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Qiu L, Lu X, Xue W, Fu H, Deng S, Li L, Chen M, Wang Y. Ischemic stroke susceptibility associated with ALPK1 single nucleotide polymorphisms by inhibiting URAT1 in uric acid hemostasis. Gene 2025; 934:149017. [PMID: 39437898 DOI: 10.1016/j.gene.2024.149017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 10/15/2024] [Accepted: 10/16/2024] [Indexed: 10/25/2024]
Abstract
OBJECTIVES Ischemic stroke (IS) prevalence rising annually, the necessity of discovering non-interventional genetic influences is progressing. Single nucleotide polymorphism (SNP) plays a pivotal role in stable inheritance of disease susceptibility. Based on the relationship between Alpha- Kinase 1 (ALPK1) and traditional IS risk factors especially hyperuricemia, our study investigated the association and function of ALPK1 SNPs with IS susceptibility. METHODS A case-control study of 1539 patients and 933 controls from northeast China was conducted. Genotyping information of ALPK1 rs2074379 and rs2074388 was collected. Four types of plasmids including rs2074379/rs2074388 G/G, A/G, G/A, and A/A were transfected into 293T cells to observe ALPK1 and SLC22A12 expression. Possible ALPK1 structures of different SNPs were predicted online. RESULTS Genotype GG (OR = 1.371, CI = 1.029-1.828, P = 0.031) and GA (OR = 1.326, CI = 1.110-1.584, P = 0.002) of rs2074379 and GA of rs2074388 (OR = 1.359, CI = 1.137-1.624, P = 0.001) were found significantly susceptible to IS, with G allele on sites to be a risk allele. Rs2074379 had a multiplicative interaction with hyperuricemia (OR = 1.637, CI = 1.157-2.315, P = 0.005). Uric acid levels differed in genotypes (P < 0.001). The expression of ALPK1 (P < 0.01) and SLC22A12 in membrane urate transporter 1 (URAT1) protein (P < 0.05) functionally changed with G allele on either site. With glycine changing into aspartic acid at rs2074388, the protein secondary structure changed, but the ALPK1 protein subtype remained still. CONCLUSIONS ALPK1 rs2074379 and rs2074388 SNPs were functionally associated with IS susceptibility. The wild allele progressed IS risk probably by reducing ALPK1 expression and inhibiting URAT1 raising the uric acid level, contributing to further exploration of pathogenetic mechanisms of stroke. Chinese Clinical Trial Registration number: ChiCTR-COC-17013559.
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Affiliation(s)
- Luying Qiu
- Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, Liaoning Province 110001, China
| | - Xiaoqin Lu
- Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, Liaoning Province 110001, China
| | - Weishuang Xue
- Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, Liaoning Province 110001, China
| | - Hefei Fu
- Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, Liaoning Province 110001, China
| | - Shumin Deng
- Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, Liaoning Province 110001, China
| | - Long Li
- Department of Neurosurgery, The First Hospital of China Medical University, China Medical University, Shenyang 110001, China
| | - Meilin Chen
- Department of Neurology, Innovation Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100069, China
| | - Yanzhe Wang
- Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, Liaoning Province 110001, China.
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Cui X, Li Y, Yuan S, Huang Y, Chen X, Han Y, Liu Z, Li Z, Xiao Y, Wang Y, Sun L, Liu H, Zhu X. Alpha-kinase1 promotes tubular injury and interstitial inflammation in diabetic nephropathy by canonical pyroptosis pathway. Biol Res 2023; 56:5. [PMID: 36732854 PMCID: PMC9893546 DOI: 10.1186/s40659-023-00416-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 01/18/2023] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Alpha-kinase 1 (ALPK1) is a master regulator in inflammation and has been proved to promote renal fibrosis by promoting the production of IL-1β in diabetic nephropathy (DN) mice. Pyroptosis is involved in high glucose (HG)-induced tubular cells injury, characterized by activation of Gasdermin D (GSDMD) and the release of IL-1β and IL-18, resulting in inflammatory injury in DN. It is reasonable to assume that ALPK1 is involved in pyroptosis-related tubular injury in DN. However, the mechanism remains poorly defined. METHODS Immunohistochemistry (IHC) staining was performed to detect the expression of pyroptosis- and fibrosis-related proteins in renal sections of DN patients and DN mice. DN models were induced through injection of streptozotocin combined with a high-fat diet. Protein levels of ALPK1, NF-κB, Caspase-1, GSDMD, IL-1β, IL-18 and α-SMA were detected by Western blot. HK-2 cells treated with high-glucose (HG) served as an in vitro model. ALPK1 small interfering RNA (siRNA) was transfected into HK-2 cells to down-regulate ALPK1. The pyroptosis rates were determined by flow cytometry. The concentrations of IL-1β and IL-18 were evaluated by ELISA kits. Immunofluorescence staining was used to observe translocation of NF-κB and GSDMD. RESULTS The heat map of differentially expressed genes showed that ALPK1, Caspase-1 and GSDMD were upregulated in the DN group. The expression levels of ALPK1, Caspase-1, GSDMD and CD68 were increased in renal biopsy tissues of DN patients by IHC. ALPK1expression and CD68+ macrophages were positively correlated with tubular injury in DN patients. Western blot analysis showed increased expressions of ALPK1, phospho-NF-κB P65, GSDMD-NT, and IL-1β in renal tissues of DN mice and HK-2 cells, accompanied with increased renal fibrosis-related proteins (FN, α-SMA) and macrophages infiltration in interstitial areas. Inhibition of ALPK1 attenuated HG-induced upregulation expressions of NF-κB, pyroptosis-related proteins Caspase-1, GSDMD-NT, IL-1β, IL-18, α-SMA, and pyroptosis level in HK-2 cells. Also, the intensity and nuclear translocation of NF-κB and membranous translocation of GSDMD were ameliorated in HG-treated HK-2 cells after treatment with ALPK1 siRNA. CONCLUSIONS Our data suggest that ALPK1/NF-κB pathway initiated canonical caspase-1-GSDMD pyroptosis pathway, resulting in tubular injury and interstitial inflammation of DN.
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Affiliation(s)
- Xinyuan Cui
- grid.452708.c0000 0004 1803 0208Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China
| | - Yifu Li
- grid.452708.c0000 0004 1803 0208Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China ,grid.452708.c0000 0004 1803 0208Center for Medical Research, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shuguang Yuan
- grid.452708.c0000 0004 1803 0208Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China
| | - Yao Huang
- grid.452708.c0000 0004 1803 0208Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China
| | - Xiaojun Chen
- grid.452708.c0000 0004 1803 0208Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China
| | - Yachun Han
- grid.452708.c0000 0004 1803 0208Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China
| | - Zhiwen Liu
- grid.452708.c0000 0004 1803 0208Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China
| | - Zheng Li
- grid.452708.c0000 0004 1803 0208Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China
| | - Yang Xiao
- grid.452708.c0000 0004 1803 0208Key Laboratory of Diabetes Immunology, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Youliang Wang
- grid.452708.c0000 0004 1803 0208Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China
| | - Lin Sun
- grid.452708.c0000 0004 1803 0208Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China
| | - Hong Liu
- grid.452708.c0000 0004 1803 0208Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China
| | - Xuejing Zhu
- grid.452708.c0000 0004 1803 0208Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011 Hunan China
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Liu X, Zhao J, Jiang H, Guo H, Li Y, Li H, Feng Y, Ke J, Long X. ALPK1 Accelerates the Pathogenesis of Osteoarthritis by Activating NLRP3 Signaling. J Bone Miner Res 2022; 37:1973-1985. [PMID: 36053817 DOI: 10.1002/jbmr.4669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 07/14/2022] [Accepted: 07/31/2022] [Indexed: 11/08/2022]
Abstract
Alpha-kinase 1 (ALPK1), a member of the alpha-kinase family, has been shown to be involved in mediating inflammatory responses and is strongly associated with gout; however, its modulatory role in osteoarthritis (OA) remains unclear. Here, we uncovered elevation of ALPK1 in degraded cartilage of destabilized medial meniscus (DMM) and collagenase-induced osteoarthritis (CIOA), two different mouse OA models induced by mechanical stress or synovitis. Intraarticular administration of recombinant human ALPK1 (rhALPK1) in vivo exacerbated OA pathogenesis in both DMM and CIOA mice, whereas ALPK1 knockout reversed this process. In vitro study demonstrated that ALPK1 aggravates metabolic disturbances in chondrocytes by enhancing the production of NOD-like receptor protein 3 (NLRP3), an inflammasome sensors driving interlukin-1β (IL-1β)-mediated inflammatory conditions. Furthermore, the selective inhibition of nuclear factor-κB (NF-κB) or NLRP3 indicates that NLRP3 is a downstream signaling governed by NF-κB in ALPK1-activated chondrocytes. Collectively, these results establish ALPK1 as a novel catabolic regulator of OA pathogenesis, and targeting this signaling may be a promising treatment strategy for OA. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Xin Liu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Jie Zhao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Henghua Jiang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Huilin Guo
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yingjie Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Huimin Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yaping Feng
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Jin Ke
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.,Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Xing Long
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.,Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, China
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Systematic Review of the Role of Alpha-Protein Kinase 1 in Cancer and Cancer-Related Inflammatory Diseases. Cancers (Basel) 2022; 14:cancers14184390. [PMID: 36139553 PMCID: PMC9497133 DOI: 10.3390/cancers14184390] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/06/2022] [Accepted: 09/06/2022] [Indexed: 11/19/2022] Open
Abstract
Simple Summary Aside from the basic phosphorylation function of alpha-kinase 1 (ALPK1), little is known about its major functions. Researchers have used various forms of biotechnology and human, animal, and cellular models to better understand the relationship of ALPK1 with cancer and cancer-related inflammatory diseases. ALPK1 is involved in the progression of breast, lung, colorectal, oral, and skin cancer as well as lymphoblastic leukemia. ALPK1 has also been implicated in gout, diabetes, and chronic kidney disease, which are thought to be associated with breast, lung, colorectal, urinary tract, pancreatic, and endometrial cancers and lymphoblastic leukemia. ALPK1 upregulates inflammatory cytokines and chemokines during carcinogenesis. The major cytokine involved in carcinogenesis is TNF-α, which activates the NF-κB pathway, and similar inflammatory responses exist in gout, diabetes, and chronic kidney disease. ALPK1 regulates downstream inflammatory mechanisms that lead to cancer development through certain pathways and plays a key role in cancer initiation and metastasis. Abstract Background: Deregulation of conventional protein kinases is associated with the growth and development of cancer cells. Alpha-kinase 1 (ALPK1) belongs to a newly discovered family of serine/threonine protein kinases with no sequence homology to conventional protein kinases, and its function in cancer is poorly understood. Methods: In this systematic review, we searched for and analyzed studies linking ALPK1 to cancer development and progression. Results: Based on the current evidence obtained using human, animal, cellular, and tissue models, ALPK1 is located upstream and triggers cancer cell development and metastasis by regulating the inflammatory response through phosphorylation. Its mRNA and protein levels were found to correlate with advanced tumor size and lymph node metastasis, which occur from the cellular cytoplasm into the nucleus. ALPK1 is also strongly associated with gout, chronic kidney disease, and diabetes, which are considered as inflammatory diseases and associated with cancer. Conclusion: ALPK1 is an oncogene involved in carcinogenesis. Chronic inflammation is the common regulatory mechanism between cancer and these diseases. Future research should focus on identifying inhibitors of serine/threonine and ALPK1 at their phosphorylation sites, which would block various signal transductions and potentially offer kinase-targeted therapeutic agents for patients with cancer and inflammatory diseases.
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Ding F, Luo X, Tu Y, Duan X, Liu J, Jia L, Zheng P. Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway. Front Immunol 2021; 12:705751. [PMID: 34621265 PMCID: PMC8490819 DOI: 10.3389/fimmu.2021.705751] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 09/06/2021] [Indexed: 11/13/2022] Open
Abstract
Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-β-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.
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Affiliation(s)
- Fei Ding
- Department of Endocrinology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Xi Luo
- Department of Endocrinology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Yiting Tu
- Department of Neurology, Shenzhen Samii International Medical Center (The Fourth People's Hospital of Shenzhen), Shenzhen, China
| | - Xianlan Duan
- Department of Endocrinology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Jia Liu
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Lijing Jia
- Department of Endocrinology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Peilin Zheng
- Department of Endocrinology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
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Lee CP, Nithiyanantham S, Hsu HT, Yeh KT, Kuo TM, Ko YC. ALPK1 regulates streptozotocin-induced nephropathy through CCL2 and CCL5 expressions. J Cell Mol Med 2019; 23:7699-7708. [PMID: 31557402 PMCID: PMC6815771 DOI: 10.1111/jcmm.14643] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 07/29/2019] [Accepted: 08/15/2019] [Indexed: 12/31/2022] Open
Abstract
ALPK1 is associated with chronic kidney disease, gout and type 2 diabetes mellitus. Raised renal ALPK1 level in patients with diabetes was reported. Accelerated fibrotic nephropathies were observed in hyperglycaemic mice with up-regulated ALPK1. The aim of this study was to identify the mediators contributing to ALPK1 effect involving in nephropathies induction. The haematoxylin and eosin staining, Masson's trichrome and immunohistochemical analysis of ALPK1, NFkB, CCL2 and CCL5 were performed in the mice kidney. Cytokine antibody array analysis was performed in streptozotocin-treated wild-type mice (WT-STZ) and streptozotocin-treated ALPK1 transgenic mice (TG-STZ). The ALPK1 levels were measured in mice kidney and in cultured cells. We found that the higher levels of renal CCL2/MCP-1, CCL5/Rantes and G-CSF expression in TG-STZ compared with the WT-STZ. Glucose increased ALPK1 expressions in monocytic THP1 and human kidney-2 cells. The protein expression of ALPK1, NFkB and lectin was up-regulated in glucose-treated HK-2 cells. Knockdown of ALPK1 reduced CCL2 and CCL5 mRNA levels, whereas overexpressed ALPK1 increased CCL2 and CCL5 in cultured kidney cells. Taken together, these results show that high glucose increases ALPK1 and chemokine levels in the kidney. Elevated ALPK1 expression enhances renal CCL2 and CCL5 expressions in vivo and in vitro. ALPK1 is a mediator for CCL2 and CCL5 chemokine up-regulation involving in diabetic nephropathies induction.
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Affiliation(s)
- Chi-Pin Lee
- Environment-Omics-Disease Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Srinivasan Nithiyanantham
- Environment-Omics-Disease Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Hui-Ting Hsu
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan
| | - Kun-Tu Yeh
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
| | - Tzer-Min Kuo
- Environment-Omics-Disease Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Ying-Chin Ko
- Environment-Omics-Disease Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
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Milivojevic M, Dangeard AS, Kasper CA, Tschon T, Emmenlauer M, Pique C, Schnupf P, Guignot J, Arrieumerlou C. ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria. PLoS Pathog 2017; 13:e1006224. [PMID: 28222186 PMCID: PMC5336308 DOI: 10.1371/journal.ppat.1006224] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Revised: 03/03/2017] [Accepted: 02/07/2017] [Indexed: 12/30/2022] Open
Abstract
During infection by invasive bacteria, epithelial cells contribute to innate immunity via the local secretion of inflammatory cytokines. These are directly produced by infected cells or by uninfected bystanders via connexin-dependent cell-cell communication. However, the cellular pathways underlying this process remain largely unknown. Here we perform a genome-wide RNA interference screen and identify TIFA and TRAF6 as central players of Shigella flexneri and Salmonella typhimurium-induced interleukin-8 expression. We show that threonine 9 and the forkhead-associated domain of TIFA are necessary for the oligomerization of TIFA in both infected and bystander cells. Subsequently, this process triggers TRAF6 oligomerization and NF-κB activation. We demonstrate that TIFA/TRAF6-dependent cytokine expression is induced by the bacterial metabolite heptose-1,7-bisphosphate (HBP). In addition, we identify alpha-kinase 1 (ALPK1) as the critical kinase responsible for TIFA oligomerization and IL-8 expression in response to infection with S. flexneri and S. typhimurium but also to Neisseria meningitidis. Altogether, these results clearly show that ALPK1 is a master regulator of innate immunity against both invasive and extracellular gram-negative bacteria. Epithelial cells line internal body cavities of multicellular organisms. They represent the first line of defense against various pathogens including bacteria and viruses. They can sense the presence of invasive pathogens and initiate the recruitment of immune cells to infected tissues via the local secretion of soluble factors, called chemokines. Although this phenomenon is essential for the development of an efficient immune response, the molecular mechanism underlying this process remains largely unknown. Here we demonstrate that the host proteins ALPK1, TIFA and TRAF6 act sequentially to activate the transcription factor NF-κB and regulate the production of chemokines in response to infection by the pathogens Shigella flexneri, Salmonella typhimurium and Neisseria meningitidis. In addition, we show that the production of chemokines is triggered after detection of the bacterial monosaccharide heptose-1,7-bisphosphate, found in gram-negative bacteria. In conclusion, our study uncovers a new molecular mechanism controlling inflammation during infection by gram-negative bacteria and identifies potential targets for treatments aiming at modulating inflammation during infection.
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Affiliation(s)
- Milica Milivojevic
- INSERM, U1016, Institut Cochin, Paris, France, CNRS, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, France
| | - Anne-Sophie Dangeard
- INSERM, U1016, Institut Cochin, Paris, France, CNRS, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, France
| | | | | | | | - Claudine Pique
- INSERM, U1016, Institut Cochin, Paris, France, CNRS, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, France
| | | | - Julie Guignot
- INSERM, U1016, Institut Cochin, Paris, France, CNRS, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, France
| | - Cécile Arrieumerlou
- INSERM, U1016, Institut Cochin, Paris, France, CNRS, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, France
- * E-mail:
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Kuo TM, Hsu HT, Chung CM, Yeh KT, Wu CT, Lee CP, Chiang SL, Huang CM, Ko YC. Enhanced alpha-kinase 1 accelerates multiple early nephropathies in streptozotocin-induced hyperglycemic mice. Biochim Biophys Acta Mol Basis Dis 2016; 1862:2034-2042. [PMID: 27542954 DOI: 10.1016/j.bbadis.2016.08.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 08/11/2016] [Accepted: 08/14/2016] [Indexed: 12/22/2022]
Abstract
Alpha-kinase 1 (ALPK1) is associated with chronic kidney disease (CKD), type 2 diabetes mellitus and gout. Elevated ALPK1 levels have been observed in the kidneys of patients with diabetes and the white blood cells of patients with gout. As renal injury is a common outcome of CKD, diabetes and gout, the aim of this study was to investigate the effect of ALPK1 in the development of renal injury in a hyperglycemic condition. Hyperglycemia was induced in wild-type and ALPK1 transgenic mice by an intraperitoneal injection of streptozotocin (STZ). Functional and histological examinations were performed after 3weeks. STZ-treated ALPK1 transgenic mice exclusively showed arteriolar sclerosis and fibrous thickening of the Bowman's capsule in the kidney. This was accompanied by body weight loss, severe hyperglycemia, and low serum insulin levels. Renal renin and serum renin protein levels were higher in STZ-treated ALPK1 transgenic mice, whereas cGKII protein level was decreased by ALPK1 in human embryonic kidney 293 (HEK293) cells. ALPK1 up-regulated TGF-beta1 levels and transcription of fibrosis-related genes, including MMP-9, FIBRONECTIN, and TIMP1. MSU crystals increased ALPK1 transcription in cultured kidney cells. Finally, ALPK1 enhanced production of MSU crystals-induced IL-1beta in mice. Stimulation of soluble sodium urate induced IL-1beta and Alpk1 mRNA production in mice kidney. Taken together, these data show that an increase in ALPK1 results in accelerated fibrotic nephropathies, primarily through the enhancement of renin, TGF-beta1, and IL-1beta. Renal or blood ALPK1 levels are involved in the induction of fibrotic renal injury in an experimental model of hyperglycemia.
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Affiliation(s)
- Tzer-Min Kuo
- Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan
| | - Hui-Ting Hsu
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
| | - Chia-Min Chung
- Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan
| | - Kun-Tu Yeh
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Cheng-Tien Wu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chi-Pin Lee
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shang-Lun Chiang
- Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan; Department of Health Risk Management, College of Public Health, China Medical University, Taichung, Taiwan
| | - Chung-Ming Huang
- Graduate Institute of Integrated Medicines, China Medical University, Taichung, Taiwan
| | - Ying-Chin Ko
- Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.
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Kuo TM, Yeh KT, Hsu HT, Chiang SL, Chang JG, Huang CM, Tu HP, Liu CS, Ko YC. ALPK1 affects testosterone mediated regulation of proinflammatory cytokines production. J Steroid Biochem Mol Biol 2015; 154:150-8. [PMID: 26275947 DOI: 10.1016/j.jsbmb.2015.08.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 08/07/2015] [Accepted: 08/09/2015] [Indexed: 12/31/2022]
Abstract
Alpha-protein kinase 1, also known as alpha-kinase 1 (ALPK1), is associated with chronic kidney disease (CKD), myocardial infarction, gout and type 2 diabetes mellitus (DM). In addition to having an inductive effect on the proinflammatory cytokines in monocytic THP1 cells, ALPK1 is expressed abundantly in the mouse testes. Low testosterone levels are commonly associated with arthritis, CKD, type 2 DM, cardiovascular disease and inflammation. The testosterone's anti-inflammatory effect has been demonstrated to reduce proinflammatory cytokines and adhesion molecules. In this study, we found that ALPK1 transgenic mice showed lower levels of testosterone in both the testes and the serum. Decreasing endogenous ALPK1 enhanced testosterone levels and transcripts of testosterone-regulated genes (P450scc, 3beta-HSD, P450C17, 17beta-HSD, StAR, and INSL3) in TM3 Leydig cells. In contrast, increasing testosterone decreased ALPK1 in both TM3 and monocytic THP1 cells. This decrease was accompanied by a reduction of the proinflammatory cytokines. Increased ALPK1 levels attenuated the testosterone effects in THP1 cells. Finally, we also found that ALPK1 increased the release of TNF-alpha and TGF-beta1 in the human embryonic kidney 293 cells, while testosterone inhibited ALPK1 in the primary kidney cells. Taken together, this data suggests that the balance between ALPK1 and testosterone plays a critical role in the testosterone-mediated inhibition of proinflammatory cytokines.
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Affiliation(s)
- Tzer-Min Kuo
- Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
| | - Kun-Tu Yeh
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
| | - Hui-Ting Hsu
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
| | - Shang-Lun Chiang
- Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan; Department of Health Risk Management, College of Management, China Medical University, Taiwan
| | - Jan-Gowth Chang
- Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Chung-Ming Huang
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Hung-Pin Tu
- Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chiu-Shong Liu
- Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ying-Chin Ko
- Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
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Kharroubi AT, Darwish HM. Diabetes mellitus: The epidemic of the century. World J Diabetes 2015; 6:850-67. [PMID: 26131326 PMCID: PMC4478580 DOI: 10.4239/wjd.v6.i6.850] [Citation(s) in RCA: 567] [Impact Index Per Article: 56.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Revised: 03/25/2015] [Accepted: 04/10/2015] [Indexed: 02/05/2023] Open
Abstract
The epidemic nature of diabetes mellitus in different regions is reviewed. The Middle East and North Africa region has the highest prevalence of diabetes in adults (10.9%) whereas, the Western Pacific region has the highest number of adults diagnosed with diabetes and has countries with the highest prevalence of diabetes (37.5%). Different classes of diabetes mellitus, type 1, type 2, gestational diabetes and other types of diabetes mellitus are compared in terms of diagnostic criteria, etiology and genetics. The molecular genetics of diabetes received extensive attention in recent years by many prominent investigators and research groups in the biomedical field. A large array of mutations and single nucleotide polymorphisms in genes that play a role in the various steps and pathways involved in glucose metabolism and the development, control and function of pancreatic cells at various levels are reviewed. The major advances in the molecular understanding of diabetes in relation to the different types of diabetes in comparison to the previous understanding in this field are briefly reviewed here. Despite the accumulation of extensive data at the molecular and cellular levels, the mechanism of diabetes development and complications are still not fully understood. Definitely, more extensive research is needed in this field that will eventually reflect on the ultimate objective to improve diagnoses, therapy and minimize the chance of chronic complications development.
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11
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Yamada Y, Matsui K, Takeuchi I, Oguri M, Fujimaki T. Association of genetic variants with hypertension in a longitudinal population-based genetic epidemiological study. Int J Mol Med 2015; 35:1189-98. [PMID: 25813534 PMCID: PMC4380208 DOI: 10.3892/ijmm.2015.2151] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 03/03/2015] [Indexed: 01/11/2023] Open
Abstract
We previously identified 9 genes and chromosomal region 3q28 as susceptibility loci for Japanese patients with myocardial infarction, ischemic stroke, or chronic kidney disease by genome-wide or candidate gene association studies. In the present study, we investigated the possible association of 13 single nucleotide polymorphisms (SNPs) at these 10 loci with the prevalence of hypertension or their association with blood pressure (BP) in community-dwelling individuals in Japan. The study subjects comprised 6,027 individuals (2,250 subjects with essential hypertension, 3,777 controls) who were recruited into the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study on atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited the Health Care Center of Inabe General Hospital for an annual health checkup, and they are followed up each year (mean follow-up period, 5 years). Longitudinal analysis with a generalized estimating equation and with adjustment for age, gender, body mass index and smoking status revealed that rs2116519 of family with sequence similarity 78, member B (FAM78B; P=0.0266), rs6929846 of butyrophilin, subfamily 2, member A1 (BTN2A1; P= 0.0013), rs146021107 of pancreatic and duodenal homeobox 1 (PDX1; P=0.0031) and rs1671021 of lethal giant larvae homolog 2 (Drosophila) (LLGL2; P=0.0372) were significantly (P<0.05) associated with the prevalence of hypertension. Longitudinal analysis with a generalized linear mixed-effect model and with adjustment for age, gender, body mass index and smoking status among individuals not taking anti-hypertensive medication revealed that rs6929846 of BTN2A1 was significantly associated with systolic (P=0.0017), diastolic (P=0.0008) and mean (P=0.0005) BP, and that rs2116519 of FAM78B, rs146021107 of PDX1 and rs1671021 of LLGL2 were significantly associated with diastolic (P=0.0495), systolic (P=0.0132), and both diastolic (P=0.0468) and mean (0.0471) BP, respectively. BTN2A1 may thus be a susceptibility gene for hypertension.
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Affiliation(s)
- Yoshiji Yamada
- Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Mie 514‑8507, Japan
| | - Kota Matsui
- Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency, Tokyo 102‑0076, Japan
| | - Ichiro Takeuchi
- Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency, Tokyo 102‑0076, Japan
| | - Mitsutoshi Oguri
- Department of Cardiology, Japanese Red Cross Nagoya First Hospital, Nagoya 453-8511, Japan
| | - Tetsuo Fujimaki
- Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Mie 511-0428, Japan
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12
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Yamada Y, Matsui K, Takeuchi I, Fujimaki T. Association of genetic variants with dyslipidemia and chronic kidney disease in a longitudinal population-based genetic epidemiological study. Int J Mol Med 2015; 35:1290-300. [PMID: 25813695 PMCID: PMC4380205 DOI: 10.3892/ijmm.2015.2152] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 03/20/2015] [Indexed: 12/21/2022] Open
Abstract
We previously identified 9 genes and chromosomal region 3q28 as susceptibility loci for myocardial infarction, ischemic stroke, or chronic kidney disease (CKD) in Japanese individuals by genome-wide or candidate gene association studies. In the present study, we examined the association of 13 polymorphisms at these 10 loci with the prevalence of hypertriglyceridemia, hyper-low-density lipoprotein (LDL) cholesterolemia, hypo-high-density lipoprotein (HDL) cholesterolemia, or CKD in community-dwelling Japanese individuals. The study subjects comprised 6,027 individuals who were recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited the Health Care Center at Inabe General Hospital for an annual health checkup, and they were followed up each year (mean follow‑up period, 5 years). Longitudinal analysis with a generalized estimating equation and with adjustment for covariates revealed that rs6929846 of butyrophilin, subfamily 2, member A1 gene (BTN2A1) was significantly associated with the prevalence of hypertriglyceridemia (P=0.0001), hyper-LDL cholesterolemia (P=0.0004), and CKD (P=0.0007); rs2569512 of interleukin enhancer binding factor 3 (ILF3) was associated with hyper-LDL cholesterolemia (P=0.0029); and rs2074379 (P=0.0019) and rs2074388 (P=0.0029) of alpha-kinase 1 (ALPK1) were associated with CKD. Longitudinal analysis with a generalized linear mixed-effect model and with adjustment for covariates among all individuals revealed that rs6929846 of BTN2A1 was significantly associated with the serum concentrations of triglycerides (P=0.0011), LDL cholesterol (P=3.3 x 10(-5)), and creatinine (P=0.0006), as well as with the estimated glomerular filtration rate (eGFR) (P=0.0004); rs2569512 of ILF3 was shown to be associated with the serum concentration of LDL cholesterol (P=0.0221); and rs2074379 (P=0.0302) and rs2074388 (P=0.0336) of ALPK1 were shown to be associated with the serum concentration of creatinine. Similar analysis among individuals not taking any anti‑dyslipidemic medication revealed that rs6929846 of BTN2A1 was significantly associated with the serum concentrations of triglycerides (P=8.3 x 10‑5) and LDL cholesterol (P=0.0004), and that rs2569512 of ILF3 was associated with the serum concentration of LDL cholesterol (P=0.0010). BTN2A1 may thus be a susceptibility gene for hypertriglyceridemia, hyper‑LDL cholesterolemia and CKD in Japanese individuals.
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Affiliation(s)
- Yoshiji Yamada
- Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Mie 514‑8507, Japan
| | - Kota Matsui
- Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency, Tokyo 102‑0076, Japan
| | - Ichiro Takeuchi
- Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency, Tokyo 102‑0076, Japan
| | - Tetsuo Fujimaki
- Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Mie 511‑0428, Japan
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Yamada Y, Matsui K, Takeuchi I, Fujimaki T. Association of genetic variants with coronary artery disease and ischemic stroke in a longitudinal population-based genetic epidemiological study. Biomed Rep 2015; 3:413-419. [PMID: 26137247 DOI: 10.3892/br.2015.440] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 02/10/2015] [Indexed: 11/06/2022] Open
Abstract
Our previous studies identified nine genes and chromosomal region 3q28 as susceptibility loci for myocardial infarction, ischemic stroke or chronic kidney disease by genome-wide or candidate gene association studies. As coronary artery disease (CAD) and ischemic stroke may share genetic architecture, certain genetic variants may confer susceptibility to the two diseases. The present study examined the association of 13 polymorphisms at these 10 loci with the prevalence of CAD or ischemic stroke in community-dwelling individuals, with the aim of identifying genetic variants that confer susceptibility to the two conditions. Study subjects (170 with CAD, 117 with ischemic stroke and 5,718 controls) were recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited for an annual health checkup and they were followed up each year (mean follow-up period, 5 years). Longitudinal analysis with a generalized estimating equation, and with adjustment for age, gender, body mass index, smoking status, the prevalence of hypertension, diabetes mellitus and dyslipidemia and the serum concentration of creatinine, revealed that rs2074380 (G→A) and rs2074381 (A→G) of the α-kinase 1 (ALPK1) gene and rs8089 (T→G) of the thrombospondin 2 (THBS2) gene were significantly (P<2×10-16) associated with the prevalence of CAD, with the AA genotype of rs2074380 and GG genotypes of rs2074381 and rs8089 being protective against this condition. Similar analysis revealed that rs9846911 (A→G) at chromosome 3q28, rs2074381 of ALPK1, rs8089 of THBS2 and rs6046 (G→A) of the coagulation factor VII gene were significantly (P<2×10-16) associated with the prevalence of ischemic stroke, with the GG genotypes of rs9846911, rs2074381 and rs8089 and the AA genotype of rs6046 being protective against this condition. ALPK1 and THBS2 may thus be susceptibility loci for CAD and ischemic stroke.
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Affiliation(s)
- Yoshiji Yamada
- Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Mie 514-8507, Japan ; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan
| | - Kota Matsui
- Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan ; Department of Scientific and Engineering Simulation, Graduate School of Engineering, Nagoya Institute of Technology, Nagoya, Aichi 466-8555, Japan
| | - Ichiro Takeuchi
- Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan ; Department of Scientific and Engineering Simulation, Graduate School of Engineering, Nagoya Institute of Technology, Nagoya, Aichi 466-8555, Japan
| | - Tetsuo Fujimaki
- Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Mie 511-0428, Japan
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Yamada Y, Matsui K, Takeuchi I, Oguri M, Fujimaki T. Association of genetic variants of the α-kinase 1 gene with type 2 diabetes mellitus in a longitudinal population-based genetic epidemiological study. Biomed Rep 2015; 3:347-354. [PMID: 26137234 DOI: 10.3892/br.2015.439] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 02/06/2015] [Indexed: 12/13/2022] Open
Abstract
Previously, our studies identified nine genes and the chromosomal region 3q28 as susceptibility loci for myocardial infarction, ischemic stroke or chronic kidney disease in individuals by genome-wide or candidate gene association studies. The present study examined the possible association of 13 polymorphisms at these 10 loci with the prevalence of type 2 diabetes mellitus (DM) in community-dwelling individuals. Study subjects comprised 6,027 individuals (797 subjects with type 2 DM and 5,230 controls) who were recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited for an annual health checkup and they were followed up each year (mean follow-up, 5 years). Longitudinal analysis with a generalized estimating equation and with adjustment for age, gender and body mass index (BMI) revealed that rs2116519 (C→T) of FAM78B (P=0.0188), as well as rs2074379 (G→A, P=0.0121) and rs2074388 (A→G, P=0.0053) of ALPK1 were significantly (P<0.05) associated with the prevalence of type 2 DM. Longitudinal analysis with a generalized linear mixed-effect model and with adjustment for age, gender and BMI among all the individuals revealed that rs2116519, rs2074379 and rs2074388 were significantly associated with fasting plasma glucose level (P=0.0352, 0.0017 and 0.0010, respectively) and to blood glycosylated hemoglobin (hemoglobin A1c) content (P=0.0065, 0.0090 and 0.0079, respectively). Similar analysis among individuals not taking antidiabetic medication revealed that rs2074379 and rs2074388 were associated with the fasting plasma glucose level (P=0.0073 and 0.0042, respectively) and blood hemoglobin A1c content (P=0.0142 and 0.0126, respectively), whereas rs2116519 was associated with blood hemoglobin A1c content only (P=0.0470). ALPK1 may thus be a susceptibility gene for type 2 DM.
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Affiliation(s)
- Yoshiji Yamada
- Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Mie 514-8507, Japan ; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan
| | - Kota Matsui
- Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan ; Department of Scientific and Engineering Simulation, Graduate School of Engineering, Nagoya Institute of Technology, Nagoya, Aichi 466-8555, Japan
| | - Ichiro Takeuchi
- Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0076, Japan ; Department of Scientific and Engineering Simulation, Graduate School of Engineering, Nagoya Institute of Technology, Nagoya, Aichi 466-8555, Japan
| | - Mitsutoshi Oguri
- Department of Cardiology, Japanese Red Cross Nagoya First Hospital, Nagoya, Aichi 453-8511, Japan
| | - Tetsuo Fujimaki
- Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Mie 511-0428, Japan
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