Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning

Wang, Yongfei; Zhang, Yan; Zhu, Zhengwei; Wang, Ting You; Morris, David L.; Shen, Jiangshan Jane; Zhang, Huoru; Pan, Hai‐Feng; Yang, Jing; Yang, Sen; Ye, Dong‐Qing; Cui, Yong; Zhang, Xuejun; Sheng, Yujun; Lau, Yu Lung; Yang, Wanling

doi:10.1136/annrheumdis-2018-213093

Cited by 32 publications

(25 citation statements)

References 46 publications

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“…These observations suggest a potentially distinct role for CD226 in controlling CD4 + T cell lineages, especially in Tregs. Despite evidence of the genetic associations of CD226 with autoimmune diseases and dysfunctional Tregs (7,44,45), as well as studies noting that CD226 + TIGIT − Tregs are associated with reduced suppressive capacity (46), the exact molecular mechanism and function role of CD226 in Tregs is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

CD226 Attenuates Treg Proliferation via Akt and Erk Signaling in an EAE Model

Wang

Fang

et al. 2020

Front. Immunol.

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Cluster of differentiation 226 (CD226) molecules play a crucial role in the activation of effector CD4 + T cells during the immune response process, but a cell-intrinsic function of CD226 in CD4 + T subsets is not clear. In this study, we showed that Cd226 −/− mice were resistant to myelin oligodendrocyte glycoprotein peptide 35-55 (MOG 35−55)-induced experimental autoimmune encephalomyelitis (EAE) with highly expressed IL-10 + CD4 + T cells and downregulated IL-17A + CD4 + T cells when compared with wild-type (WT) mice. Th17 cell infiltration into the central nervous system (CNS) was largely decreased in the absence of CD226 during EAE. CD226 deficiency facilitated the proliferation of regulatory T cells (Tregs), with increased numbers of Tregs observed in EAE mice, and supported the elevated induced regulatory T cell (iTregs) proliferation in vitro. The Akt and Erk signaling pathways were shown to be involved in Cd226 −/− Treg proliferation and function in vivo and in vitro. These findings collectively indicate that CD226 is a key molecule regulating the Treg-mediated suppression of autoimmune responses by inhibiting Treg proliferation. Thus, the results of this study identify additional mechanisms by which CD226 regulates Treg functions in EAE and supports the potential therapeutic effects of anti-CD226 molecules on autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

CD226 Attenuates Treg Proliferation via Akt and Erk Signaling in an EAE Model

Wang

Fang

et al. 2020

Front. Immunol.

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“…Further replication effort by Molineros et al confirmed five novel susceptibility loci ( MYNN , ATG16L2 , CCL22 , ANKS1A, and RNASEH2C ) in the Hong Kong cohort (Molineros et al, ). Our most recent work further identified ST3AGL4 , MFHAS1 , CSNK2A2, and CD226 to be associated with the disease (Wang et al, ).…”

Section: Replication Studies Of Gwas Findingsmentioning

confidence: 85%

“…This process highlights the significance of genetic studies in opening a window to understanding the functions of genes, although it may take years of functional characterizations. Our recent study showed enriched interaction between SLE susceptibility genes and targets for available SLE drugs, and demonstrated a potential role of genetic studies in drug repurposing (Wang et al, ).…”

Section: Functional Characterizations Of the Associated Genesmentioning

confidence: 87%

“…For example, we confirmed the association of ITGAM in the Hong Kong population by using Sanger sequencing, considering the low MAF in Asians (Yang, Zhao, et al, ). Our recent work in mapping SLE novel loci also made use of data of SLE GWAS in Europeans for suggestive loci, and followed them up by large‐scale replications in Asians (Wang et al, ).…”

Section: The Genetic Loci Demonstrating Population Differencesmentioning

confidence: 99%

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Genetic studies on systemic lupus erythematosus in East Asia point to population differences in disease susceptibility

Wang

Lau

Yang

2019

American J of Med Genetics Pt C

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Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with extreme clinical heterogeneity and significant differences between populations. East Asian populations are known to have higher prevalence and more severe clinical manifestations for SLE than Europeans. The difference could be the result of genetic and environmental factors, and the interactions between them. Thus, identifying genetic associations from diverse populations provides an opportunity to better understand the genetic architecture of this heterogeneous disease. It is also necessary to elucidate population differences and to apply the findings in future stratified treatment of the disease, with ethnicity likely a major factor to consider. Indeed, it has shown that there are significant differences between East Asians and European populations in several genetic loci for SLE. Genetic studies on SLE are very active in East Asian countries and there have been close collaborations among scientists in this region. Here, we document some work done in this region on SLE genetic research and discuss the aspect of population differences.

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“…The GWAS datasets used in the discovery stage are from published studies (Bentham et al, 2015;Morris et al, 2016;Sun et al, 2016), with European cohorts comprising 4,943 SLE cases and 8,483 controls (EUR), and Asian cohorts including 2,485 cases and 3,947 controls (AS). The samples included in the replication stage in this study partially overlapped with those used in our previous studies (Yang et al, 2009(Yang et al, , 2011(Yang et al, , 2013Wanling et al, 2010;Li et al, 2012;Zhang et al, 2015aZhang et al, ,b,c, 2016Wang et al, 2018), which were collected from Hong Kong (1,255 SLE cases and 951 healthy controls, HK_rep) and Anhui Province, China (1,014 cases and 4,122 controls, AH_rep), respectively. Briefly, SLE cases in the Hong Kong cohort were recruited from five public hospitals in Hong Kong, namely Queen Mary Hospital, Tuen Mun Hospital, Queen Elizabeth Hospital, Princess Margaret Hospital, and Pamela Youde Nethersole Eastern Hospital.…”

Section: Subjectsmentioning

confidence: 99%

Independent Replication on Genome-Wide Association Study Signals Identifies IRF3 as a Novel Locus for Systemic Lupus Erythematosus

et al. 2020

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Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease. Despite the significant progress made in identifying susceptibility genes for SLE, the genetic architecture of the disease is far from being understood. In this study, we set to replicate a number of suggestive association signals found in genome-wide association studies (GWASs) in additional independent cohorts. Replication studies were performed on Han Chinese cohorts from Hong Kong and Anhui, involving a total of 2,269 cases and 5,073 controls. We identified a missense variant in IRF3 (rs7251) reaching genomewide significance through a joint analysis of GWAS and replication data (OR = 0.876, P = 4.40E-08). A significant correlation was observed between rs7251 and lupus nephritis (LN) by subphenotype stratification (OR = 0.785, P = 0.0128). IRF3 is a key molecule in type I interferon production upon nucleic acid antigen stimulations and may inhibit regulatory T cell differentiation. Further elucidation of the mechanism of this association could help us better understand the pathogenesis of SLE.

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Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning

Abstract: This study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.

Cited by 32 publications

References 46 publications

CD226 Attenuates Treg Proliferation via Akt and Erk Signaling in an EAE Model

CD226 Attenuates Treg Proliferation via Akt and Erk Signaling in an EAE Model

Genetic studies on systemic lupus erythematosus in East Asia point to population differences in disease susceptibility

Independent Replication on Genome-Wide Association Study Signals Identifies IRF3 as a Novel Locus for Systemic Lupus Erythematosus

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