared to the deletion in the single FCGR3B locus (3.6-fold). In addition, duplications in these genes were indeed more frequent in healthy subjects, suggesting that high FCGR3B/ADAM3A gene copy numbers are protective factors against to disease development. Overall, 21 rare CNVs were identified in SLE patients using a four-step pipeline created for identification of rare variants. Furthermore, heterozygous deletions overlapping the CFHR4, CFHR5 and HLA-DPB2 genes were described for the first time in SLE patients. Here we present the first genome-wide CNV study of SLE patients in a tri-hybrid population. The results show that novel susceptibility loci to SLE can be found once the distribution of structural variants is analyzed throughout the whole genome.
Highlights
Systemic lupus erythematosus (SLE, MIM 152700) is an autoimmune polygenic disease characterized by local or systemic inflammation from the production of autoantibodies and immune complex deposition in several tissues [1]
Case-control comparisons with logistic regression models adjusted for sex and ancestry showed that duplications were present in smaller number (p = 0.001, OR = 0.7 [95% confidence interval (95% CI), 0.6– 0.9]) in systemic lupus erythematosus (SLE) patients than in healthy subjects
In an independent copy number variation (CNV) assay, we showed that deletion in the FCGR3B gene is associated with increased susceptibility to SLE (p = 1.66 x 10−3, OR = 3.6 [95% CI, 1.7–8.3]), while duplication in this gene is a protective factor for the development of SLE (p = 1.55 x 10−4, OR = 0.2 [95% CI, 0.1–0.4]) (S4 Fig)
Summary
Systemic lupus erythematosus (SLE, MIM 152700) is an autoimmune polygenic disease characterized by local or systemic inflammation from the production of autoantibodies and immune complex deposition in several tissues [1]. SLE has a wide range of clinical manifestations such as malar rash, discoid lesions, nephritis, and arthritis [2]. CNV profile in SLE (http://www.faepa.br/), and Conselho Nacional de Desenvolvimento Cientıfico e Tecnologico (CNPq; http://cnpq.br/).
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