Association of a rare variant of the TNFSF13B gene with susceptibility to Rheumatoid Arthritis and Systemic Lupus Erythematosus

González‐Serna, David; Ortiz-Fernández, Lourdes; Vargas, Sofia; Delgado, Antonio; Raya, Enrique; Fernández‐Gutiérrez, Benjamín; López‐Longo, Francisco Javier; Balsa, Alejandro; González‐Álvaro, Isidoro; Narváez, Javier; Gómez-Vaquero, Carmen; Sabio, José Mario; García-Portales, Rosa; González‐Escribano, María Francisca; Tolosa, Carles; Carreira, Patrícia; Kiemeney, Lambertus A.; Coenen, Marieke J. H.; Witte, Torsten; Schneider, Matthias; Martı́n, Javier

doi:10.1038/s41598-018-26573-4

Cited by 21 publications

(19 citation statements)

References 29 publications

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“…Overexpression of the cytokine and drug target B-cell activating factor (BAFF; encoded by TNFSF13B) has been associated with susceptibility to SLE, multiple sclerosis and rheumatoid arthritis. The functional causal variant denoted as BAFF-var (a combination of rs374039502 and an insertion-deletion variant GCTGT→A [rs200748895]) has been initially identified by Genome Wide Association study (GWAS) in the Sardinian population and recently replicated in other cohorts of patients [78,79,144]. The BAFF-var is more frequent among Sardinians (MAF = 33%) than other populations (Europeans MAF = 3-5%) and was shown to yield a shorter transcript that escapes microRNA inhibition.…”

Section: Tnfsf13b/baffmentioning

confidence: 99%

“…RASopathies, which are caused by dominantly inherited mutations in several genes (KRAS, NRAS, PTPN11, RAF, SHOC2 and SOS1), are a group of neurodevelopmental disorders including Noonan syndrome (NS; OMIM 163950) and Noonan-related syndromes (NS2- 11;OMIM 605275, 609942, 610733, 611553, 613224, 613706, 615355, 616559, 616564, 618499). Beside classical phenotype patients with these disorders may present with features of SLE, autoimmune thyroiditis, vitiligo, celiac disease and Degos [79,145]. The affected proteins participate in the RAS/MAPK pathway that is involved in regulation of different cellular processes by transduction of growth factor signals [145].…”

Section: Rasopathiesmentioning

confidence: 99%

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New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

Demirkaya

Şahin

Romano

et al. 2020

JCM

107

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Systemic lupus erythematosus (SLE) is a clinically and genetically heterogeneous autoimmune disease. The etiology of lupus and the contribution of genetic, environmental, infectious and hormonal factors to this phenotype have yet to be elucidated. The most straightforward approach to unravel the molecular pathogenesis of lupus may rely on studies of patients who present with early-onset severe phenotypes. Typically, they have at least one of the following clinical features: childhood onset of severe disease (<5 years), parental consanguinity, and presence of family history for autoimmune diseases in a first-degree relative. These patients account for a small proportion of patients with lupus but they inform considerable knowledge about cellular pathways contributing to this inflammatory phenotype. In recent years with the aid of new sequencing technologies, novel or rare pathogenic variants have been reported in over 30 genes predisposing to SLE and SLE-like diseases. Future studies will likely discover many more genes with private variants associated to lupus-like phenotypes. In addition, genome-wide association studies (GWAS) have identified a number of common alleles (SNPs), which increase the risk of developing lupus in adult age. Discovery of a possible shared immune pathway in SLE patients, either with rare or common variants, can provide important clues to better understand this complex disorder, it’s prognosis and can help guide new therapeutic approaches. The aim of this review is to summarize the current knowledge of the clinical presentation, genetic diagnosis and mechanisms of disease in patents with lupus and lupus-related phenotypes.

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Section: Tnfsf13b/baffmentioning

confidence: 99%

Section: Rasopathiesmentioning

confidence: 99%

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

Demirkaya

Şahin

Romano

et al. 2020

JCM

107

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“…Autoimmune disorders, such as RA, are very heterogeneous and share symptoms, risk genes, comorbidities, and familial aggregation, suggesting a common genetic architecture that is extensively recognized in autoimmunity [66,67]. Several studies have revealed these shared genetics through simple comparisons of the associated genes [68], as was the case in a study conducted by our group, where González-Serna et al [69] considered the association of a rare variant in the TNFSF13B gene with RA and replicated this association in systemic lupus erythematosus (SLE) patients. TNFSF13B encodes the (B-cell activating factor) BAFF cytokine, which is essential for B-cell homeostasis and the regulation of B-cell maturation, differentiation, and survival [70].…”

Section: Shared Genetics In Autoimmunity and Drug Repurposingmentioning

confidence: 90%

The Potential Role of Genomic Medicine in the Therapeutic Management of Rheumatoid Arthritis

Acosta‐Herrera

González‐Serna

Martín

2019

JCM

Self Cite

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During the last decade, important advances have occurred regarding understanding of the pathogenesis and treatment of rheumatoid arthritis (RA). Nevertheless, response to treatment is not universal, and choosing among different therapies is currently based on a trial and error approach. The specific patient’s genetic background influences the response to therapy for many drugs: In this sense, genomic studies on RA have produced promising insights that could help us find an effective therapy for each patient. On the other hand, despite the great knowledge generated regarding the genetics of RA, most of the investigations performed to date have focused on identifying common variants associated with RA, which cannot explain the complete heritability of the disease. In this regard, rare variants could also contribute to this missing heritability as well as act as biomarkers that help in choosing the right therapy. In the present article, different aspects of genetics in the pathogenesis and treatment of RA are reviewed, from large-scale genomic studies to specific rare variant analyses. We also discuss the shared genetic architecture existing among autoimmune diseases and its implications for RA therapy, such as drug repositioning.

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“…Previous studies demonstrated that the frequency of the BAFF-var allele was higher among SLE patients from various European cohorts than among the corresponding control populations, a finding suggesting a relationship between the BAFF-var and SLE [17, 19]. The frequency of BAFF-var allele carriers (9.2%) and the MAF of the BAFF-var allele (4.6%) identified in our SLE study cohort were in line with and support the findings of case-control studies performed by González-Serna et al [19]. We detected the BAFF-var allele in 7.1% of SLE patients in our German cohort and the corresponding MAF was 3.69%.…”

Section: Discussionmentioning

confidence: 99%

“…The prevalence of BAFF-var is notably elevated among patients with autoimmune diseases, such as multiple sclerosis, SLE, and rheumatoid arthritis. This fact implies a link between BAFF-var variant and susceptibility to autoimmune processes [17, 19]. However, to date the relationship between BAFF-var and SLE disease activity in specific organs has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Susceptibility of BAFF-var allele carriers to severe SLE with occurrence of lupus nephritis

et al. 2019

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Background: Dysregulation of the B-cell activating factor (BAFF) system is involved in the pathogenesis of systemic lupus erythematosus (SLE). Increased serum concentrations of BAFF are related to lupus nephritis and disease activity among SLE patients. Recently, a variant of the BAFF-encoding gene, BAFF-var, was identified to be associated with autoimmune diseases, in particular SLE, and to promote the production of soluble BAFF. The present study aimed to assess the prevalence of BAFF-var in a cohort of 195 SLE patients and to analyze the association of the BAFF-var genotype (TNSF13B) with various manifestations of SLE. Methods: A cohort of 195 SLE patients from Central Europe, including 153 patients from the Swiss SLE Cohort Study and 42 patients from the University Hospital Essen, Germany, underwent genotyping for detection of BAFFvar allele. Results: Of the 195 patients, 18 (9.2%) tested positive for BAFF-var variant according to the minor allele frequency of 4.6%. The presence of BAFF-var was associated with the occurrence of lupus nephritis (p = 0.038) (p = 0.03 and p = 0.003). Among various organ manifestations of SLE, the presence of BAFF-var was associated with the occurrence of lupus nephritis (p = 0.038; odds ratio [OR], 2.4; 95% confidence interval [CI], 0.89-6.34) and renal activity markers such as proteinuria and hematuria (p = 0.03; OR, 2.4; 95% CI, 0.9-6.4 for proteinuria; p = 0.003; OR, 3.9; 95% CI, 1.43-10.76 for hematuria). SLE patients carrying the BAFF-var allele exhibited increased disease activity at study entry, as determined by the physician's global assessment (PGA: p = 0.002; OR, 4.8; 95% CI, 1.54-14.93) and the SLE Disease Activity Index (p = 0.012; OR, 3.5; 95% CI, 1.12-11.18). Consistent with that, the percentage of patients treated with immunosuppressive agents at study entry was higher among those carrying the BAFF-var allele than among those tested negative for BAFF-var (p = 0.006; OR, 3.7; 95% CI, 1.27-10.84). Conclusions: Our results indicate an association between the BAFF-var genotype and increased severity of SLE. Determining the BAFF-var status of SLE patients may improve the risk stratification of patients for whom the development of lupus nephritis is more likely and thus may be helpful in the follow-up care and treatment of SLE patients.

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Association of a rare variant of the TNFSF13B gene with susceptibility to Rheumatoid Arthritis and Systemic Lupus Erythematosus

Cited by 21 publications

References 29 publications

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

The Potential Role of Genomic Medicine in the Therapeutic Management of Rheumatoid Arthritis

Susceptibility of BAFF-var allele carriers to severe SLE with occurrence of lupus nephritis

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