Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population

Okada, Yukinori; Terao, Chikashi; Ikari, Katsunori; Kochi, Yuta; Ohmura, Koichiro; Suzuki, Akari; Kawaguchi, Takahisa; Stahl, Eli A.; Kurreeman, Fina; Nishida, Nao; Ohmiya, Hiroko; Myouzen, Keiko; Takahashi, Meiko; Sawada, Tetsuji; Nishioka, Yuichi; Yukioka, Masao; Matsubara, Tsukasa; Wakitani, Shigeyuki; Teshima, Ryota; Tohma, Shigeto; Takamatsu, Kiyoshi; Shimada, Kota; Murasawa, Akira; Honjo, Shigeru; Matsuo, Keitaro; Tanaka, Hideo; Tajima, Kazuo; Suzuki, Taku; Iwamoto, Takuji; Kawamura, Yoshiya; Tanii, Hisashi; Okazaki, Yuji; Sasaki, Tsukasa; Gregersen, Peter K.; Padyukov, Leonid; Worthington, Jane; Siminovitch, Katherine A.; Lathrop, Mark; Taniguchi, Atsuo; Takahashi, Atsushi; Tokunaga, Katsushi; Kubo, Michiaki; Nakamura, Yusuke; Kamatani, Naoyuki; Mimori, Tsuneyo; Plenge, Robert M.; Yamanaka, Hisashi; Momohara, Shigeki; Yamada, Ryo; Matsuda, Fumihiko; Yamamoto, Kazuhiko

doi:10.1038/ng.2231

Cited by 294 publications

(269 citation statements)

References 27 publications

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“…Recent studies showed two autoimmune diseases, sclerosis and rheumatoid arthritis, were related to PLD4 mutation (16,17). Although PLD4 seemed to have some immunological functions, little was known about its function in cells.…”

Section: Discussionmentioning

confidence: 99%

“…After treated with LPS, the expression of the PLD4 in microglia was increased which could promote the function of phagocytosis (15). Recent studies have indicated mutation in PLD4 gene was associated with two autoimmune diseases, named systemic sclerosis (16) and rheumatoid arthritis (17), both had abnormal inflammatory skin lesions symptoms (18). Although PLD4 was involved in microglia phagocytosis, there is little known on its function and the mechanism, thus PLD4 needed to be explored.…”

Section: Introductionmentioning

confidence: 99%

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PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells

Gao

Zhou

et al. 2016

Oncology Reports

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Abstract. Phospholipase D4 (PLD4) is a newly identified protein expressed in microglia. However, the function of PLD4 in tumor-associated macrophages (TAMs) is unknown. In the present study, we revealed that the expression of PLD4 was located in macrophages in the colon cancer mesenchymal and lymph nodes as shown by immunohistochemical analysis. furthermore, its expression was associated with clinical staging of colon cancer. Then, THP-1 as a cell model induced into TAMs. Western blot and RT-PCR analysis showed that PLD4 was mainly presented in M1 phenotype TAMs. The secretion of pro-inflammatory cytokines in M1 macrophages was significantly reduced after the expression of PLD4 inhibited by PLD4-siRNA. furthermore, co-cultured with condition-medium from control or PLD4-siRNA M1 macrophages for 24 h, cell apoptosis, cycle and proliferation of cancer cells improved compared to control. These results indicated that PLD4 could be involved in the activation process of M1 phenotype macrophages.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells

Gao

Zhou

et al. 2016

Oncology Reports

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“…Genome-wide association studies have identified loci associated with increased susceptibility to renal dysfunction in humans (12,13). Additionally, mouse models and genome-wide transcriptome analyses of kidneys from patients with CKD and fibrosis have facilitated the identification of a number of signaling pathways associated with renal fibrosis, including the Notch, Wnt, and Hedgehog pathways (3).…”

mentioning

confidence: 99%

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Leung

Wilson

Voltzke

et al. 2017

Molecular and Cellular Biology

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Tubulointerstitial fibrosis (TIF) is recognized as a final phenotypic manifestation in the transition from chronic kidney disease (CKD) to end-stage renal disease (ESRD). Here we show that conditional inactivation of Sav1 in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss of Sav1 induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis. Treatment of mice with the YAP inhibitor verteporfin (VP) inhibited activation of genes associated with senescence, SASPs, and activation of Stat3 as well as impeded the development of fibrosis. Collectively, our studies offer novel insights into molecular events that are linked to fibrosis development from Sav1 loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF.

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“…Several genome-wide association studies revealed numerous gene loci that mediate susceptibility to IBD [4]. Among them is the locus encoding the protein tyrosine phosphatase non-receptor type 2 (PTPN2) (also called T cell protein tyrosine phosphatase (TCPTP)) [5,6], which was also found to be associated with other chronic inflammatory and autoimmune diseases such as type 1 diabetes (T1D) and rheumatoid arthritis (RA) [7,8]. …”

Section: Introductionmentioning

confidence: 99%

A Cell Type-Specific Role of Protein Tyrosine Phosphatase Non-Receptor Type 2 in Regulating ER Stress Signalling

Kasper

Spalinger²,

Raselli³

et al. 2015

Digestion

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Background/Aims: Genetic polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) have been associated with inflammatory bowel disease (IBD). A recent study demonstrated that PTPN2 regulates ER stress signalling in pancreatic β-cells. Therefore, we investigated whether PTPN2 regulates ER stress pathways, apoptosis and cytokine secretion in human intestinal epithelial cells (IECs) and monocytes. Methods: THP-1 and HT-29 IECs were stimulated with 2 µg/ml tunicamycin (TNM) for the indicated periods of time. For knockdown experiments, cells were transfected using a mixture of three different PTPN2-specific siRNA oligonucleotides. Cell lysates were analysed by Western blot and real-time PCR. Cytokine secretion was studied by ELISA measurements of cell culture supernatant. Results: TNM treatment reduced PTPN2 protein levels in HT-29 IECs and THP-1 monocytes. Knockdown of PTPN2 in THP-1 monocytes led to an exaggerated induction of phospho-eIF2α, enhanced PARP cleavage, indicative of apoptosis, and attenuated IL-8 and TNF secretion upon TNM stimulation. In HT-29 cells PTPN2 deficiency caused reduced phosphorylation of eIF2α and PARP cleavage under ER stress conditions. Conclusions: Whereas the knockdown of PTPN2 made THP-1 cells more susceptible to ER stress, PTPN2 deficiency reduced ER stress responses in HT-29 IECs. This suggests that PTPN2 regulates adaptation to ER stress in a cell type-specific manner.

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Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population

Cited by 294 publications

References 27 publications

PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells

PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

A Cell Type-Specific Role of Protein Tyrosine Phosphatase Non-Receptor Type 2 in Regulating ER Stress Signalling

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