Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus

Han, Jianwen; Zheng, Hou-Feng; Cui, Yong; Sun, Liangdan; Ye, Dong-Qing; Hu, Zhiyan; Xu, Jinhua; Cai, Zhiming; Huang, Wei; Zhao, Guoping; Xie, Hongfu; Fang, Hong; Lu, Qianjin; Xu, Jianhua; Li, Xiang-Pei; Pan, Yunfeng; Deng, Di; Zeng, Fang; Ye, Zhizhong; Zhang, Xiaoyan; Wang, Qingwen; Fei, Hao; Ma, Li; Zuo, Xianbo; Zhou, Fusheng; Du, W.-D.; Cheng, Yuxiang; Yang, Jun‐Qi; Shen, Songke; Li, Jian; Sheng, Yujun; Zuo, Xiaoxia; Zhu, Weifang; Gao, Fei; Zhang, Peilian; Guo, Qing; Li, Bo; Gao, Min; Xiao, Feng‐Li; Cheng, Qimin; Zhang, Chi; Zhang, Zheng; Zhu, Kun-Ju; Yang, Li; Hu, Da-Yan; Lu, Wensheng; Huang, Jianlin; Liu, Shengxiu; Li, Hui; Ren, Yunqing; Wang, Zaixing; Yang, Chonglin; Wang, Peiguang; Zhou, Wenming; Lv, Yongmei; Zhang, Anping; Zhang, Shengquan; Lin, Da; Li, Yang; Low, Hui Qi; Shen, Min; Zhai, Zhifang; Wang, Ying; Zhang, Fengyu; Yang, Sen; Liu, Jing; Zhang, Xuejun

doi:10.1038/ng.472

Cited by 856 publications

(775 citation statements)

References 28 publications

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“…Recently reported SLE susceptibility genes, which have yet to be replicated in Japanese such as TNFSF4 4,5,37 were not included. For the same reason, we did not include the multiple SNPs in the HLA region, which were shown to be independently associated with SLE in other populations.…”

Section: Association Between Cumulative Risk Allele Number and Clinicmentioning

confidence: 99%

Cumulative association of eight susceptibility genes with systemic lupus erythematosus in a Japanese female population

et al. 2011

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Although large-scale studies established many susceptibility genes to systemic lupus erythematosus (SLE), effect of each gene is not sufficiently large to be used alone to identify individuals with strong genetic predisposition. In this study, we analyzed the cumulative number of risk alleles at eight established susceptibility loci, HLA-DRB1, IRF5, STAT4, BLK, TNFAIP3, TNIP1, FCGR2B and TNFSF13, in 282 Japanese female SLE and 222 healthy female controls. The average number of risk alleles was significantly increased in SLE (8.07 ± 1.60) than healthy controls (7.02 ± 1.64) (P¼1.63Â10 À12 ). Significant gene-gene interaction was not detected. When the subjects carrying seven risk alleles were used as a reference, the odds ratio (OR) for individuals carrying 10 and 11-13 risk alleles were 4.17 (95% confidence interval (CI) 1.89-9.19, P¼0.0002) and 8.77 (95% CI 1.92-40.0, P¼0.0016), respectively. In contrast, subjects with p4 risk alleles were significantly decreased in SLE (OR 0.15, CI 0.03-0.67, P¼0.007). The proportion of the patients with neurologic disorder was significantly increased in those carrying X10 risk alleles than those with o10 (OR 2.30, CI 1.09-4.83, P¼0.025). This study suggested that the cumulative number of risk alleles may efficiently distinguish groups with high and low genetic predisposition to SLE and its severe manifestation.

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Section: Association Between Cumulative Risk Allele Number and Clinicmentioning

confidence: 99%

Cumulative association of eight susceptibility genes with systemic lupus erythematosus in a Japanese female population

et al. 2011

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“…2 In China, SLE is a major public health problem with a prevalence of 31 to 70 cases per 100 000 people. 3,4 This disease has a huge impact on quality of life due to side effects of the currently available therapies and a significantly increased risk of developing cardiovascular diseases, certain types of cancer and many other kinds of diseases. [5][6][7][8][9] However, the precise etiology of SLE remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Increased expression of human T-cell immunoglobulin- and mucin-domain-containing molecule-4 in peripheral blood mononuclear cells from patients with system lupus erythematosus

Zhao

Wang³

et al. 2010

Cell Mol Immunol

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Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease. Innate and adaptive immunity cooperatively contribute to the development of SLE. Antigen-presenting cells (APCs) have been suggested to link innate and adaptive immunity. T-cell immunoglobulin-and mucin-domain-containing molecule-4 (Tim-4; also known as Timd4), expressed primarily on the surface of APCs, is a member of the TIM family, a recently described group of molecules that have received much attention as potential regulators of the immune system. In this study, we used quantitative real-time reverse transcription-polymerase chain reaction to examine the mRNA expression of Tim-4 in peripheral blood mononuclear cells (PBMCs) from SLE patients and further analyzed the correlation between the expression of Tim-4 and Tim-1 (a potential ligand for Tim-4) in PBMCs and serum tumor necrosis factor (TNF)-a levels. The results showed that Tim-4 mRNA expression in PBMCs was significantly higher in SLE patients than in healthy controls, especially those patients in the active phase of disease. Moreover, Tim-4 mRNA levels were closely correlated with Tim-1 mRNA levels in PBMCs and with serum TNF-a levels in SLE patients but not in the control group. Taken together, these results demonstrate that Tim-4 may be involved in the pathogenesis of SLE.

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“…Studies suggest an essential role of Aiolos at later stages of B cell differentiation (61,63). Numerous studies have identified polymorphisms in IKZF1 and IKZF3 to be associated with a risk for development of SLE (64)(65)(66)(67)(68)(69)(70)(71). Thus, modulation of Aiolos and Ikaros expression has the potential to correct multiple aspects of the immune dysregulation mediated by B cells and differentiation into autoantibody-secreting cells associated with SLE.…”

mentioning

confidence: 99%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines.

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Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus

Cited by 856 publications

References 28 publications

Cumulative association of eight susceptibility genes with systemic lupus erythematosus in a Japanese female population

Cumulative association of eight susceptibility genes with systemic lupus erythematosus in a Japanese female population

Increased expression of human T-cell immunoglobulin- and mucin-domain-containing molecule-4 in peripheral blood mononuclear cells from patients with system lupus erythematosus

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

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