Large-scale DNA sequencing identifies rare variants associated with Systemic Lupus Erythematosus susceptibility in known risk genes

• Published in: Gene Vol. 907; p. 148279
• Main Authors: Latini, Andrea, Borgiani, Paola, De Benedittis, Giada, Ciccacci, Cinzia, Novelli, Lucia, Pepe, Gerardo, Helmer-Citterich, Manuela, Baldini, Isabella, Perricone, Carlo, Ceccarelli, Fulvia, Conti, Fabrizio, Ianniciello, Generoso, Caceres, Juan, Ottalevi, Riccardo, Capulli, Mattia, Novelli, Giuseppe
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 20.05.2024
• Subjects: Genome sequencing; Rare variants; Systemic Lupus Erythematosus; Systemic Lupus Erythematosus; CADD; WGS; GWAS; Genome sequencing; WES; Rare variants; SLE; BAM; MAF; VUS; VCF; SNVs
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2024.148279

•Common genetic variants often have a modest effect on the SLE risk.•Rare variants in genes associated to SLE could have an effect on susceptibility.•Genomic DNA of 200 SLE patients was sequenced by whole exome sequencing.•19 rare variants were identified in TNFAIP3, TRAF3IP2, STAT4 and HCP5 genes.•Rare variants associated to SLE could help to understand its pathogenic mechanisms. The identification of rare genetic variants associated to Systemic Lupus Erythematosus (SLE) could also help to understand the pathogenic mechanisms at the basis of the disease. In this study we have analyzed a cohort of 200 Italian SLE patients in order to explore the rare protein-coding variants in five genes (TNFAIP3, STAT4, IL10, TRAF3IP2, and HCP5) already investigated for commons variants found associated in our previous studies. Genomic DNA of 200 SLE patients was sequenced by whole exome sequencing. The identified variants were filtered by frequency and evaluated by in silico predictions. Allelic association analysis was performed with standard Fisher’s exact test. Introducing a cutoff at MAF < 0.01, a total of 19 rare variants were identified. Seven of these variants were ultra-rare (MAF < 0.001) and six were absent in the GnomAD database. For TNFAIP3 gene, the variant c.A1939C was observed in 4 SLE patients and it is located in a region enriched in phosphorylation sites and affects the predict affinity of specific kinases. In TRAF3IP2 gene, we observed 5 different rare variants, including the novel variant c.G410A, located in the region that mediates interaction with TRAF6, and therefore a possible risk factor for SLE development. In STAT4 gene, we identified 6 different rare variants. Among these, three missense variants decrease the stability of this protein. Moreover, 3 novel rare variants were detected in 3 SLE patients. In particular, c.A767T variant was predicted as damaging by six prediction tools. Concluding, we have observed that even in genes whose common variability is associated with SLE susceptibility, it is possible to identify rare variants that could have a strong effect in the disease development and could therefore allow a better understanding of the functional domain involved.