Follow-up study identifies two novel susceptibility loci PRKCB and 8p11.21 for systemic lupus erythematosus

Sheng, Yujun; Gao, Jinping; Li, Jian; Han, Jianwen; Xu, Qiang; Hu, Wenlong; Pan, Ting-Meng; Cheng, Yuxiang; Yu, Ze-Ying; Ni, Cheng; Yao, Sha; He, Cai-Feng; Liu, Yangsheng; Li, Yun; Ge, Hongmei; Xiao, Feng‐Li; Sun, Liangdan; Yang, Sen; Zhang, Xuejun

doi:10.1093/rheumatology/keq313

Cited by 62 publications

(42 citation statements)

References 33 publications

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“…TNIP1 (TNFAIP3 interacting protein 1) , encoding the A20-interacting protein, has also been associated with the risk of SLE 47 48. Additional genes within the NFκB pathway associated with SLE susceptibility include: SLC15A4 (solute carrier family 15, member 4) encoding a peptide transporter that participates in NOD1-dependent NFκB signalling;48 PRKCB (protein kinase C, β), which is involved in B-cell receptor-mediated NFκB activation;54 and UBE2L3 (ubiquitin-conjugating enzyme E2L 3), encoding the enzyme UBCH7, which participates in the ubiquitination of an NFκB precursor, and may play a role in cell proliferation 55. A risk haplotype of UBE2L3 confers increased UBCH7 expression in patients with SLE;56 a variant contained in this haplotype has been associated with the presence of anti-dsDNA antibodies 15…”

Section: Genetic Variation Of the Nfκb Pathwaymentioning

confidence: 99%

Recent insights into the genetic basis of systemic lupus erythematosus

2012

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Many identified genetic risk factors for SLE contribute to the function of the immune system, which has expanded our understanding of disease pathogenesis. We outline the genetic variants in the recently identified SLE-associated loci, the immunologic pathways affected by these gene products, and the disease manifestations linked to these loci. Pathways potentially influenced by SLE risk variants include: apoptosis, DNA degradation and clearance of cellular debris; antigen-presentation; type I interferon, Toll-like receptor and NFκB activation; defective clearance of immune complexes containing nuclear antigens; B- and T-cell function and signaling; and monocyte and neutrophil function and signaling. These identified SLE susceptibility loci are predominantly common variants that have been confirmed among multiple ancestries, suggesting shared mechanisms in disease etiology. Ongoing genetic studies continue the investigation of specific functional variants, and their potential consequences upon immune dysregulation, enhancing our understanding of links between genotypes and specific disease manifestations. The next generation sequencing explores the identification of causal rare variants that may contribute robust genetic effects to developing SLE. Novel insights coming from genetic studies of SLE provide the opportunity to elucidate pathogenic mechanisms as well as contribute to the development of innovative therapeutic targets for this complex disease.

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Section: Genetic Variation Of the Nfκb Pathwaymentioning

confidence: 99%

Recent insights into the genetic basis of systemic lupus erythematosus

2012

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“…In recent years, understanding of SLE’s genetic etiology has been transformed by GWASs, with the largest study in Europeans3 (4,036 cases and 6,959 controls) finding evidence of association at 41 autosomal loci. Meanwhile, two published GWASs4,5 in Chinese populations and follow-up studies in Asians6–10 found association at 31 loci, 11 of which are not published for Europeans. Thus 52 SLE disease-susceptibility autosomal loci have been mapped by GWASs in these two populations.…”

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confidence: 99%

Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus

et al. 2016

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Systemic lupus erythematosus (SLE; OMIM 1 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.

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“…It is possible therefore that abnormalities in PKC activity induced by one or more of these polymorphisms may lead to altered T-cell function. PRKCA has been reported to be associated with MS risk in UK, Finish and Canadian populations,31 32 and PRKCB and PRKCH had been associated with the risk of similar autoimmune diseases including systemic lupus erythematosus (SLE)33 and rheumatoid arthritis 34 35. In rheumatoid arthritis, PRKCH messenger RNA was expressed at high levels in T cells and was significantly down-regulated during immune response 34…”

Section: Discussionmentioning

confidence: 99%

Novel modulating effects of PKC family genes on the relationship between serum vitamin D and relapse in multiple sclerosis

Lin

Taylor

Simpson

et al. 2013

Journal of Neurology, Neurosurgery & Psychiatry

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Follow-up study identifies two novel susceptibility loci PRKCB and 8p11.21 for systemic lupus erythematosus

Abstract: Our findings provided novel insights into the genetic architecture of SLE and emphasized the contribution of multiple variants of modest effect. Further study focused on PRKCB, 8p11.21, should advance our understanding on the pathogenesis of SLE.

Cited by 62 publications

References 33 publications

Recent insights into the genetic basis of systemic lupus erythematosus

Recent insights into the genetic basis of systemic lupus erythematosus

Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus

Novel modulating effects of PKC family genes on the relationship between serum vitamin D and relapse in multiple sclerosis

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