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Yang Y, Chen Q, Zhong W. The role of cytokines in the pathogenesis of SAPHO syndrome. Front Immunol 2024; 15:1427784. [PMID: 39286247 PMCID: PMC11402674 DOI: 10.3389/fimmu.2024.1427784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 07/09/2024] [Indexed: 09/19/2024] Open
Abstract
SAPHO syndrome is a complex inflammatory disorder affecting the skin and bones, characterized by osteomyelitis, acne, and pustulosis. Cytokines play a pivotal role in the pathogenesis of SAPHO syndrome, especially in inflammatory responses and immune regulation. This article reviews the cytokines involved in the pathogenesis of SAPHO syndrome, such as tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-6, IL-10, and transforming growth factor-β (TGF-β), and discusses their potential as intervention points for treatment. These findings elucidate the intricate immune regulatory network of SAPHO syndrome and provide a theoretical foundation for the development of new targeted therapeutic strategies.
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Affiliation(s)
- Yi Yang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, China
| | - Qianzhu Chen
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, China
| | - Weiyang Zhong
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, China
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2
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Wei H, Zhao Y, Xiang L. Bone health in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2023; 17:921-935. [PMID: 37589220 DOI: 10.1080/17474124.2023.2248874] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 08/14/2023] [Indexed: 08/18/2023]
Abstract
INTRODUCTION Inflammatory bowel disease (IBD) is a chronic disease characterized by the presence of systemic inflammation, manifesting not only as gastrointestinal symptoms but also as extraintestinal bone complications, including osteopenia and osteoporosis. However, the association between IBD and osteoporosis is complex, and the presence of multifactorial participants in the development of osteoporosis is increasingly recognized. Unlike in adults, delayed puberty and growth hormone/insulin-like growth factor-1 axis abnormalities are essential risk factors for osteoporosis in pediatric patients with IBD. AREAS COVERED This article reviews the potential pathophysiological mechanisms contributing to osteoporosis in adult and pediatric patients with IBD and provides evidence for effective prevention and treatment, focusing on pediatric patients with IBD. A search was performed from PubMed and Web of Science inception to February 2023 to identify articles on IBD, osteoporosis, pediatric, and fracture risk. EXPERT OPINION A comprehensive treatment pattern based on individualized principles can be used to manage pediatric IBD-related osteoporosis.
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Affiliation(s)
- Hao Wei
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yihan Zhao
- Department of Cardiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Lisha Xiang
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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3
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Xu D, Chen Y, Gao X, Xie W, Wang Y, Shen J, Yang G, Xie B. The genetically predicted causal relationship of inflammatory bowel disease with bone mineral density and osteoporosis: evidence from two-sample Mendelian randomization. Front Immunol 2023; 14:1148107. [PMID: 37275908 PMCID: PMC10233018 DOI: 10.3389/fimmu.2023.1148107] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 05/08/2023] [Indexed: 06/07/2023] Open
Abstract
Background Many existing studies indicated that patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), tend to have the risk of low total body bone mineral density (BMD), and are more likely to have osteoporosis (OS). To determine the causal relationship between IBD and bone metabolic disorders, we herein performed a two-sample Mendelian randomization analysis (TSMR) using publicly available summary statistics. Methods Summary statistics of total body BMD, OS and IBD were downloaded from the Open Genome-Wide Association Study (GWAS), FinnGen consortium and International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). The European and East Asian populations have consisted in this Mendelian Randomization (MR) work. A range of quality control procedures were taken to select eligible instrument SNPs closely associated with total body BMD, OS and IBD. To make the conclusions more reliable, we applied five robust analytical methods, among which the inverse variance weighting (IVW) method acted as the major method. Besides, heterogeneity, pleiotropy and sensitivity were evaluated. Results In the European population, the genetic association of UC on total body BMD (OR=0.97, 95%CI=0.96,0.99, P<0.001) and overall IBD on total body BMD (OR=0.98, 95%CI=0.97,1.00, P=0.013) were significant, while the effect of CD on total body BMD was not significant enough (OR=0.99, 95%CI=0.98,1.00, P=0.085). All of UC, CD and overall IBD can be the genetic risk factor of having OS with pathological fracture (UC: OR=1.13, 95%CI=1.02,1.26, P=0.024, CD: OR=1.14, 95%CI=1.05,1.25, P=0.003, overall IBD: OR=1.13, 95%CI=1.02,1.24, P=0.015). In East Asian groups, only CD had a causal relationship with OS (OR=1.04, 95% CI=1.01,1.07, P=0.019). Conclusion Our study revealed genetically predicted associations between IBD on total body BMD and OS in European and East Asian populations. This work supplemented the results of previous retrospective studies and demonstrated the necessity of BMD monitoring in patients with IBD.
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Affiliation(s)
- Dengyong Xu
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yao Chen
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xing Gao
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Weidong Xie
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ya Wang
- Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China
- Department of Hospital Infection-Control, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China
- Department of Hospital Infection-Control, Zhejiang Cancer Hospital, Hangzhou, China
| | - Jiaying Shen
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Guang Yang
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Binbin Xie
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Peng R, Dong Y, Kang H, Guo Q, Zhu M, Li F. Identification of Genes with Altered Methylation in Osteoclast Differentiation and Its Roles in Osteoporosis. DNA Cell Biol 2022; 41:575-589. [PMID: 35699379 DOI: 10.1089/dna.2021.0699] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Osteoporosis is one of the most common metabolic skeletal diseases, which affects more than 200 million people worldwide, especially elderly and postmenopausal women. One of the main processes of osteoporosis is attenuated bone formation. Abundant evidence has confirmed that overactivated osteoclasts are responsible for the attenuated bone formation. This study aims at identifying novel methylation-associated biomarkers and therapeutic targets in osteoclasts by integrally analyzing methylation profiles and gene expression data. DNA methylation profile and gene expression data were obtained from the Gene Expression Omnibus (GEO) database. Subsequently, we integrated the two sets of data to screen for differentially expressed genes with differential methylation level (DM-DEGs) between osteoclasts and CD14+ monocytes from donors. Then, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to uncover the enriched functions and pathways of identified DM-DEGs. In addition, by combining protein-protein interaction analysis and receiver-operator characteristic analysis, we finally identified four hub DM-DEGs. Gene Set Enrichment Analysis was utilized to validate and investigate the potential biological functions of the four hub DM-DEGs. Finally, Real-time quantitative PCR (QPCR) was performed to validate the mRNA expression level of the four identified hub DM-DEGs during osteoclast differentiation. CCRL2, CCL18, C1QB, and SELL were highly correlated with osteoclastic differentiation and osteoporosis phenotype. QPCR revealed that the expression of CCRL2, CCL18, and C1QB was increased during osteoclast differentiation, whereas the expression of SELL was decreased. The present study indicated a connection between gene expression and DNA methylation during osteoclast differentiation and that four hub DM-DEGs in osteoclastogenesis and osteoporosis pathogenesis might be potential candidates for intensive research and therapeutic targets for the treatment of osteoporosis.
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Affiliation(s)
- Renpeng Peng
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yimin Dong
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Honglei Kang
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Guo
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meipeng Zhu
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Li
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Biological Engineering and Regenerative Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Velissari A, Vassilakopoulos TP, Angelopoulou MK, Korkolopoulou P, Bamias G, Daikos G, Konstantopoulos K, Siakantaris M. Genetic polymorphisms and risk of MALT lymphoma in Greek population. Curr Res Transl Med 2022; 70:103330. [PMID: 34979486 DOI: 10.1016/j.retram.2021.103330] [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: 07/01/2021] [Revised: 11/22/2021] [Accepted: 12/20/2021] [Indexed: 11/03/2022]
Abstract
PURPOSE MALT lymphoma is thought to have a genetic component. Genetic studies in the greek population are rare and genetic determinants remain to be established. The current study aimed to seek correlations between genetic polymorphisms and risk of MALT lymphoma in the Greek population. PATIENTS AND METHODS 83 MALT lymphoma patients and 60 age-matched healthy outpatients were recruited. SNPs in TNFa, LTA and CTLA-4 genes and IL1RN-VNTR and GSTT1 and GSTTM1 null polymorphisms were genotyped using published PCR/PCR-RFLP methods, while two novel PCR-RFLP methods were developed for IL-22 rs7314777 and TCF19 rs7750641 SNPs. Part of the results was validated by DNA-sequencing. Statistical analysis was performed using SPSS and the SNPstats bioinformatic tool. RESULTS The mean age of the patients and controls were 55.9 and 56.2 years respectively. The majority of patients (63) suffered gastric marzinal zone lymphoma (GMZL) and 71.1% were stage I at diagnosis. A statistically significant association was noted for the CTLA-4 49A/ G G variant (OR:2.56,p: 0.006) and the TCF19 rs7750641 SNP T variant (OR: 3.86, p:0.023). CONCLUSIONS Our study confirmed a role for CTLA-4 49A/G and TCF19 rs7750641 SNPs in the Greek population. Additional studies could help confirm these associations and possibly link them to prognosis or response to treatment parameters.
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Affiliation(s)
- A Velissari
- Hematology Department, National and Kapodistrian University of Athens, Laiko General Hospital.
| | - T P Vassilakopoulos
- Hematology Department, National and Kapodistrian University of Athens, Laiko General Hospital
| | - M K Angelopoulou
- Hematology Department, National and Kapodistrian University of Athens, Laiko General Hospital
| | - P Korkolopoulou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens
| | - G Bamias
- Gastrenterology Department, National and Kapodistrian University of Athens, Laiko General Hospital
| | - G Daikos
- First Department of Internal Medicine, National and Kapodistrian University of Athens, Laiko General Hospital
| | - K Konstantopoulos
- Hematology Department, National and Kapodistrian University of Athens, Laiko General Hospital
| | - M Siakantaris
- Hematology Department, National and Kapodistrian University of Athens, Laiko General Hospital
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6
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GPNMB contributes to a vicious circle for chronic obstructive pulmonary disease. Biosci Rep 2020; 40:225097. [PMID: 32478378 PMCID: PMC7308735 DOI: 10.1042/bsr20194459] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 05/15/2020] [Accepted: 05/26/2020] [Indexed: 12/13/2022] Open
Abstract
Osteoporosis (OP) is significant and debilitating comorbidity of chronic obstructive pulmonary disease (COPD). We hypothesize that genetic variance identified with OP may also play roles in COPD. We have conducted a large-scale relation data analysis to explore the genes implicated with either OP or COPD, or both. Each gene linked to OP but not to COPD was further explored in a mega-analysis and partial mega-analysis of 15 independently collected COPD RNA expression datasets, followed by gene set enrichment analysis (GSEA) and literature-based pathway analysis to explore their functional linked to COPD. A multiple linear regression (MLR) model was built to study the possible influence of sample size, population region, and study date on the gene expression data in COPD. At the first step of the analysis, we have identified 918 genes associated with COPD, 581 with OP, and a significant overlap (P<2.30e-140; 210 overlapped genes). Partial mega-analysis showed that, one OP gene, GPNMB presented significantly increased expression in COPD patients (P-value = 0.0018; log fold change = 0.83). GPNMB was enriched in multiple COPD pathways and plays roles as a gene hub formulating multiple vicious COPD pathways included gene MMP9 and MYC. GPNMB could be a novel gene that plays roles in both COPD and OP. Partial mega-analysis is valuable in identify case-specific genes for COPD.
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Chedid VG, Kane SV. Bone Health in Patients With Inflammatory Bowel Diseases. J Clin Densitom 2020; 23:182-189. [PMID: 31375349 DOI: 10.1016/j.jocd.2019.07.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 07/09/2019] [Accepted: 07/10/2019] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory medical condition with relapses and remission. Metabolic bone disease, including osteoporosis, is associated with IBD and imparts a significant morbidity if pathologic fractures were to occur. There has been a significant amount of research that evaluated the pathophysiology and associations between IBD and osteoporosis. Although corticosteroids contribute to the risk of low bone mineral density, osteoporosis and fractures, older age, female gender, smoking, and family history of fracture have been shown to contribute. Additionally, intestinal inflammation affects bone resorption and formation through proinflammatory cytokines such as tumor necrosis factor-a, interleukin-1, and interleukin-6 further accelerating bone loss. Little information is available on standardizing screening or treatment. It is important to recognize the risk factors that are associated with IBD and osteoporosis to identify the patient population at risk and initiate treatment/prevention strategies early. Treatment can include calcium, vitamin D, or bisphosphonates. Some studies showed benefit of treating the underlying IBD to improve bone mineral density.
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Affiliation(s)
- Victor G Chedid
- Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, MN, USA
| | - Sunanda V Kane
- Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, MN, USA.
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van Bodegraven AA, Bravenboer N. Perspective on skeletal health in inflammatory bowel disease. Osteoporos Int 2020; 31:637-646. [PMID: 31822927 PMCID: PMC7075921 DOI: 10.1007/s00198-019-05234-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 11/14/2019] [Indexed: 12/18/2022]
Abstract
Osteopenia and osteoporosis are common features in inflammatory bowel disease (IBD), comprising both Crohn's disease and ulcerative colitis. Moreover, Crohn's disease is associated with increased fracture risk. The etiology of bone loss in IBD is multifactorial. It includes insufficient intake or absorption of calcium, vitamin D, and potassium; smoking; a low peak bone mass; a low body mass index; and decreased physical activity. In several studies, it has been shown that elevated concentrations of systemic and local pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interferon-γ (IFNγ), interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-13, and IL-17, present in IBD patients are potentially detrimental for bone metabolism and may be responsible for bone loss and increased fracture risk. This perspective aims to review the current literature on the role of inflammatory factors in the pathophysiology of skeletal problems in IBD and to suggest potential treatment to improve bone health, based on a combination of evidence and clinical and pathophysiological reasoning.
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Affiliation(s)
- A. A. van Bodegraven
- Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine(Co-MIK), Zuyderland MC, Sittard-Geleen-Heerlen, Dr H van der Hoffplein 1, 6162 BG Geleen, Netherlands
- Department of Gastroenterology, Amsterdam UMC, Location Vrije Universiteit, PO Box 7057, 1007 MB Amsterdam, Netherlands
| | - N. Bravenboer
- Department of Clinical Chemistry, Research Institute Amsterdam Movement Sciences Amsterdam UMC, Location Vrije Universiteit, PO Box 7057, 1007 MB Amsterdam, Netherlands
- Department of Internal Medicine, Endocrinology Section, Centre for Bone Quality LUMC, Albinusdreef 2, Leiden, 2333 ZA Netherlands
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Zhou T, Pan J, Lai B, Cen L, Jiang W, Yu C, Shen Z. Bone mineral density is negatively correlated with ulcerative colitis: a systematic review and meta-analysis. Clin Transl Med 2020; 9:18. [PMID: 32072320 PMCID: PMC7028885 DOI: 10.1186/s40169-020-00270-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 02/09/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Newer epidemiological studies suggest that the incidence of ulcerative colitis might be increasing rapidly. Furthermore, osteoporosis in ulcerative colitis patients has gained great attention, but the epidemiologic evidence remains controversial. Therefore, a meta-analysis was performed to explore the association between bone density and ulcerative colitis. METHODS Two investigators used PubMed, EMBASE and the Cochrane Library databases to identify all studies published before August 2019. Depending on the outcomes, investigators divided these studies into four groups (OR, SMD [BMD], SMD [z-score] and SMD [t-score]). To address the use of steroids, which is a major confounding factor in this analysis, another subgroup analysis of studies of steroid-free patients was conducted. Additionally, heterogeneity, sensitivity and stratified analyses were also performed. RESULTS A total of 13 cross-sectional studies that involved 1154 participants were included in the present meta-analysis, and three of them were included in the steroid-free subgroup analysis. The pooled OR was 6.41 (95% CI 2.59-15.87) and the pooled SMD (BMD), SMD (t-score) and SMD (z-score) were - 0.24 (95% CI - 0.44 to - 0.04), - 0.55 (95% CI - 0.72 to - 0.37), and - 0.38 (95% CI - 0.56 and - 0.19), respectively. Since steroids are a significant confounder, the pooled SMD of the steroid-free subgroup was - 0.55 (- 0.85 to - 0.25), which revealed a strong negative relationship between bone density and ulcerative colitis in steroid-free patients. Additionally, other subgroup analyses also revealed a strong relationship. CONCLUSIONS This meta-analysis provides evidence for the potential association between ulcerative colitis and decreased bone density. It is essential for clinicians to consider bone mineral density in ulcerative colitis patients regardless of steroid-therapy.
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Affiliation(s)
- Tianyu Zhou
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jiaqi Pan
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Bin Lai
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- People's Hospital of Jianggan District, Hangzhou, China
| | - Li Cen
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Wenxi Jiang
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhe Shen
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
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Mechanisms Underlying Bone Loss Associated with Gut Inflammation. Int J Mol Sci 2019; 20:ijms20246323. [PMID: 31847438 PMCID: PMC6940820 DOI: 10.3390/ijms20246323] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 11/29/2019] [Accepted: 12/10/2019] [Indexed: 12/11/2022] Open
Abstract
Patients with gastrointestinal diseases frequently suffer from skeletal abnormality, characterized by reduced bone mineral density, increased fracture risk, and/or joint inflammation. This pathological process is characterized by altered immune cell activity and elevated inflammatory cytokines in the bone marrow microenvironment due to disrupted gut immune response. Gastrointestinal disease is recognized as an immune malfunction driven by multiple factors, including cytokines and signaling molecules. However, the mechanism by which intestinal inflammation magnified by gut-residing actors stimulates bone loss remains to be elucidated. In this article, we discuss the main risk factors potentially contributing to intestinal disease-associated bone loss, and summarize current animal models, illustrating gut-bone axis to bridge the gap between intestinal inflammation and skeletal disease.
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11
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Sgambato D, Gimigliano F, De Musis C, Moretti A, Toro G, Ferrante E, Miranda A, De Mauro D, Romano L, Iolascon G, Romano M. Bone alterations in inflammatory bowel diseases. World J Clin Cases 2019; 7:1908-1925. [PMID: 31423424 PMCID: PMC6695530 DOI: 10.12998/wjcc.v7.i15.1908] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 06/14/2019] [Accepted: 06/26/2019] [Indexed: 02/05/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are characterized by a multifactorial partially unknown etiology that involves genetic, immunological and environmental factors. Up to 50% of IBD patients experience at least one extraintestinal manifestation; among them is the involvement of bone density which is referred to as metabolic bone disease (MBD), including osteopenia and osteoporosis. Bone alterations in IBDs population appear to have a multifactorial etiology: Decreased physical activity, inflammation-related bone resorption, multiple intestinal resections, dietary malabsorption of minerals and vitamin D deficiency, genetic factors, gut-bone immune signaling interaction, steroid treatment, microbiota and pathogenic micro-organisms interaction, and dietary malabsorption of minerals, that, all together or individually, may contribute to the alteration of bone mineral density. This review aims to summarize the prevalence and pathophysiology of metabolic bone alterations in IBD subjects outlining the main risk factors of bone fragility. We also want to underline the role of the screening and prophylaxis of bone alterations in Crohn's disease and ulcerative colitis patients and the importance of treating appropriately MBD.
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Affiliation(s)
- Dolores Sgambato
- Departments of Precision Medicine and Polyspecialistic Internal Medicine, University of Campania ‘‘Luigi Vanvitelli’’ and University Hospital, Naples 80131, Italy
| | - Francesca Gimigliano
- Department of Physical and Mental Health, University of Campania “Luigi Vanvitelli”, Naples 80131, Italy
| | - Cristiana De Musis
- Departments of Precision Medicine and Polyspecialistic Internal Medicine, University of Campania ‘‘Luigi Vanvitelli’’ and University Hospital, Naples 80131, Italy
| | - Antimo Moretti
- Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Naples 80131, Italy
| | - Giuseppe Toro
- Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Naples 80131, Italy
| | - Emanuele Ferrante
- Departments of Precision Medicine and Polyspecialistic Internal Medicine, University of Campania ‘‘Luigi Vanvitelli’’ and University Hospital, Naples 80131, Italy
| | - Agnese Miranda
- Departments of Precision Medicine and Polyspecialistic Internal Medicine, University of Campania ‘‘Luigi Vanvitelli’’ and University Hospital, Naples 80131, Italy
| | - Domenico De Mauro
- Departments of Precision Medicine and Polyspecialistic Internal Medicine, University of Campania ‘‘Luigi Vanvitelli’’ and University Hospital, Naples 80131, Italy
| | - Lorenzo Romano
- Surgical Digestive Endoscopy, Department of Clinical Medicine and Surgery, Federico II University, Naples 80131, Italy
| | - Giovanni Iolascon
- Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Naples 80131, Italy
| | - Marco Romano
- Departments of Precision Medicine and Polyspecialistic Internal Medicine, University of Campania ‘‘Luigi Vanvitelli’’ and University Hospital, Naples 80131, Italy
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12
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Li L, Shi B, Zheng W, Xing W, Zhao Y, Li F, Xin D, Jin T, Zhu Y, Yang X. Association of IL-1A and IL-1B polymorphisms with ankylosing spondylitis among the Chinese Han population: a case-control study. Oncotarget 2018; 8:28278-28284. [PMID: 28423679 PMCID: PMC5438649 DOI: 10.18632/oncotarget.16004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 02/21/2017] [Indexed: 01/13/2023] Open
Abstract
Ankylosing spondylitis (AS) is a complex and chronic inflammatory disease with a high heritage. Previous study has shown that IL-1A and IL-1B involved in inflammatory reaction. But little is known about single nucleotide polymorphisms (SNPs) of IL-1A and IL-1B associated with AS. We conducted a case-control study among 267 AS cases and 297 healthy controls from China. In the genetic model analysis, we found the “T” genotype of rs3783550 was associated with decreased AS risk in the dominant model (p = 0.044) and log-additive model (p = 0.023); the “C” genotype of rs3783546 was significantly associated with decreased AS risk based in the dominant model (p = 0.044) and log-additive model (p = 0.023). Additionally, the minor allele “A” of rs2853550 may also reduce the risk of AS in dominant (p = 0.025) and log-additive model (p = 0.024). Our results suggested that the polymorphisms of IL-1A and IL-1B are associated with the AS susceptibility in the Chinese Han population. Further studies are needed to characterize the functional sequences that cause AS.
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Affiliation(s)
- Lei Li
- Inner Mongolia Medical University, Hohhot 010020, China.,The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010030, China
| | - Baolan Shi
- Inner Mongolia Medical University, Hohhot 010020, China.,Inner Mongolia Medical University Chifeng Clinical Medical College, ChiFeng, 024000, China
| | - Wenkai Zheng
- Inner Mongolia Medical University, Hohhot 010020, China.,The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010030, China
| | - Wenhua Xing
- The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010030, China
| | - Yan Zhao
- The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010030, China
| | - Feng Li
- The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010030, China
| | - Daqi Xin
- The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010030, China
| | - Tianbo Jin
- Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, Shaanxi 710069, China
| | - Yong Zhu
- The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010030, China
| | - Xuejun Yang
- The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010030, China
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Khosravi A, Javan B, Tabatabaiefar MA, Ebadi H, Fathi D, Shahbazi M. Association of interleukin-1 gene cluster polymorphisms and haplotypes with multiple sclerosis in an Iranian population. J Neuroimmunol 2015; 288:114-9. [DOI: 10.1016/j.jneuroim.2015.09.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 09/22/2015] [Indexed: 10/23/2022]
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Significance of IL-1RA Polymorphism in Iranian Patients with Inflammatory Bowel Disease. Dig Dis Sci 2015; 60:1389-95. [PMID: 25466956 DOI: 10.1007/s10620-014-3457-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Accepted: 11/20/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIM Interleukin (IL)-1 family members play an important role in the pathogenesis of inflammatory bowel disease (IBD). There are conflicting results regarding the association of IL-1 gene cluster single nucleotide polymorphisms (SNPs) with IBD and its clinical features. The aim of this study was to examine IL-1α -889 C/T, IL-1β -511 C/T, IL-1β +3962 C/T, IL-1R Pst-I1970 C/T, and IL-1RA Mspa-I11100 C/T SNPs in Iranian patients. METHODS In this study, SNPs of IL-1 family members were investigated in 75 patients with IBD (40 CD and 35 UC), using polymerase chain reaction with sequence-specific primers method. RESULTS IL-1β -511 CC genotype was significantly less present in UC compared to controls, while IL-1RA Mspa-I11100 CC was significantly associated with both Crohn's disease (CD) and ulcerative colitis (UC). IL-1α -889 TT genotype was more frequently associated with extraintestinal manifestations. A significant association was observed between IL-1β +3962 TT genotype and the disease activity in IBD. IL-1RA Mspa-I11100 CC was significantly less frequent in CD patients who need immunosuppressive therapy. IL-1RA Mspa-I11100 CT was associated with earlier age of onset in IBD, while TT genotype was associated with higher age of onset in IBD. CONCLUSIONS IL-1 SNPs seem to be associated with IBD and could affect the disease severity as well.
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Wada Y, Hisamatsu T, Naganuma M, Matsuoka K, Okamoto S, Inoue N, Yajima T, Kouyama K, Iwao Y, Ogata H, Hibi T, Abe T, Kanai T. Risk factors for decreased bone mineral density in inflammatory bowel disease: A cross-sectional study. Clin Nutr 2015; 34:1202-9. [PMID: 25618799 DOI: 10.1016/j.clnu.2015.01.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 12/29/2014] [Accepted: 01/04/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIM Although inflammatory bowel disease (IBD) patients are at risk for metabolic bone disease, studies analyzing this correlation have identified various risk factors, including disease phenotype, age, sex and steroid therapy. Furthermore, few studies have assessed risk factors for bone loss in Japanese IBD patients. This study analyzed risk factors for metabolic bone disease in Japanese IBD patients. METHODS This cross-sectional study assessed 388 patients with IBD aged 20-50 years, including 232 with ulcerative colitis (UC) and 156 with Crohn's disease (CD). Bone mineral density of the femoral neck, total femur and lumbar spine was quantified by dual-energy X-ray absorptiometry. The blood concentrations of bone metabolism markers were measured. History of smoking and bone fracture, and nutritional intake were assessed using questionnaires. RESULTS Of the 388 patients with IBD, 78 (20.1%; UC, 17.2%; CD, 24.4%) had osteopenia and 17 (4.4%; UC, 3.4%; CD, 5.8%) had osteoporosis, as assessed by T-score. Bone mineral density of the lumbar vertebrae was lower in males than in females. Multivariate regression analysis showed that risk factors for bone loss in UC patients were male sex, low body mass index (BMI), high steroid dose and disease location. Risk factors for bone loss in CD patients were male sex and low BMI. CONCLUSION Among Japanese patients with IBD, male sex and low BMI were associated with increased risk for metabolic bone disease. In addition, Steroid therapy shouldn't be indiscriminate in UC patients. These findings may help identify patients at particularly high risk of metabolic bone disease and may help implement appropriate therapies in a timely manner and improve long-term quality of life.
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Affiliation(s)
- Yasuyo Wada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan; Center for Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tadakazu Hisamatsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
| | - Makoto Naganuma
- Center for Diagnostic and Therapeutic Endoscopy, School of Medicine, Keio University, Tokyo, Japan
| | - Katsuyoshi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Susumu Okamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Nagamu Inoue
- Center for Diagnostic and Therapeutic Endoscopy, School of Medicine, Keio University, Tokyo, Japan
| | - Tomoharu Yajima
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Keisuke Kouyama
- Center for Clinical Research, School of Medicine, Keio University, Tokyo, Japan
| | - Yasushi Iwao
- Center for Preventive Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Haruhiko Ogata
- Center for Diagnostic and Therapeutic Endoscopy, School of Medicine, Keio University, Tokyo, Japan
| | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Takayuki Abe
- Center for Clinical Research, School of Medicine, Keio University, Tokyo, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
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Posovszky C, Pfalzer V, Lahr G, Niess JH, Klaus J, Mayer B, Debatin KM, von Boyen GBT. Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn's disease. BMC Gastroenterol 2013; 13:77. [PMID: 23635032 PMCID: PMC3659055 DOI: 10.1186/1471-230x-13-77] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Accepted: 04/26/2013] [Indexed: 02/08/2023] Open
Abstract
Background Influence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn’s disease (CD). Methods 85 pediatric- and 117 adult-onset CD patients were tested for the three main NOD2 CD-associated variants (p.R702W, p.G908R and p.10007fs) and clinical data of at least two years of follow-up were compared regarding disease behaviour and activity, response to therapy and bone mineral density (BMD). Results Chronic active and moderate to severe course of CD is associated in patients with pediatric-onset (p=0.0001) and NOD2 variant alleles (p=0.0001). In pediatric-onset CD the average PCDAI-Score was significantly higher in patients carrying NOD2 variants (p=0.0008). In addition, underweight during course of the disease (p=0.012) was associated with NOD2 variants. Interestingly, osteoporosis was found more frequently in patients carrying NOD2 variant alleles (p=0.033), especially in pediatric-onset CD patients with homozygous NOD2 variants (p=0.037). Accordingly, low BMD in pediatric-onset CD is associated with a higher PCDAI (p=0.0092), chronic active disease (p=0.0148), underweight at diagnosis (p=0.0271) and during follow-up (p=0.0109). Furthermore, pediatric-onset CD patients with NOD2 variants are more frequently steroid-dependent or refractory (p=0.048) and need long-term immunosuppressive therapy (p=0.0213). Conclusions These data suggests that the presence of any of the main NOD2 variants in CD is associated with osteoporosis and an age of onset dependent influence towards underweight, higher disease activity and a more intensive immunosuppressive therapy. This observation supports the idea for an early intensive treatment strategy in children and adolescent CD patients with NOD2 gene variants.
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Affiliation(s)
- Carsten Posovszky
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstr, 24, Ulm, 89075, Germany.
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Fernández-Figueroa EA, Rangel-Escareño C, Espinosa-Mateos V, Carrillo-Sánchez K, Salaiza-Suazo N, Carrada-Figueroa G, March-Mifsut S, Becker I. Disease severity in patients infected with Leishmania mexicana relates to IL-1β. PLoS Negl Trop Dis 2012; 6:e1533. [PMID: 22629474 PMCID: PMC3358333 DOI: 10.1371/journal.pntd.0001533] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2011] [Accepted: 01/03/2012] [Indexed: 12/31/2022] Open
Abstract
Leishmania mexicana can cause both localized (LCL) and diffuse (DCL) cutaneous leishmaniasis, yet little is known about factors regulating disease severity in these patients. We analyzed if the disease was associated with single nucleotide polymorphisms (SNPs) in IL-1β (−511), CXCL8 (−251) and/or the inhibitor IL-1RA (+2018) in 58 Mexican mestizo patients with LCL, 6 with DCL and 123 control cases. Additionally, we analyzed the in vitro production of IL-1β by monocytes, the expression of this cytokine in sera of these patients, as well as the tissue distribution of IL-1β and the number of parasites in lesions of LCL and DCL patients. Our results show a significant difference in the distribution of IL-1β (−511 C/T) genotypes between patients and controls (heterozygous OR), with respect to the reference group CC, which was estimated with a value of 3.23, 95% CI = (1.2, 8.7) and p-value = 0.0167), indicating that IL-1β (−511 C/T) represents a variable influencing the risk to develop the disease in patients infected with Leishmania mexicana. Additionally, an increased in vitro production of IL-1β by monocytes and an increased serum expression of the cytokine correlated with the severity of the disease, since it was significantly higher in DCL patients heavily infected with Leishmania mexicana. The distribution of IL-1β in lesions also varied according to the number of parasites harbored in the tissues: in heavily infected LCL patients and in all DCL patients, the cytokine was scattered diffusely throughout the lesion. In contrast, in LCL patients with lower numbers of parasites in the lesions, IL-1β was confined to the cells. These data suggest that IL-1β possibly is a key player determining the severity of the disease in DCL patients. The analysis of polymorphisms in CXCL8 and IL-1RA showed no differences between patients with different disease severities or between patients and controls. Leishmania mexicana is an intracellular parasite that causes two polarly opposed diseases: One is a self-limited disease, characterized by ulcerative lesions associated with a low infectious load, as found in patients with localized cutaneous leishmaniasis (LCL). And the other pole is characterized by a progressive disease where abundant parasites spread uncontrollably throughout the skin inside heavily infected phagocytic cells, as occurs in patients with diffuse cutaneous leishmaniasis (DCL). The cause of this severe form of the disease is unknown, although the early encounter between the parasite and the inflammatory response of the host possibly plays a decisive role in the disease outcome. We here show that polymorphism in the gene encoding IL-1β (−511 C/T) represents a variable influencing the risk to develop the disease for patients infected with Leishmania mexicana. In vitro experiments showed that monocytes of DCL patients secreted significantly higher levels of the proinflammatory cytokine IL-1β as compared to LCL patients. DCL patients also had augmented levels of IL-1β in serum, and the cytokine was diffusely distributed throughout lesions, which was correlated with the numbers of parasites in the lesions. We propose that IL-1β possibly plays a key role in establishing the disease severity in patients infected with Leishmania mexicana.
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Affiliation(s)
- Edith A. Fernández-Figueroa
- Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México Distrito Federal, México
| | | | | | | | - Norma Salaiza-Suazo
- Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México Distrito Federal, México
| | - Georgina Carrada-Figueroa
- Secretaría de Salud del Estado de Tabasco, Universidad Juárez Autónoma de Tabasco, Tabasco, México
- Universidad Juárez Autónoma, de Tabasco, Tabasco, México
| | | | - Ingeborg Becker
- Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México Distrito Federal, México
- * E-mail:
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Agrawal M, Arora S, Li J, Rahmani R, Sun L, Steinlauf AF, Mechanick JI, Zaidi M. Bone, inflammation, and inflammatory bowel disease. Curr Osteoporos Rep 2011; 9:251-7. [PMID: 21935582 DOI: 10.1007/s11914-011-0077-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Osteoporosis is a leading cause of morbidity in patients with inflammatory bowel disease (IBD). Bone loss is an early systemic process and occurs even before clinical disease manifests. Bone disease is attributed to vitamin D deficiency, steroid use, and/or systemic inflammation. In this review, we discuss the molecular pathways of bone loss mediated by inflammatory cytokines and other mediators. Further research will hopefully clarify the mechanisms of inflammation-induced bone loss in IBD and guide effective treatment modalities.
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Affiliation(s)
- Manasi Agrawal
- Department of Gastroenterology, Maimonides Medical Center, Brooklyn, NY 11201, USA.
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Chiurillo MA, Moran YH, Cañas M, Valderrama EJ, Armanie E. Infection with specific Helicobacter pylori-cag pathogenicity island strains is associated with interleukin-1B gene polymorphisms in Venezuelan chronic gastritis patients. Dig Dis Sci 2011; 56:449-56. [PMID: 20585978 DOI: 10.1007/s10620-010-1316-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2010] [Accepted: 06/14/2010] [Indexed: 12/17/2022]
Abstract
BACKGROUND The cag pathogenicity island (cag-PAI) is one of the major virulence factors of Helicobacter pylori, showing considerable geographic variation. AIM We investigated the prevalence of cagA, cagE, and cagT genes of cag-PAI and their association with proinflammatory IL-1B-511/-31/+3954 polymorphisms in Venezuelan chronic gastritis patients from a high-risk gastric cancer region. METHODS Presence of cag-PAI genes and IL-1B polymorphisms in 121 biopsy specimens was evaluated by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP), respectively. RESULTS cagA (+) and triple-positive (cagAET (+)) strains were detected in 79.3% and 70.2% of patients, respectively. We found that infection with cagA (+) and cagAET (+) strains was associated (P < 0.05) with hosts harboring both IL-1B +3954C allele and IL-1B-511T/-31C/+3954C haplotype (TCC (+)). The frequency of gastric atrophy was significantly higher (P < 0.020) among cagAET (+)/IL-1B-TCC (+) combined genotype carriers. CONCLUSION Carriage of IL-1B +3954C allele and IL-1B-TCC (+) haplotype could favor colonization of bacterial cagAET (+) strains, and the combination of these bacterial and host haplotypes could play a synergistic role in development of premalignant gastric lesions. This work contributes to understanding of the complex interaction between H. pylori virulence factors and cytokine genotypes involved in gastrointestinal diseases.
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Affiliation(s)
- Miguel Angel Chiurillo
- Decanato de Ciencias de la Salud, Universidad Centroccidental Lisandro Alvarado (UCLA), Barquisimeto, Venezuela.
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Miheller P, Lőrinczy K, Lakatos PL. Clinical relevance of changes in bone metabolism in inflammatory bowel disease. World J Gastroenterol 2010; 16:5536-5542. [PMID: 21105186 PMCID: PMC2992671 DOI: 10.3748/wjg.v16.i44.5536] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2010] [Revised: 09/18/2010] [Accepted: 09/25/2010] [Indexed: 02/06/2023] Open
Abstract
Low bone mineral density is an established, frequent, but often neglected complication in patients with inflammatory bowel disease (IBD). Data regarding the diagnosis, therapy and follow-up of low bone mass in IBD has been partially extrapolated from postmenopausal osteoporosis; however, the pathophysiology of bone loss is altered in young patients with IBD. Fracture, a disabling complication, is the most important clinical outcome of low bone mass. Estimation of fracture risk in IBD is difficult. Numerous risk factors have to be considered, and these factors should be weighed properly to help in the identification of the appropriate patients for screening. In this editorial, the authors aim to highlight the most important clinical aspects of the epidemiology, prevention, diagnosis and treatment of IBD-related bone loss.
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MESH Headings
- Bone Density
- Bone Diseases, Metabolic/diagnosis
- Bone Diseases, Metabolic/epidemiology
- Bone Diseases, Metabolic/etiology
- Bone Diseases, Metabolic/metabolism
- Bone Diseases, Metabolic/pathology
- Bone Diseases, Metabolic/prevention & control
- Bone Remodeling
- Bone and Bones/metabolism
- Bone and Bones/pathology
- Fractures, Bone/epidemiology
- Fractures, Bone/etiology
- Fractures, Bone/metabolism
- Fractures, Bone/pathology
- Fractures, Bone/prevention & control
- Humans
- Inflammatory Bowel Diseases/complications
- Inflammatory Bowel Diseases/metabolism
- Inflammatory Bowel Diseases/pathology
- Inflammatory Bowel Diseases/therapy
- Mass Screening
- Predictive Value of Tests
- Risk Assessment
- Risk Factors
- Treatment Outcome
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Chao TH, Yu HN, Huang CC, Liu WS, Tsai YW, Wu WT. Association of interleukin-1 beta (-511C/T) polymorphisms with osteoporosis in postmenopausal women. Ann Saudi Med 2010; 30:437-41. [PMID: 20940514 PMCID: PMC2994158 DOI: 10.4103/0256-4947.71062] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Osteoporosis is a common disease of the elderly, in which genetic and clinical factors contribute to the disease phenotype. Since the production of interleukin-1 (IL-1) has been implicated in the bone mass and skeletal disorders, we investigated whether IL-1 system gene polymorphisms are associated with the pathogenesis of osteoporosis in postmenopausal Taiwanese women. METHODS Osteoporosis is diagnosed by dual-energy x-ray absorptiometry, which measures bone mineral density (BMD) at multiple skeletal sites. We studied the IL-1α (-889C/T), IL-1β (-511C/T) and the 86 base pair variable number tandem repeat (VNTR) in intron 2 of the IL-1 receptor antagonist (IL-1ra) gene in 117 postmenopausal women with osteoporosis and 135 control subjects without a history of symptomatic osteoporosis. These gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymerase. Blood sugar and other risk factors were also determined. RESULTS The frequencies of IL-1β (-511C/T) genotypes (P=.022, odds ratio=1.972) and alleles (P=.02, odds ratio=2.909) showed a statistically significant difference between the two groups. However, we did not find any statistically significant difference in IL-1β and IL-1ra polymorphisms (P>.05). We also observed a positive relationship between osteoporosis and cholesterol and a weak inverse relationship between blood sugar and osteoporosis in postmenopausal women. CONCLUSIONS These experimental results suggest that the pathogenesis of osteoporosis is associated with IL-1β (-511C/T) polymorphism in postmenopausal women. This polymorphism is an independent risk factor for osteoporosis.
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Affiliation(s)
- Tai-Hung Chao
- Department of Orthopedics, Zuoying Armed Forces General Hospital, Kaohsiung, Taiwan
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Schmidt S, Mellström D, Norjavaara E, Sundh V, Saalman R. Familial resemblance of bone mineral density in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2010; 51:146-50. [PMID: 20531019 DOI: 10.1097/mpg.0b013e3181dbf42c] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND AIM Low bone mineral density (BMD) has recently been recognized as a potential health problem in children with inflammatory bowel disease (IBD). Our aim was to investigate the familial resemblance of BMD in pediatric patients with IBD. PATIENTS AND METHODS In this population-based study from western Sweden, we assessed 144 children with IBD, 83 with ulcerative colitis, 45 with Crohn disease, 16 with indeterminate colitis, and their parents (136 mothers and 130 fathers) with dual-energy X-ray absorptiometry (DEXA). After adjustment for sex, age, weight, height, and parental IBD, we correlated the BMD of the patients to the BMD of their mothers, fathers, and the midparent value ([mother's BMD + father's BMD]/2) at different skeletal sites and calculated the Pearson correlation coefficient (r) to evaluate the extent of familial resemblance. RESULTS The BMD of the children with IBD was clearly related to the BMD of their parents. The strongest correlation was found in the femoral neck with r = 0.55 (P < 0.001, 95% CI 0.41-0.66) between BMD of the children and the midparent value. The group of children with IBD had an odds ratio of 5.96 for decreased BMD (lumbar spine z score < -1 standard deviation) given that decreased BMD was diagnosed in both parents. CONCLUSIONS We conclude that BMD in children and adolescents with IBD is significantly related to that of their parents. In a clinical setting, it may be helpful to assess the parents of children with IBD with DEXA to interpret the children's DEXA measurements.
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Affiliation(s)
- Susanne Schmidt
- Department of Pediatrics, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
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Chiurillo MA, Moran Y, Cañas M, Valderrama E, Alvarez A, Armanie E. Combination of Helicobacter pylori-iceA2 and proinflammatory interleukin-1 polymorphisms is associated with the severity of histological changes in Venezuelan chronic gastritis patients. ACTA ACUST UNITED AC 2010; 59:170-6. [PMID: 20482626 DOI: 10.1111/j.1574-695x.2010.00675.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Helicobacter pylori is a major cause of chronic gastritis (CG) and a firmly established carcinogen for gastric adenocarcinoma. However, the underlying pathogenic mechanisms are not fully understood. In this work we studied the association of the allelic variation of H. pylori-iceA virulence factor and human proinflammatory interleukin (IL)-1 polymorphisms (IL-1B-31, IL-1B-511, IL-1B+3954 and IL-1RN) with histopathological changes in the gastric mucosa of patients with CG in Venezuela, a country with a high incidence of and mortality from gastric cancer. Although in this work the iceA1 allele was found more frequently (69.7%), iceA2 allele prevalence was higher in samples with atrophic gastritis (AG) and more severe grades of granulocytic (G2/G3) [P=0.02; odds ratio (OR) 3.3] and lymphocytic infiltration (L2/L3). The carriage of iceA2 strains combined with proinflammatory IL-1 polymorphisms IL-1-31C or IL-1-511T allele carrier genotypes increased even more the risk of presenting G2/G3 with ORs of 5.1 and 5.4, respectively. Moreover, the iceA2/IL-1B-511T and iceA2/IL-1B-31C/-511T/IL-1RN(*)2 bacteria/host genotype combinations showed a significant association with AG and L2/L3, respectively. Despite not being well established, the bacterial risk factor iceA2 seems an important predictor of severe histological changes in CG, separately or in combination with host genetic factors in the Venezuelan population.
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Lee G, Buchman AL. DNA-driven nutritional therapy of inflammatory bowel disease. Nutrition 2009; 25:885-91. [DOI: 10.1016/j.nut.2009.06.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2009] [Revised: 06/17/2009] [Accepted: 06/17/2009] [Indexed: 12/12/2022]
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Kuwabara A, Tanaka K, Tsugawa N, Nakase H, Tsuji H, Shide K, Kamao M, Chiba T, Inagaki N, Okano T, Kido S. High prevalence of vitamin K and D deficiency and decreased BMD in inflammatory bowel disease. Osteoporos Int 2009; 20:935-42. [PMID: 18825300 DOI: 10.1007/s00198-008-0764-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2007] [Accepted: 09/03/2008] [Indexed: 12/19/2022]
Abstract
SUMMARY Vitamin K and D deficiency and decreased bone mineral density (BMD) were highly prevalent in patients with inflammatory bowel disease (IBD), especially Crohn's disease (CD). Dietary intakes of these vitamins, however, were above the Japanese adequate intakes in IBD patients, suggesting that malabsorption is the basis for hypovitaminosis K and D and decreased BMD. INTRODUCTION We have studied the possible involvement of vitamin K and D deficiency in the pathogenesis of decreased BMD in IBD. METHODS Seventy patients with IBD were evaluated for their BMD; plasma levels of vitamin K; phylloquinone (PK), menaquinone-7 (MK-7), and 25OH-D; serum PTH, protein induced by vitamin K absence (PIVKA-II), and undercarboxylated osteocalcin (ucOC) levels; and their food intake. RESULTS Compared with ulcerative colitis (UC) patients, CD patients had significantly lower plasma vitamin K and 25OH-D concentrations; significantly higher serum levels of PTH, PIVKA-II, and ucOC; and significantly lower BMD scores at almost all measurement sites. More IBD patients were vitamin K deficient in bone than in liver. Multiple regression analyses revealed that low plasma concentrations of vitamin K and 25OH-D were independent risk factors for low BMD and that they were associated with the patients' fat intake, but not with their intake of these vitamins. CONCLUSION IBD patients have high prevalence of decreased BMD and vitamin K and D deficiency probably caused by malabsorption of these vitamins.
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Affiliation(s)
- A Kuwabara
- Department of Food and Nutrition, Kyoto Women's University, 35, Imakumano-kitahiyoshicho, Higashiyama, Kyoto 605-8501, Japan
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Van Schaik FDM, Verhagen MAMT, Siersema PD, Oldenburg B. High prevalence of low bone mineral density in patients with Inflammatory Bowel Disease in the setting of a peripheral Dutch hospital. J Crohns Colitis 2008; 2:208-13. [PMID: 21172212 DOI: 10.1016/j.crohns.2008.03.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2008] [Accepted: 03/18/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Osteopenia and osteoporosis are frequently encountered in patients with Inflammatory Bowel Disease (IBD). Our aims were to evaluate the actual practice of screening for low bone mineral density (BMD) by dual energy X-ray absorptiometry (DEXA), to determine the prevalence of low BMD and to investigate the risk factors associated with a low BMD in the IBD population of a regional Dutch hospital. METHODS A retrospective chart review was performed in 474 patients (259 with ulcerative colitis, 210 with Crohn's disease and 5 with indeterminate colitis). DEXA results and potential predictive factors of low BMD were documented. Predictive factors of low BMD were assessed by logistic regression. RESULTS DEXA was performed in 168 IBD patients (35.4%). A low BMD (T-score<-1) was present in 64.3%. Osteoporosis (T-score<-2.5) was found in 23.8%. Low BMI, older age at the moment of diagnosis and male gender were found to be predictive factors of low BMD. For patients with osteoporosis, disease duration was an additional predictive factor. After subgroup analysis predictive factors were found to be the same in patients with Crohn's disease. CONCLUSIONS The prevalence of osteopenia and osteoporosis in IBD patients in a regional centre is as high as the prevalence rates reported from tertiary referral centres. A low BMI, an older age at the moment of diagnosis and male gender were predictive factors of low BMD. Prediction of osteoporosis and osteopenia using risk factors identified in this and previous studies is presently not feasible.
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Affiliation(s)
- Fiona D M Van Schaik
- Department of Gastroenterology, University Medical Centre Utrecht, The Netherlands
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Abstract
Half of all patients with inflammatory bowel disease show a significant reduction of their bone mass during the course of their chronic inflammatory disease. In contrast to women with postmenopausal osteoporosis these patients are much younger and a significant subgroup develops vertebral fractures which are mostly asymptomatic. The activity of the chronic inflammatory disease and the steroid treatment leads to bone loss predominantly through the TNFα-driven osteoprotegerin system. Clinical useful genetic markers to identify patients at risk for fractures have not been developed so far. Long-term clinical remission leads in most patients to normalisation of the bone density. Patients with reduced bone density should be substituted with calcium and vitamin D. Patients with vertebral fractures should receive bisphosphonates.
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Affiliation(s)
- Max Reinshagen
- Department of Medicine I, Klinikum Braunschweig, Germany
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Kim KS, Kim GS, Hwang JY, Lee HJ, Park MH, Kim KJ, Jung J, Cha HS, Shin HD, Kang JH, Park EK, Kim TH, Hong JM, Koh JM, Oh B, Kimm K, Kim SY, Lee JY. Single nucleotide polymorphisms in bone turnover-related genes in Koreans: ethnic differences in linkage disequilibrium and haplotype. BMC MEDICAL GENETICS 2007; 8:70. [PMID: 18036257 PMCID: PMC2222243 DOI: 10.1186/1471-2350-8-70] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2006] [Accepted: 11/26/2007] [Indexed: 12/20/2022]
Abstract
Background Osteoporosis is defined as the loss of bone mineral density that leads to bone fragility with aging. Population-based case-control studies have identified polymorphisms in many candidate genes that have been associated with bone mass maintenance or osteoporotic fracture. To investigate single nucleotide polymorphisms (SNPs) that are associated with osteoporosis, we examined the genetic variation among Koreans by analyzing 81 genes according to their function in bone formation and resorption during bone remodeling. Methods We resequenced all the exons, splice junctions and promoter regions of candidate osteoporosis genes using 24 unrelated Korean individuals. Using the common SNPs from our study and the HapMap database, a statistical analysis of deviation in heterozygosity depicted. Results We identified 942 variants, including 888 SNPs, 43 insertion/deletion polymorphisms, and 11 microsatellite markers. Of the SNPs, 557 (63%) had been previously identified and 331 (37%) were newly discovered in the Korean population. When compared SNPs in the Korean population with those in HapMap database, 1% (or less) of SNPs in the Japanese and Chinese subpopulations and 20% of those in Caucasian and African subpopulations were significantly differentiated from the Hardy-Weinberg expectations. In addition, an analysis of the genetic diversity showed that there were no significant differences among Korean, Han Chinese and Japanese populations, but African and Caucasian populations were significantly differentiated in selected genes. Nevertheless, in the detailed analysis of genetic properties, the LD and Haplotype block patterns among the five sub-populations were substantially different from one another. Conclusion Through the resequencing of 81 osteoporosis candidate genes, 118 unknown SNPs with a minor allele frequency (MAF) > 0.05 were discovered in the Korean population. In addition, using the common SNPs between our study and HapMap, an analysis of genetic diversity and deviation in heterozygosity was performed and the polymorphisms of the above genes among the five populations were substantially differentiated from one another. Further studies of osteoporosis could utilize the polymorphisms identified in our data since they may have important implications for the selection of highly informative SNPs for future association studies.
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Affiliation(s)
- Kyung-Seon Kim
- Center for Genome Science, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, Republic of Korea.
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Lee N, Fowler E, Mason S, Lincoln D, Taaffe DR, Radford-Smith G. Tumor necrosis factor-alpha haplotype is strongly associated with bone mineral density in patients with Crohn's disease. J Gastroenterol Hepatol 2007; 22:913-9. [PMID: 17565648 DOI: 10.1111/j.1440-1746.2006.04679.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND AND AIM There is limited consensus on the major variables that determine bone integrity and bone loss in patients with Crohn's disease. Twin and family studies in the general population indicate that up to 85% of variance in bone mineral density is inherited. The aim was to determine the prevalence of bone loss and both molecular and clinical risk factors for bone loss in a large Crohn's disease population. METHODS This was a cross-sectional study of 304 patients with Crohn's disease attending the Inflammatory Bowel Disease unit at Royal Brisbane and Women's Hospital, Queensland. The results of bone density testing were ascertained directly and by a mailed questionnaire. Bone mineral density data were combined with clinical information and correlated with single nucleotide polymorphisms within the tumor necrosis factor-alpha (TNF-alpha), interleukin-10, and NOD2/CARD15 genes. RESULTS Of 304 Crohn's disease patients, 101 had undergone previous bone density testing. Forty-five patients (45%) had been diagnosed with osteopenia and 18 (18%) were osteoporotic. After multivariate analysis, both the TNF-alpha GT haplotype and the -857 CC genotype showed strong associations with bone mineral density overall (P = 0.003 and P = 0.002, respectively). Body mass index (P = 0.01) and previous bowel resection in female patients (P = 0.03) were predictive of a higher spine bone density, while body mass index (P = 0.003) and the effect of years since first bowel resection (P = 0.02) remained independent predictors of proximal femur bone mineral density. There were no other significant associations observed. CONCLUSIONS This study has identified a novel protective association between a TNF-alpha haplotype and bone mineral density in Crohn's disease. It confirms the important influence of body mass index and intestinal resection on bone loss in this population.
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Affiliation(s)
- Naomi Lee
- School of Human Movement Studies, University of Queensland, Brisbane, Queensland, Australia
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Lakatos PL, Fischer S, Lakatos L, Gal I, Papp J. Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors: pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take "toll" ? World J Gastroenterol 2006; 12:1829-1841. [PMID: 16609988 PMCID: PMC4087507 DOI: 10.3748/wjg.v12.i12.1829] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2005] [Revised: 10/20/2005] [Accepted: 11/10/2005] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of inflammatory bowel disease (IBD) is only partially understood. Various environmental and host (e.g. genetic-, epithelial-, immune and non-immune) factors are involved. It is a multifactorial polygenic disease with probable genetic heterogeneity. Some genes are associated with IBD itself, while others increase the risk of ulcerative colitis (UC) or Crohn's disease (CD) or are associated with disease location and/or behaviour. This review addresses recent advances in the genetics of IBD. The article discusses the current information on the crosstalk between microbial and genetic factors (e.g. NOD2/CARD15, SLC22A46A5 and DLG5). The genetic data acquired in recent years help in understanding the pathogenesis of IBD and can identify a number of potential targets for therapeutic intervention. In the future, genetics may help more accurately diagnose and predict disease course in IBD.
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Affiliation(s)
- Peter Laszlo Lakatos
- 1st Department of Medicine, Semmelweis University, Koranyi str. 2/A, H-1083 Budapest, Hungary.
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Barisani D, Ceroni S, Meneveri R, Cesana BM, Bardella MT. IL-10 polymorphisms are associated with early-onset celiac disease and severe mucosal damage in patients of Caucasian origin. Genet Med 2006; 8:169-174. [PMID: 16540751 DOI: 10.1097/01.gim.0000204464.87540.39] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
PURPOSE Polymorphisms in cytokine genes can determine their level of expression and affect the phenotypic expression of immunomediated diseases, such as celiac disease (CD). We thus evaluated cytokine polymorphism prevalence in CD patients and population controls, and assessed the correlation between specific polymorphisms and celiacs' clinical characteristics. METHODS 155 CD patients and 202 population controls were enrolled in the study. Cytokine polymorphisms (TNFalpha -308 and -238, IL-1beta -511 and +3954, IL-1b RN + 2018, IL-6 -174, IL-10 -1082, -819 and -592, TGFbeta1 + 29 and +74, IFN-gamma + 874) and HLA class II alleles were determined by sequence-specific primer polymerase chain reaction or restriction fragment length polymorphism analysis. Duodenal histology was classified using Marsh's criteria. Variables significantly associated with CD patients' characteristics were identified by multivariate logistic regression analysis. RESULTS A significantly higher frequency of -308 TNFalpha polymorphism was observed in CD patients compared to the entire population control group, although no difference was detected when population controls were stratified according to HLA class II. Among celiacs, early onset of the disease (< or =2 year old) and the presence of a severe intestinal lesion (Marsh 3C) were significantly associated with the -1082 A/A IL-10 genotype which corresponds to a low producer phenotype (OR 3.28, 95% CI 1.49-7.19 and OR 2.60, 95% CI 1.04-6.49, respectively). CONCLUSION The association between IL-10 genotypes and both histological severity at diagnosis and age of onset could be related to an alteration in cytokine balance, and supports the idea that the various clinical manifestations of the disease could be determined by a different genetic background.
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Affiliation(s)
- Donatella Barisani
- Department of Experimental, Environmental Medicine and Medical Biotechnology, University of Milano Bicocca, Monza, Milan
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Kornman KS. Interleukin 1 genetics, inflammatory mechanisms, and nutrigenetic opportunities to modulate diseases of aging. Am J Clin Nutr 2006; 83:475S-483S. [PMID: 16470016 DOI: 10.1093/ajcn/83.2.475s] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Inflammation plays a central role in many diseases of aging, and genetic differences in the inflammatory response appear to influence different disease courses among individuals. Variations in the genes for the family of interleukin 1 (IL-1) proteins are inherited together in a small set of patterns and provide an example of the role of inflammatory genetics as a modifier of diseases of aging. The IL-1 genetic variations are associated with variation in both the inflammatory response and the clinical presentation of a range of diseases, including coronary artery disease, Alzheimer disease, gastric cancer, and periodontitis. This growing understanding of the role of genetic variation in inflammation and chronic disease presents opportunities to identify healthy persons who are at increased risk of disease and to potentially modify the trajectory of disease to prolong healthy aging. Nutrition represents one of the promising approaches to modulation of the risk of diseases of aging because of the effects of certain nutrients on gene expression. One of the most practical applications of nutritional modulation of chronic disease may be nutrients that regulate the expression of key inflammatory genes.
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Chen H, Wilkins LM, Aziz N, Cannings C, Wyllie DH, Bingle C, Rogus J, Beck JD, Offenbacher S, Cork MJ, Rafie-Kolpin M, Hsieh CM, Kornman KS, Duff GW. Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context. Hum Mol Genet 2006; 15:519-29. [PMID: 16399797 DOI: 10.1093/hmg/ddi469] [Citation(s) in RCA: 234] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
We questioned the significance of haplotype structure in gene regulation by testing whether individual single nucleotide polymorphisms (SNPs) within a gene promoter region [interleukin-1-beta (IL1B)] might affect promoter function and, if so, whether function was dependent on haplotype context. We sequenced genomic DNA from 25 individuals of diverse ethnicity, focusing on exons and upstream flanking regions of genes of the cluster. We identified four IL1B promoter region SNPs that were active in transient transfection reporter gene assays. To substantiate allelic differences found in reporter gene assays, we also examined nuclear protein binding to promoter sequence oligonucleotides containing different alleles of the SNPs. The effect of individual SNPs on reporter gene transcription varied according to which alleles of the three other SNPs were present in the promoter construct. The SNP patterns that influenced function reflected common haplotypes that occur in the population, suggesting functionally significant interactions between SNPs according to haplotype context. Of the haplotypes that include the four functional IL1B promoter SNPs (-3737, -1464, -511, -31), the four haplotypes that showed different contextual effects on SNP function accounted for >98% of the estimated haplotypes in Caucasian and African-American populations. This finding underlines the importance of understanding the haplotype structure of populations used for genetic studies and may be especially important in the functional analysis of genetic variation across gene regulatory regions.
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Affiliation(s)
- Hongmin Chen
- Interleukin Genetics Inc., 135 Beaver Street, Waltham, MA 02452, USA
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Kim JG, Lim KS, Ku SY, Kim SH, Choi YM, Moon SY. Relations between interleukin-1, its receptor antagonist gene polymorphism, and bone mineral density in postmenopausal Korean women. J Bone Miner Metab 2006; 24:53-57. [PMID: 16369899 DOI: 10.1007/s00774-005-0646-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2005] [Accepted: 06/30/2005] [Indexed: 10/25/2022]
Abstract
We investigated the relation between polymorphisms in the interleukin-1(IL-1) and IL-1 receptor antagonist (IL-1ra) gene, and bone mineral density (BMD) in postmenopausal Korean women. The IL-1alpha C(-889)T polymorphism, and IL-1beta C(-511)T polymorphism were examined by restriction fragment length polymorphism, and 86-bp variable number tandem repeat polymorphism in the IL-1ra gene was analyzed by the polymerase chain reaction and electrophoresis in 202 postmenopausal Korean women. Serum osteocalcin, and C-telopeptide of type I collagen were measured using a radioimmunoassay and enzyme-linked immunosorbent assay, respectively. BMD at the lumbar spine and proximal femur was measured by dual-energy X-ray absorptiometer. No significant differences in BMD or in serum bone markers levels were noted across the IL-1alpha or IL-1beta genotype. There were no significant differences in the distribution of IL-1alpha or IL-1beta genotype according to the status of bone mass. BMD in women carrying the A2 allele of the IL-1ra gene was significantly lower than those without this allele, and the A2 allele was more frequent in osteoporotic women than in normal women. These data suggest that IL-1ra gene VNTR polymorphism is a genetic factor that may affect BMD in Korean women.
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Affiliation(s)
- Jung Gu Kim
- Department of Obstetrics and Gynecology, College of Medicine, Seoul National University Hospital, 28 Yeunkeun-dong, Chongno-gu, Seoul 110-744, Korea.
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Abstract
Crohn's disease (CD) is associated with a number of secondary conditions including osteoporosis, which increases the risk of bone fracture. The cause of metabolic bone disease in this population is believed to be multifactorial and may include the disease itself and associated inflammation, high-dose corticosteroid use, weight loss and malabsorption, a lack of exercise and physical activity, and an underlying genetic predisposition to bone loss. Reduced bone mineral density has been reported in between 5% to 80% of CD sufferers, although it is generally believed that approximately 40% of patients suffer from osteopenia and 15% from osteoporosis. Recent studies suggest a small but significantly increased risk of fracture compared with healthy controls and, perhaps, sufferers of other gastrointestinal disorders such as ulcerative colitis. The role of physical activity and exercise in the prevention and treatment of CD-related bone loss has received little attention, despite the benefits of specific exercises being well documented in healthy populations. This article reviews the prevalence of and risk factors for low bone mass in CD patients and examines various treatments for osteoporosis in these patients, with a particular focus on physical activity.
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Affiliation(s)
- Naomi Lee
- School of Human Movement Studies, The University of Queensland, Queensland, Australia
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Kwon KH, Murakami A, Hayashi R, Ohigashi H. Interleukin-1beta targets interleukin-6 in progressing dextran sulfate sodium-induced experimental colitis. Biochem Biophys Res Commun 2005; 337:647-54. [PMID: 16202978 DOI: 10.1016/j.bbrc.2005.09.107] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2005] [Accepted: 09/17/2005] [Indexed: 10/25/2022]
Abstract
Inflammatory bowel disease (IBD) is an immunologically mediated disorder that is characterized by chronic, relapsing, and inflammatory responses. Dextran sulfate sodium (DSS)-induced experimental colitis in mice has been recognized as a useful model for human IBD and interleukin (IL)-1beta is a key cytokine in the onset of IBD. The purpose of the present study was to clarify which pro-inflammatory mediators are targeted by IL-1beta in mice with DSS-induced colitis. First, we found that DSS markedly induced IL-1beta production in both dose- and time-dependent manners (P < 0.05 and P < 0.01, respectively) in murine peritoneal macrophages (pMphi), while that of tumor necrosis factor-alpha was insignificant. Further, the expressions of mRNA and protein for IL-1beta were increased in colonic mucosa and pMphi from mice that received drinking water containing 5% DSS for 7 days (P < 0.01, each). In addition, the expressions of IL-6, granulocyte macrophage-colony stimulating factor, inducible nitric oxide synthase, and cyclooxygenase-2 mRNA were also time dependently increased (P < 0.01, each). Furthermore, administration of rIL-1beta (10 microg/kg, i.p.) significantly induced the expressions of IL-1beta and IL-6 mRNA in colonic mucosa from non-treated mice (P < 0.01). Anti-mIL-1beta antibody treatments (50 microg/kg, i.p.) attenuated DSS-induced body weight reduction and shortening of the colorectum (P < 0.05, each), and abrogated the expressions of IL-1beta and IL-6 mRNA in colonic mucosa (P < 0.01, each). Our results evidently support the previous findings that IL-1beta is involved in the development of DSS-induced experimental colitis in mice, and strongly suggest that IL-1beta targets itself and IL-6 for progressing colonic inflammation.
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Affiliation(s)
- Ki Han Kwon
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Japan
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37
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Moreno ML, Crusius JBA, Cherñavsky A, Sugai E, Sambuelli A, Vazquez H, Mauriño E, Peña AS, Bai JC. The IL-1 gene family and bone involvement in celiac disease. Immunogenetics 2005; 57:618-20. [PMID: 16133447 DOI: 10.1007/s00251-005-0033-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2005] [Accepted: 07/19/2005] [Indexed: 01/09/2023]
Abstract
Celiac disease (CD) is associated with decreased bone mineral mass. Its pathogenesis is multifactorial since both systemic and local mechanisms may play a role. Our objective was to determine whether single-nucleotide polymorphisms in genes encoding members of the interleukin-1 family are associated with bone damage measured by densitometry in a series of 71 adult CD patients assessed at diagnosis. When compared with non-carrier CD patients, carriers of allele T of the interleukin-1beta gene (IL1B-511T) had a significantly lower bone mass at the total skeleton level (p = 0.0484) and a greater prevalence of osteopenia/osteoporosis (p = 0.0102). To our knowledge, this is the first evidence on the association between a genetic predisposition and low bone mass in CD patients. This finding supports the postulated inflammation-associated bone loss pathogenesis as one of the causes of bone weakness in CD.
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Affiliation(s)
- M L Moreno
- Department of Medicine, C. Bonorino Udaondo Gastroenterology Hospital, Buenos Aires, Argentina
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Huang G, Niu T, Peng S, Ling D, Liu J, Zhang X, Xu X. Association between the interleukin-1beta C(-511)T polymorphism and blood pressure in a Chinese hypertensive population. Immunol Lett 2004; 91:159-62. [PMID: 15019285 DOI: 10.1016/j.imlet.2003.11.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2003] [Revised: 11/24/2003] [Accepted: 11/25/2003] [Indexed: 10/26/2022]
Abstract
The interleukin-1beta (IL-1beta) is an important pro-inflammatory cytokine in a broad spectrum of physiological processes. Previous investigations have observed that levels of the IL-1beta were higher in essential hypertensive patients and the IL-1beta gene polymorphism has been shown to be related to IL-1 production. We hypothesized that genetically determined differences in activity or responsiveness of cytokine(s) might contribute to hypertension. In this report, we utilized a family-based design to test the association between the IL-1beta C(-511)T polymorphism and blood pressure levels in hypertensive patients chosen from rural communities in Anhui, China. In men, carriers of the IL-1beta (-511)*C allele were found to have lower systolic (P = 0.049) blood pressure levels compared with T homozygotes, which conforms to an additive effect model. By contrast, no significant association between the IL-1beta gene and blood pressure levels was revealed in women. Our results suggested a significant role of the IL-1beta C(-511)T polymorphism in the control of blood pressure in Chinese hypertensives.
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Affiliation(s)
- Guo Huang
- School of Life Sciences, University of Science and Technology of China, Hefei
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Kimura R, Nishioka T, Soemantri A, Ishida T. Cis-acting effect of the IL1B C−31T polymorphism on IL-1β mRNA expression. Genes Immun 2004; 5:572-5. [PMID: 15356674 DOI: 10.1038/sj.gene.6364128] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Since the effect of IL1B polymorphisms on IL-1beta production is still controversial, we selected two polymorphisms to test their cis-acting effect on IL-1beta mRNA expression by means of the allele-specific transcript quantification and the haplotype analysis. As for the C-31T polymorphism, we found that expression of the -31T allele was 2.2 times of the -31C allele. This higher transcription efficiency may correspond to the fact that C-31T is located in a TATA box. The other polymorphism, C+3954T, did not alter the levels of transcription. The use of the allele-specific transcript quantification enables us to exclude trans-acting effects of polymorphisms on the gene expression and contributes to understanding the roles of the IL1B polymorphisms in susceptibility to multifactorial diseases.
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Affiliation(s)
- R Kimura
- Unit of Human Biology and Genetics, Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
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40
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Mak YT, Hampson G, Beresford JN, Spector TD. Variations in genome-wide gene expression in identical twins - a study of primary osteoblast-like culture from female twins discordant for osteoporosis. BMC Genet 2004; 5:14. [PMID: 15176972 PMCID: PMC436052 DOI: 10.1186/1471-2156-5-14] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2003] [Accepted: 06/04/2004] [Indexed: 11/16/2022] Open
Abstract
Background Monozygotic twin pairs who are genetically identical would be potentially useful in gene expression study for specific traits as cases and controls, because there would be much less gene expression variation within pairs compared to two unrelated individuals. However the twin pair has to be discordant for the particular trait or phenotype excluding those resulting from known confounders. Such discordant monozygotic twin pairs are rare and very few studies have explored the potential usefulness of this approach. Results We studied genome-wide gene expression in primary osteoblast-like culture from marrow aspirates obtained from three pairs of monozygotic twins. We used the latest Affymetrix microchip contains probe sets for more than 20,000 genes. Two pairs were discordant for bone mineral density at the hip by more than one standard deviation, and the third pair was unrelated concordant and used as control. Only 1.5% on average of genes showed variation in expression within pairs as compared to 5% between pairs or over 15% from the literature. Importantly we identified several groups of genes showing variations within the discordant pairs and not within the concordant pair such as chondroitin beta 1,4 N-acetylgalactosaminyltransferase, inhibin beta A, interleukin 1 beta and colony stimulating factor 1 macrophage. These genes are known to have potential roles in bone physiology relating to bone density, osteoporosis and osteoarthritis. Conclusion Using the example of osteoblast-like cells in our monozygotic discordant twins for osteoporosis, we identified genes showing differential expression. Although without further experiment, we cannot confirm or conclude these are genes definitely related to bone physiology, we believe we have shown the potential and cost-effectiveness of further gene expression studies in discordant monozygotic twin pairs. A replication study for confirmation is essential.
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Affiliation(s)
- Ying T Mak
- Twin Research and Genetic Epidemiology Unit, St. Thomas' Hospital, London SE1 7EH, United Kingdom
| | - Geeta Hampson
- Department of Chemical Pathology, St. Thomas' Hospital, London SE1 7EH, United Kingdom
| | - Jon N Beresford
- Department of Pharmacy and Pharmacology, Claverton Campus, University of Bath, Bath BA2 7AY, United Kingdom
| | - Tim D Spector
- Twin Research and Genetic Epidemiology Unit, St. Thomas' Hospital, London SE1 7EH, United Kingdom
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Abstract
Studies using dual-energy X-ray absorptiometry have suggested a high prevalence of osteoporosis in inflammatory bowel disease. However, population-based data on fracture incidence suggest only a small increased risk of fracture amongst patients with inflammatory bowel disease compared with the general population. Therefore, it would be helpful to identify patients with inflammatory bowel disease at particularly high risk for fracture so that these risks might be modified or interventions might be undertaken. The data on calcium intake as a predictor of bone mineral density are conflicting. Although there are data suggesting that a one-time survey to determine current calcium intake will not help to predict bone mineral density in inflammatory bowel disease, persistently reduced calcium intake does appear to lead to lower bone mineral density. In the general population, body mass is strongly correlated with bone mineral density, which also appears to be true in Crohn's disease. Hence, subjects with inflammatory bowel disease and considerable weight loss, or who are obviously malnourished, could be considered for bone mineral density testing, and the finding of a low bone mineral density would suggest the need for more aggressive nutritional support. Although vitamin D is undoubtedly important in bone health, vitamin D intake and serum vitamin D levels do not correlate well with bone mineral density. Sex hormone deficiency can also adversely affect bone health, although a well-developed strategy for sex hormone measurements in patients with inflammatory bowel disease remains to be established. Ultimately, the determination of genetic mutations that accurately predict fracture susceptibility may be the best hope for developing a simplified strategy for managing bone health in inflammatory bowel disease. The therapy of osteoporosis in inflammatory bowel disease has been adapted from other osteoporosis settings, such as post-menopausal or corticosteroid-induced osteoporosis. To date, there remains no therapy proven to be efficacious in inflammatory bowel disease-related osteoporosis; however, calcium and vitamin D supplementation and bisphosphonates have their roles.
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Affiliation(s)
- C N Bernstein
- University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, and Manitoba Osteoporosis Programme, Winnipeg, Man., Canada.
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42
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Klein GL. Glucocorticoid-induced bone loss in children. Clin Rev Bone Miner Metab 2004. [DOI: 10.1007/s12018-004-0011-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Koivurova OP, Karhukorpi JMJ, Joensuu ET, Koistinen PO, Valtonen JM, Karttunen TJ, Niemelä SE, Karttunen RA. IL-1 RN 2/2 genotype and simultaneous carriage of genotypes IL-1 RN 2/2 and IL-1beta-511 T/T associated with oesophagitis in Helicobacter pylori-negative patients. Scand J Gastroenterol 2003; 38:1217-22. [PMID: 14750640 DOI: 10.1080/00365520310006504] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Interleukin-1 receptor antagonist genotype 2/2 is associated with a prolonged and enhanced inflammatory response. It is suspected of being a risk factor for atrophic gastritis and gastric cancer and for some autoimmune diseases. No specific genetic risk factors for oesophagitis have been identified so far and there are no reports of IL-1 polymorphism in relation to oesophageal disease. METHODS We studied the IL-1RN, IL-1beta-511 and IL-1beta + 3953 polymorphisms in an unselected series of 142 adult patients scheduled for gastrointestinal endoscopy because of dyspepsia. The control group consisted of university staff and students (n = 179). Helicobacter pylori status was determined by antibody testing and bacterial detection. RESULTS Endoscopic oesophagitis was noted in 40 patients. The IL-1RN 2/2 genotype was significantly more prevalent in the patients with H. pylori-negative oesophagitis than in the control subjects (27% versus 9%; OR 3.574, CI 1.23-10.35, P = 0.034) or in the dyspeptic patients (27% versus 7%; OR 5.089. CI 1.51-17.11, P = 0.009). IL-1beta-511 T/T genotype tended to be more frequent in the H. pylori-negative patients with oesophagitis than in the control subjects (P = 0.071). The strongest association was between the simultaneous carriage of genotypes IL-1RN 2/2 and IL-1beta -511 T/T and H. pylori-negative oesophagitis. where the combined genotype was more prevalent than in the control subjects (23% versus 6%; OR 4.492, CI 1.40-14.46, P = 0.012) or the dyspeptic patients without oesophagitis (23% versus 3%: OR 9.706. CI 2.12-44.42, P = 0.003). CONCLUSIONS The results indicate that the IL-1RN 2/2 genotype and the carriage of combined genotypes IL-1RN 2/2 + IL-1beta-511 T/T are associated with H. pylori-negative oesophagitis. This is the first report on the association between IL-1 gene polymorphism and oesophagitis.
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Affiliation(s)
- O P Koivurova
- Dept. of Internal Medicine, Oulu University Hospital, Oulu, Finland.
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Mamula P, Markowitz JE, Baldassano RN. Inflammatory bowel disease in early childhood and adolescence: special considerations. Gastroenterol Clin North Am 2003; 32:967-95, viii. [PMID: 14562584 DOI: 10.1016/s0889-8553(03)00046-3] [Citation(s) in RCA: 126] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Several aspects of IBD overlap between pediatric and adult population. Those include nutritional issues, bone density, and medical and surgical therapies. Some aspects like natural course of the disease, and epidemiology and genetics are more easily examined and researched in the pediatric population. Others like pubertal and growth delay, and transition of health care are unique to pediatric patients. This article examines some of the similarities, as well as differences of IBD in these two populations.
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Affiliation(s)
- Petar Mamula
- University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
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Zheng CQ, Hu GZ, Zeng ZS, Lin LJ, Gu GG. Progress in searching for susceptibility gene for inflammatory bowel disease by positional cloning. World J Gastroenterol 2003; 9:1646-56. [PMID: 12918095 PMCID: PMC4611518 DOI: 10.3748/wjg.v9.i8.1646] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) includes two clinical subtypes: Crohn disease (CD) and ulcerative colitis (UC). The general prevalence is about 1.0%-2.0% in Western countries. It is predominantly regarded as a multifactorial disorder involving environmental factors and polygenic defects. The view was confirmed by a lot of evidences from clinical attributions and animal models, especially from epidemiological investigations. So the etiological study of IBD has been focused on searching for susceptibility genes by positional cloning, which consists of two steps: linkage analysis and association analysis. Linkage analysis has been an important method of searching for susceptibility genes to polygenic diseases as well as single-gene disorders. IBD, as a polygenic disease, has been widely investigated by linkage analysis for susceptibility gene since 1996. The paper reviewed 38 articles, which covered almost all original researches in relation to IBD and linkage analysis. So far, several loci, such as 16q, 12q, 6p and 3p, have been identified by the studies. The most striking is 16q12 (IBD1), which linked only with CD not UC in the majority of studies. Association analysis, as one essential step for positional cloning, is usually carried out by genotyping candidate genes selected by means of linkage analysis or other methods, for figuring out the frequencies of alleles and comparing the frequencies between IBD group and healthy control group to identify the specific allele. It has been established that IBD is implicated in immune disorder. So the studies were centered on the genes of NOD2/CARD15, HLA-II, cytokine, cytokine receptor and adhesion molecule. This paper reviewed 14 original articles on association between NOD2 and IBD that have been published since 2001. All results, with the exception of one report from a Japanese group, provide evidences that the three kinds of variants of NOD2 are susceptibility factors for IBD. This article also comprehensively analyzed 18 original researches of HLA gene polymorphism in IBD. We found extensive discrepancy among the conclusions and a novel hypothesis was put forward to explain the discordance. Most studies published recently on association between IBD and cytokine gene polymorphism were reviewed.
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Affiliation(s)
- Chang-Qing Zheng
- Department of Gastroenterology, the Second Affiliated Clinical College of China Medical University, Shenyang 110001, Liaoning Province, China.
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Lamb EJ, Wong T, Smith DJ, Simpson DE, Coakley AJ, Moniz C, Muller AF. Metabolic bone disease is present at diagnosis in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16:1895-902. [PMID: 12390098 DOI: 10.1046/j.1365-2036.2002.01363.x] [Citation(s) in RCA: 63] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
AIM To establish whether bone disease is present at diagnosis in inflammatory bowel disease and to identify contributory metabolic abnormalities. METHODS Newly diagnosed patients with inflammatory bowel disease (19 males, 15 females; mean age, 44 years; range, 17-79 years; 23 ulcerative colitis, 11 Crohn's disease) were compared against standard reference ranges and a control group with irritable bowel syndrome (eight males, 10 females; mean age, 40 years; range, 19-64 years). Bone mineral density (g/cm2, dual-energy X-ray absorptiometry: lumbar spine and femoral neck) and biochemical bone markers were measured. RESULTS Femoral neck bone mineral density, T- and Z-scores (mean +/- s.d., respectively) were lower in inflammatory bowel disease patients than in irritable bowel syndrome controls (0.78 +/- 0.12 vs. 0.90 +/- 0.16, P = 0.0046; - 0.88 +/- 0.92 vs. 0.12 +/- 1.17, P = 0.0018; - 0.30 +/- 0.89 vs. 0.61 +/- 1.10, P = 0.0030). Lumbar spine bone mineral density and T-scores were also significantly lower in patients than controls (0.98 +/- 0.15 vs. 1.08 +/- 0.13, P = 0.0342; - 1.05 +/- 1.39 vs. - 0.14 +/- 1.19, P = 0.0304). Compared with controls, the urinary deoxypyridinoline : creatinine ratio was increased (7.66 vs. 5.70 nmol/mmol, P = 0.0163) and serum 25-hydroxy vitamin D was decreased (18.7 vs. 28.5 micro g/L, P = 0.0016); plasma osteocalcin and serum parathyroid hormone did not differ (P > 0.05). CONCLUSIONS The bone mineral density is reduced at diagnosis, prior to corticosteroid treatment, in both Crohn's disease and ulcerative colitis. Our data suggest that this is attributable to increased resorption rather than decreased bone formation.
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Affiliation(s)
- E J Lamb
- Department of Clinical Biochemistry, East Kent Hospitals NHS Trust, Kent, UK.
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Loftus EV, Crowson CS, Sandborn WJ, Tremaine WJ, O'Fallon WM, Melton LJ. Long-term fracture risk in patients with Crohn's disease: a population-based study in Olmsted County, Minnesota. Gastroenterology 2002; 123:468-75. [PMID: 12145800 DOI: 10.1053/gast.2002.34779] [Citation(s) in RCA: 131] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Osteoporosis is common in patients with Crohn's disease, but less is known about their risk of actual fractures. METHODS The medical records of all 238 Olmsted County, Minnesota, residents diagnosed with Crohn's disease between 1940 and 1993 were reviewed for evidence of subsequent fractures compared with a control group of county residents matched by age and sex. The risk ratio of fracture in patients relative to controls was estimated using the Cox proportional hazards regression model. The cumulative incidence of fracture following diagnosis was estimated using the Kaplan-Meier method. RESULTS Sixty-three patients had 117 different fractures. The cumulative incidence of any fracture from the time of diagnosis onward was 36% at 20 years versus 32% in controls (P = 0.792). Compared with controls, the overall risk ratio for any fracture was 0.9 (95% confidence interval [CI], 0.6-1.4), whereas the relative risk for an osteoporotic fracture was 1.4 (95% CI, 0.7-2.7). The risk ratio for thoracolumbar vertebral fracture was 2.2 (95% CI, 0.9-5.5). Cox proportional hazards regression identified only age as a significant clinical predictor of fracture risk (hazard ratio per 10-year increase in age, 1.3; 95% CI, 1.1-1.5). Specifically, use of corticosteroids and surgical resection did not predict risk of fracture among these unselected patients with Crohn's disease from the community. CONCLUSIONS In this population-based inception cohort of patients with Crohn's disease, the risk of fracture was not elevated relative to age- and sex-matched controls.
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Affiliation(s)
- Edward V Loftus
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
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Griffin WST, Mrak RE. Interleukin‐1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer’s disease. J Leukoc Biol 2002. [DOI: 10.1189/jlb.72.2.233] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- W. Sue T. Griffin
- Department of Geriatrics, Medicine, and Psychiatry, Veterans Affairs Medical Center, Little Rock
- Department of Geriatric and Mental Health Research Education and Clinical Centers, Veterans Affairs Medical Center, Little Rock
| | - Robert E. Mrak
- Department of Pathology, University of Arkansas for Medical Sciences, Veterans Affairs Medical Center, Little Rock
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Griffin WST, Mrak RE. Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease. J Leukoc Biol 2002; 72:233-8. [PMID: 12149413 PMCID: PMC3835694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2023] Open
Abstract
Interleukin-1 (IL-1), a key molecule in systemic immune responses in health and disease, has analogous roles in the brain where it may contribute to neuronal degeneration. Numerous findings suggest that this is the case. For example, IL-1 overexpression in the brain of Alzheimer patients relates directly to the development and progression of the cardinal neuropathological changes of Alzheimer's disease, i.e., the genesis and accumulation of beta-amyloid (Abeta) plaques and the formation and accumulation of neurofibrillary tangles in neurons, both of which contribute to neuronal dysfunction and demise. Several genetic studies show that inheritance of a specific IL-1A gene polymorphism increases risk for development of Alzheimer's disease by as much as sixfold. Moreover, this increased risk is associated with earlier age of onset of the disease. Homozygosity for this polymorphism in combination with another in the IL-1B gene further increases risk.
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Affiliation(s)
- W Sue T Griffin
- Department of Geriatrics, Medicine, and Psychiatry, University of Arkansas for Medical Sciences, Veterans Affairs Medical Center, Little Rock, USA.
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Yamada Y, Ando F, Niino N, Shimokata H. Association of a polymorphism of the CC chemokine receptor-2 gene with bone mineral density. Genomics 2002; 80:8-12. [PMID: 12079277 DOI: 10.1006/geno.2002.6793] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The possible association of the 190G-->A (Val64Ile) polymorphism of the CC chemokine receptor-2 gene (CCR2) with bone mineral density (BMD) was examined in 2215 subjects (1125 men, 1090 women), all of whom were community-dwelling individuals aged 40 to 79 years. Among men aged < 60 years, BMD for the distal radius, lumbar spine, or Ward's triangle was significantly greater in those with the AA genotype than in those with the GG or GA genotypes. For postmenopausal women, BMD for the distal radius or femoral neck was significantly greater in those with the AA genotype than in those with the GG or GA genotypes. In contrast, for men aged > or =60 years and for premenopausal women, BMD was not associated with the CCR2 genotype. These results suggest that CCR2 may be a new candidate for a susceptibility locus for bone mass in middle-aged men and postmenopausal women.
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Affiliation(s)
- Yoshiji Yamada
- Department of Gene Therapy, Gifu International Institute of Biotechnology and Institute of Applied Biochemistry, Mitake, Gifu, 505-0116, Japan.
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