Genome-wide association study identifies three novel susceptibility loci for systemic lupus erythematosus in Han Chinese

Liu, L.; Zuo, Xianbo; Zhu, Zhengwei; Wen, Leilei; Yang, Chao; Zhu, Caihong; Tang, Lili; Cheng, Yan; Chen, M.; Zhou, Fusheng; Zheng, Xiaodong; Wang, W.; Yin, Xianyong; Tang, Huayang; Sun, Liangdan; Yang, Sen; Sheng, Yujun; Cui, Yong; Zhang, X.

doi:10.1111/bjd.16500

Cited by 7 publications

(5 citation statements)

References 8 publications

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“…Specifically, in this study, we investigated the role of TNFAIP3 polymorphisms in Italian patients affected by the three different diseases, each one represented by a well-characterized cohort of patients. Indeed, although there are several studies on TNFAIP3 and even meta-analysis [6] regarding the association of this gene in many diseases, it has not been investigated in the Italian patients with autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

“…In the last decade, due to the use of new genomic technologies, many genetic factors have been identified as associated with the susceptibility to different autoimmune diseases. In a particular way, genome-wide association studies (GWAS) brought a great contribution to the identification of new genetic risk factors for these diseases [1–6]. Among the three diseases, SLE and RA have been the most investigated regarding their genetic basis, and more than 100 different loci have been confirmed as associated with their susceptibility [7, 8].…”

Section: Introductionmentioning

confidence: 99%

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TNFAIP3 Gene Polymorphisms in Three Common Autoimmune Diseases: Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Primary Sjogren Syndrome—Association with Disease Susceptibility and Clinical Phenotypes in Italian Patients

Ciccacci

Latini

Perricone

et al. 2019

Journal of Immunology Research

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Autoimmune diseases (AIDs) are complex diseases characterized by persistent or recurrent inflammation, alteration of immune response, and production of specific autoantibodies. It is known that different AIDs share several susceptibility genetic loci. Tumor necrosis factor alpha inducible protein 3 (TNFAIP3) encodes the ubiquitin-modifying enzyme A20, which downregulates inflammation by restricting NF-κB, a transcription factor that regulates expression of various proinflammatory genes. Variants in TNFAIP3 gene have been described as associated with susceptibility to several AIDs. Here, we analyzed two TNFAIP3 polymorphisms in Italian patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjogren’s syndrome (pSS), to verify if the genetic variability of TNFAIP3 gene is involved in genetic predisposition to AIDs also in the Italian population. We recruited 313 SLE patients, 256 RA patients, 195 pSS patients, and 236 healthy controls. Genotyping of rs2230926 and rs6920220 in TNFAIP3 gene was performed by an allelic discrimination assay. We carried out a case/control association study and a genotype/phenotype correlation analysis. A higher risk to develop SLE was observed for rs2230926 (P=0.02, OR=1.92). No association was observed between this SNP and the susceptibility to pSS or RA. However, the rs2230926 variant allele seems to confer a higher risk to develop lymphoma in pSS patients, while in RA patients, the presence of RF resulted significantly associated with the variant allele. Regarding the rs6920220 SNP, we observed a significant association of the variant allele with SLE (P=0.03, OR=1.53), pSS (P=0.016, OR=1.69), and RA (P=0.0001, OR=2.35) susceptibility. Furthermore, SLE patients carrying the variant allele showed a higher risk to develop pericarditis, pleurisy, and kidney complications. Our results support the importance of the TNFAIP3 gene variant role in the development of different autoimmune diseases in the Italian population and furtherly confirm a sharing of genetic predisposing factors among these three pathologies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TNFAIP3 Gene Polymorphisms in Three Common Autoimmune Diseases: Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Primary Sjogren Syndrome—Association with Disease Susceptibility and Clinical Phenotypes in Italian Patients

Ciccacci

Latini

Perricone

et al. 2019

Journal of Immunology Research

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“…Variant selection and DNA sequence generation. All SLE-associated genetic risk loci reaching genome-wide significance published through March 2018 were included in this study 31,38,44,58,[69][70][71][72][73][74][75][76][77][78] . A total of 91 genetic risk loci were used for linkage disequilibrium (LD) expansion (r 2 > 0.8) based on 1000 Genomes Data 79 in the ancestry(ies) of the initial genetic association using PLINK(v1.90b) 80 (Supplementary Data 1).…”

Section: Methodsmentioning

confidence: 99%

Global discovery of lupus genetic risk variant allelic enhancer activity

Xiaoting

Forney

et al. 2021

Nat Commun

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Genome-wide association studies of Systemic Lupus Erythematosus (SLE) nominate 3073 genetic variants at 91 risk loci. To systematically screen these variants for allelic transcriptional enhancer activity, we construct a massively parallel reporter assay (MPRA) library comprising 12,396 DNA oligonucleotides containing the genomic context around every allele of each SLE variant. Transfection into the Epstein-Barr virus-transformed B cell line GM12878 reveals 482 variants with enhancer activity, with 51 variants showing genotype-dependent (allelic) enhancer activity at 27 risk loci. Comparison of MPRA results in GM12878 and Jurkat T cell lines highlights shared and unique allelic transcriptional regulatory mechanisms at SLE risk loci. In-depth analysis of allelic transcription factor (TF) binding at and around allelic variants identifies one class of TFs whose DNA-binding motif tends to be directly altered by the risk variant and a second class of TFs that bind allelically without direct alteration of their motif by the variant. Collectively, our approach provides a blueprint for the discovery of allelic gene regulation at risk loci for any disease and offers insight into the transcriptional regulatory mechanisms underlying SLE.

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“…High-density SNP analysis has identified and facilitated to focus on disease-associated loci where patients and healthy controls exhibit different frequencies of trait-associated alleles which are potential disease-causal variants or their proxies [47]. To date, about 100 SLE susceptibility loci have been identified, mostly in European and Asian populations [49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86], explaining the heritability of SLE up to around 30% [74,75].…”

Section: Genetics In Slementioning

confidence: 99%

Update on the Genetics of Systemic Lupus Erythematosus: Genome-Wide Association Studies and Beyond

Kwon

Chun

Kim

et al. 2019

Cells

101

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of complex etiology that primarily affects women of childbearing age. The development of SLE is attributed to the breach of immunological tolerance and the interaction between SLE-susceptibility genes and various environmental factors, resulting in the production of pathogenic autoantibodies. Working in concert with the innate and adaptive arms of the immune system, lupus-related autoantibodies mediate immune-complex deposition in various tissues and organs, leading to acute and chronic inflammation and consequent end-organ damage. Over the past two decades or so, the impact of genetic susceptibility on the development of SLE has been well demonstrated in a number of large-scale genetic association studies which have uncovered a large fraction of genetic heritability of SLE by recognizing about a hundred SLE-susceptibility loci. Integration of genetic variant data with various omics data such as transcriptomic and epigenomic data potentially provides a unique opportunity to further understand the roles of SLE risk variants in regulating the molecular phenotypes by various disease-relevant cell types and in shaping the immune systems with high inter-individual variances in disease susceptibility. In this review, the catalogue of SLE susceptibility loci will be updated, and biological signatures implicated by the SLE-risk variants will be critically discussed. It is optimistically hoped that identification of SLE risk variants will enable the prognostic and therapeutic biomarker armamentarium of SLE to be strengthened, a major leap towards precision medicine in the management of the condition.

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Genome-wide association study identifies three novel susceptibility loci for systemic lupus erythematosus in Han Chinese

Cited by 7 publications

References 8 publications

TNFAIP3 Gene Polymorphisms in Three Common Autoimmune Diseases: Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Primary Sjogren Syndrome—Association with Disease Susceptibility and Clinical Phenotypes in Italian Patients

TNFAIP3 Gene Polymorphisms in Three Common Autoimmune Diseases: Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Primary Sjogren Syndrome—Association with Disease Susceptibility and Clinical Phenotypes in Italian Patients

Global discovery of lupus genetic risk variant allelic enhancer activity

Update on the Genetics of Systemic Lupus Erythematosus: Genome-Wide Association Studies and Beyond

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