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Di Brina ALP, Palmieri O, Cannarozzi AL, Tavano F, Guerra M, Bossa F, Gentile M, Merla A, Biscaglia G, Cuttitta A, Perri F, Latiano A. Focus on Achalasia in the Omics Era. Int J Mol Sci 2024; 25:10148. [PMID: 39337632 PMCID: PMC11431880 DOI: 10.3390/ijms251810148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/17/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Achalasia is a rare and complex esophageal disease of unknown etiology characterized by difficulty in swallowing due to the lack of opening of the lower esophageal sphincter and the absence of esophageal peristalsis. Recent advancements in technology for analyzing DNA, RNA and biomolecules in high-throughput techniques are offering new opportunities to better understand the etiology and the pathogenetic mechanisms underlying achalasia. Through this narrative review of the scientific literature, we aim to provide a comprehensive assessment of the state-of-the-art knowledge on omics of achalasia, with particular attention to those considered relevant to the pathogenesis of the disease. The notion and importance of the multi-omics approach, its limitations and future directions are also introduced, and it is highlighted how the integration of single omics data will lead to new insights into the development of achalasia and offer clinical tools which will allow early diagnosis and better patient management.
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Affiliation(s)
- Anna Laura Pia Di Brina
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Orazio Palmieri
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Anna Lucia Cannarozzi
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Francesca Tavano
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Maria Guerra
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Fabrizio Bossa
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Marco Gentile
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Antonio Merla
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Giuseppe Biscaglia
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Antonello Cuttitta
- Unit of Thoracic Surgery, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - Francesco Perri
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Anna Latiano
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
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Savarino EV, Salvador R, Ghisa M, Mari A, Forattini F, Costantini A, De Giorgio R, Zaninotto G. Research gap in esophageal achalasia: a narrative review. Dis Esophagus 2024; 37:doae024. [PMID: 38525929 DOI: 10.1093/dote/doae024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 03/08/2024] [Indexed: 03/26/2024]
Abstract
In recent years, new translational evidence, diagnostic techniques, and innovative therapies have shed new light on esophageal achalasia and revamped the attention on this relatively rare motility disorder. This narrative review aims to highlight the most recent progress and the areas where further research is needed. The four senior authors identified five topics commonly discussed in achalasia management: i.e. pathogenesis, role of functional lumen imaging probe in the diagnostic flow chart of achalasia, how to define the outcome of achalasia treatments, how to manage persistent chest pain after the treatment, and if achalasia patients' may benefit from a regular follow-up. We searched the bibliographic databases to identify systematic reviews, meta-analyses, randomized control trials, and original research articles in English up to December 2023. We provide a summary with the most recent findings in each of the five topics and the critical points where to address future research, such as the immune-genetic patterns of achalasia that might explain the transition among the different phenotypes, the need for a validated clinical definition of treatment success, the use of neuromodulators to manage chest pain, and the need for identifying achalasia patients at risk for cancer and who may benefit of long-term follow-up. Although undoubtedly, progress has been made on the definition and management of achalasia, unmet needs remain. Debated aspects range from mechanistic insights, symptoms, objective measure relationships, and accurate clinical responses to therapeutic interventions. Translational research is eagerly awaited to answer these unresolved questions.
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Affiliation(s)
- Edoardo Vincenzo Savarino
- Gastroenterology Unit, Azienda Ospedale Università of Padua, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Renato Salvador
- Chirurgia Generale 1, Azienda Ospedale Università of Padua, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Matteo Ghisa
- Gastroenterology Unit, Azienda Ospedale Università of Padua, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Amir Mari
- Gastroenterology Unit, Nazareth Hospital EMMS, The Azrieli Faculty of Medicine, Bar-Ilan University, Tel Aviv, Israel
| | - Francesca Forattini
- Chirurgia Generale 1, Azienda Ospedale Università of Padua, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Andrea Costantini
- Chirurgia Generale 1, Azienda Ospedale Università of Padua, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Roberto De Giorgio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
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Chanpong A, Alves MM, Bonora E, De Giorgio R, Thapar N. Evaluating the molecular and genetic mechanisms underlying gut motility disorders. Expert Rev Gastroenterol Hepatol 2023; 17:1301-1312. [PMID: 38117595 DOI: 10.1080/17474124.2023.2296558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 12/14/2023] [Indexed: 12/22/2023]
Abstract
INTRODUCTION Gastrointestinal (GI) motility disorders comprise a wide range of different diseases affecting the structural or functional integrity of the GI neuromusculature. Their clinical presentation and burden of disease depends on the predominant location and extent of gut involvement as well as the component of the gut neuromusculature affected. AREAS COVERED A comprehensive literature review was conducted using the PubMed and Medline databases to identify articles related to GI motility and functional disorders, published between 2016 and 2023. In this article, we highlight the current knowledge of molecular and genetic mechanisms underlying GI dysmotility, including disorders of gut-brain interaction, which involve both GI motor and sensory disturbance. EXPERT OPINION Although the pathophysiology and molecular mechanisms underlying many such disorders remain unclear, recent advances in the assessment of intestinal tissue samples, genetic testing with the application of 'omics' technologies and the use of animal models will provide better insights into disease pathogenesis as well as opportunities to improve therapy.
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Affiliation(s)
- Atchariya Chanpong
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
- Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK
| | - Maria M Alves
- Department of Clinical Genetics, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Elena Bonora
- Department of Medical and Surgical Sciences, DIMEC, University of Bologna, Bologna, Italy
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, AOUB, Bologna, Italy
| | - Roberto De Giorgio
- Department of Translational Sciences, University of Ferrara, Ferrara, Italy
| | - Nikhil Thapar
- Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK
- Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Australia
- School of Medicine, University of Queensland, Brisbane, Australia
- Woolworths Centre for Child Nutrition Research, Queensland University of Technology, Brisbane, Australia
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Abstract
Idiopathic achalasia is a motility disorder affecting the lower esophageal sphincter. Dysphagia is a hallmark symptom, but patients may exhibit other symptoms. The aim of this review is to compare achalasia symptoms globally. PubMed and Google Scholar were filtered from 1952–2021 with the search terms achalasia, epidemiology, diet, countries, and genetics. A total of 14 articles addressed demographics, symptom profiles, genetics, and diagnosis criteria amongst 2463 patients. Data on countries’ climate and diet were obtained through Arc Geographic Information System (GIS) and Our World in Data. Countries were grouped by similar climate zones and diets. Achalasia symptoms varied by region. In West Africa, patients exhibit parotid swelling, anemia, and dehydration; diminished appetite in East Asia; dysphagia and weight loss in West Asia and Europe; respiratory symptoms, reflux, and retrosternal pain in North America; and vomiting in Southern Asia. Weighted percentages of dietary oils/fats were (24.3%) in North America, Western Asia (17.8%); Europe (17.7%); East Asia (17.6%); West Africa (14.7%); Southern Asia (13.8%); North Africa (12.4%); Northeast Africa (10.1%). Conditions such as Down Syndrome and Triple A syndrome are associated with achalasia. There was no correlation for achalasia presentation and climate zones. Achalasia symptoms are likely multifactorial. Diet, genetics, and environmental factors may play significant roles.
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Li Q, Chen W, Wang C, Liu Z, Gu Y, Xu X, Xu J, Jiang T, Xu M, Wang Y, Chen C, Zhong Y, Zhang Y, Yao L, Jin G, Hu Z, Zhou P. Whole-exome sequencing reveals common and rare variants in immunologic and neurological genes implicated in achalasia. Am J Hum Genet 2021; 108:1478-1487. [PMID: 34197731 DOI: 10.1016/j.ajhg.2021.06.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 06/02/2021] [Indexed: 11/15/2022] Open
Abstract
Idiopathic achalasia (IA) is a severe motility disorder characterized by neuronal degeneration in the myenteric plexus, but the etiology remains largely unknown. We performed whole-exome sequencing (WES) in 100 IA-affected individuals and 313 non-IA control subjects and validated the results in 230 IA-affected individuals and 1,760 non-IA control subjects. Common missense variants rs1705003 (CUTA, GenBank: NC_000006.11:g.33385953A>G) and rs1126511 (HLA-DPB1, GenBank: NC_000006.11:g.33048466G>T) at 6p21.32 were reproducibly associated with increased risk of IA (rs1126511: OR = 1.83, p = 2.34 × 10-9; rs1705003: OR = 2.37, p = 3.21 × 10-7), meeting exome-wide significance. Both variants can affect the expression of their target genes at the transcript level. An array-based association analysis in 280 affected individuals and 1,121 control subjects determined the same signal at 6p21.32. Further conditional analyses supported that the two missense variants identified in WES-based association study were potential causal variants of IA. For rare variants, the top genes identified by gene-based analysis were significantly enriched in nerve and muscle phenotypic genes in the mouse. Moreover, the functional rare variants in these genes tended to cooccur in IA-affected individuals. In an independent cohort, we successfully validated three rare variants (CREB5, GenBank: NC_000007.13:g.28848865G>T; ESYT3, GenBank: NC_000003.11:g.138183253C>T; and LPIN1, GenBank: NC_000002.11:g.11925128A>G) which heightens the risk of developing IA. Our study identified and validated two common variants and three rare variants associated with IA in immunologic and neurological genes, providing new insight into the etiology of IA.
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Affiliation(s)
- Quanlin Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Weifeng Chen
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Cheng Wang
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211116, China
| | - Zuqiang Liu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yayun Gu
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Xiaoyue Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jiaxing Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Tao Jiang
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Meidong Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yifeng Wang
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Congcong Chen
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Yunshi Zhong
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yiqun Zhang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liqing Yao
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Guangfu Jin
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China.
| | - Pinghong Zhou
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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GHOLIPOUR M, MIKAELI J, MOWLA SJ, BAKHTIARIZADEH MR, SAGHAEIAN JAZI M, JAVID N, FAZLOLLAHI N, KHOSHNIA M, BEHNAMPOUR N, MORADI A. Identification of differentially expressed microRNAs in primary esophageal achalasia by next-generation sequencing. Turk J Biol 2021; 45:262-274. [PMID: 34377051 PMCID: PMC8313935 DOI: 10.3906/biy-2101-61] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/08/2021] [Indexed: 11/29/2022] Open
Abstract
Molecular knowledge regarding the primary esophageal achalasia is essential for the early diagnosis and treatment of this neurodegenerative motility disorder. Therefore, there is a need to find the main microRNAs (miRNAs) contributing to the mechanisms of achalasia. This study was conducted to determine some patterns of deregulated miRNAs in achalasia. This case-control study was performed on 52 patients with achalasia and 50 nonachalasia controls. The miRNA expression profiling was conducted on the esophageal tissue samples using the next-generation sequencing (NGS). Differential expression of miRNAs was analyzed by the edgeR software. The selected dysregulated miRNAs were additionally confirmed using the quantitative reverse transcription polymerase chain reaction (qRT-PCR). Fifteen miRNAs were identified that were significantly altered in the tissues of the patients with achalasia. Among them, three miRNAs including miR-133a-5p, miR-143-3p, and miR-6507-5p were upregulated. Also, six miRNAs including miR-215-5p, miR-216a-5p, miR-216b-5p, miR-217, miR-7641 and miR-194-5p were downregulated significantly. The predicted targets for the dysregulated miRNAs showed significant disease-associated pathways like neuronal cell apoptosis, neuromuscular balance, nerve growth factor signaling, and immune response regulation. Further analysis using qRT-PCR showed significant down-regulation of hsa-miR-217 (p-value = 0.004) in achalasia tissue. Our results may serve as a basis for more future functional studies to investigate the role of candidate miRNAs in the etiology of achalasia and their application in the diagnosis and probably treatment of the disease.
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Affiliation(s)
- Mahin GHOLIPOUR
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, GorganIran
| | - Javad MIKAELI
- Autoimmune and Motility Disorders Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, TehranIran
| | - Seyed Javad MOWLA
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, TehranIran
| | | | - Marie SAGHAEIAN JAZI
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, GorganIran
| | - Naeme JAVID
- Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, GorganIran
| | - Narges FAZLOLLAHI
- Autoimmune and Motility Disorders Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, TehranIran
| | - Masoud KHOSHNIA
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, GorganIran
| | - Naser BEHNAMPOUR
- Department of Biostatistics, Faculty of Health, Golestan University of Medical Sciences, GorganIran
| | - Abdolvahab MORADI
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, GorganIran
- Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, GorganIran
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Hoefsmit EP, Rozeman EA, Haanen JBAG, Blank CU. Susceptible loci associated with autoimmune disease as potential biomarkers for checkpoint inhibitor-induced immune-related adverse events. ESMO Open 2019; 4:e000472. [PMID: 31423333 PMCID: PMC6677983 DOI: 10.1136/esmoopen-2018-000472] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 03/01/2019] [Accepted: 03/19/2019] [Indexed: 12/13/2022] Open
Abstract
Unprecedented successes regarding cancer immunotherapy have been achieved, in which therapeutic agents are used to target immune cells rather than cancer cells. The most effective immunotherapy to date is the group of immune checkpoint inhibitors (CPI), targeting, for example, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death protein (PD-1). TThe combination of these therapies (anti-PD-1 with anti-CTLA-4) induces high response rates, and seem to be increased further when applied in early-stage disease. However, combined CTLA-4 plus PD-1 blockade causes frequent high-grade immune-related adverse events (irAE). To date, research on biological mechanism of irAEs is scarce and no widely accepted biomarkers predicting onset of severe irAEs have been identified. The similarity of irAEs to autoimmune disorders fuels the hypothesis that irAEs may be linked to susceptible genetic loci related to various autoimmune diseases. In this review, we extensively searched for susceptible loci associated with various autoimmune diseases, and pooled them in groups most likely to be associated with CPI-induced irAEs. These sets could be used in future research on predicting irAEs and guide physicians in a more refined and personal manner.
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Affiliation(s)
- Esmée P Hoefsmit
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Elisa A Rozeman
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Medical Oncology Department, Netherlands Cancer Institute-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands
| | - John B A G Haanen
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Medical Oncology Department, Netherlands Cancer Institute-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands
| | - Christian U Blank
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Medical Oncology Department, Netherlands Cancer Institute-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands
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Busch A, Žarković M, Lowe C, Jankofsky M, Ganschow R, Buers I, Kurth I, Reutter H, Rutsch F, Hübner CA. Mutations in CRLF1 cause familial achalasia. Clin Genet 2017; 92:104-108. [PMID: 27976805 DOI: 10.1111/cge.12953] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 12/06/2016] [Accepted: 12/07/2016] [Indexed: 12/14/2022]
Abstract
We here report a family from Libya with three siblings suffering from early onset achalasia born to healthy parents. We analyzed roughly 5000 disease-associated genes by a next-generation sequencing (NGS) approach. In the analyzed sibling we identified two heterozygous variants in CRLF1 (cytokine receptor-like factor 1). Mutations in CRLF1 have been associated with autosomal recessive Crisponi or cold-induced sweating syndrome type 1 (CS/CISS1), which among other symptoms also manifests with early onset feeding difficulties. Segregation analysis revealed compound heterozygosity for all affected siblings, while the unaffected mother carried the c.713dupC (p.Pro239Alafs*91) and the unaffected father carried the c.178T>A (p.Cys60Ser) variant. The c.713dupC variant has already been reported in affected CS/CISS1 patients, the pathogenicity of the c.178T>A variant was unclear. As reported previously for pathogenic CRLF1 variants, cytokine receptor-like factor 1 protein secretion from cells transfected with the c.178T>A variant was severely impaired. From these results we conclude that one should consider a CRLF1-related disorder in early onset achalasia even if other CS/CISS1 related symptoms are missing.
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Affiliation(s)
- A Busch
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - M Žarković
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - C Lowe
- Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany
| | - M Jankofsky
- Clinic of General Pediatrics, University Hospital Bonn, Bonn, Germany
| | - R Ganschow
- Clinic of General Pediatrics, University Hospital Bonn, Bonn, Germany
| | - I Buers
- Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany
| | - I Kurth
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - H Reutter
- Department of Neonatology and Pediatric Intensive Care, University Hospital Bonn, Bonn, Germany.,Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - F Rutsch
- Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany
| | - C A Hübner
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
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Abstract
This review examines the etiology and pathogenesis of idiopathic achalasia. This disease is clinically characterized by dysphagia of solids and liquids due to the presence of simultaneous or absent esophageal contractions and impaired or absent relaxation of the lower esophageal sphincter. It includes a review of (a) etiology and pathogenesis of this inflammatory process that damage the ganglion cells of the Auerbach plexus that is limited to the esophagus; (b) genetic abnormalities and polymorphisms associated with this disease that may help explain its heterogeneity expressed by the different motility abnormalities of its phenotypes as well as differences in its clinical progression. These different genetic abnormalities may be responsible for the slow progression of types I or II phenotypes; (c) indirect evidence of viruses present in these patients that may initiate its development; (d) the abnormalities of the muscle layer that may be responsible for the dilation of the body of the esophagus that ultimately causes the sigmoid-like esophagus in the very last phase of this disease. This progression to the end-stage phase tends to occur in about 5% of patients. And, (e) the chronic inflammatory abnormalities in the squamous mucosa that may be the cause of the dysplastic and neoplastic changes that may lead to squamous cell carcinoma whose incidence in this disease is increased. These mucosal abnormalities are usually present in patients with markedly dilated body of the esophagus and severe food stasis.
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Sarnelli G, Grosso M, Palumbo I, Pesce M, D’Alessandro A, Zaninotto G, Annese V, Petruzzelli R, Izzo P, Sepulveres R, Bruzzese D, Esposito G, Cuomo R. Allele-specific transcriptional activity of the variable number of tandem repeats of the inducible nitric oxide synthase gene is associated with idiopathic achalasia. United European Gastroenterol J 2017; 5:200-207. [PMID: 28344787 PMCID: PMC5349359 DOI: 10.1177/2050640616648870] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 04/15/2016] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Polymorphisms of genes involved in the regulation of the immune response are risk factors for achalasia, but their contribution to disease pathogenesis is unknown. Nitric oxide is involved both in immune function and inhibitory neurotransmission. OBJECTIVE The objective of this article is to assess the association and the functional relevance of the CCTTT-inducible nitric oxide synthase (NOS2) gene promoter polymorphism in achalasia. METHODS Genomic DNA was isolated from 181 achalasia patients and 220 controls. Genotyping of the (CCTTT)n repeats was performed by PCR and capillary electrophoresis, and data analyzed by considering the frequency of the different alleles. HT29 cells were transfected with iNOS luciferase promoter-reporter plasmids containing different (CCTTT)n. RESULTS The alleles' distribution ranged from 7 to 18, with a peak frequency at 12 repeats. Analysis of the allele frequencies revealed that individuals carrying 10 and 13 CCTTT repeats were respectively less and more frequent in achalasia (OR 0.5, 95% CI 0.3-0.5 and OR 1.6, 95% CI 1-2.4, all p < 0.05). Long repeats were also significantly associated with an earlier onset of the disease (OR 1.69, 95% CI 1.13-2.53, p = 0.01). Transfection experiments revealed a similar allele-specific iNOS transcriptional activity. CONCLUSION The functional polymorphism (CCTTT) of NOS2 promoter is associated with achalasia, likely by an allele-specific modulation of nitric oxide production.
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Affiliation(s)
- Giovanni Sarnelli
- Gastroenterology Unit, Department of
Clinical Medicine and Surgery University Federico II, Naples, Italy
| | - Michela Grosso
- Department of Biochemistry and Medical
Biotechnology, University Federico II, Naples, Italy
| | - Ilaria Palumbo
- Gastroenterology Unit, Department of
Clinical Medicine and Surgery University Federico II, Naples, Italy
| | - Marcella Pesce
- Gastroenterology Unit, Department of
Clinical Medicine and Surgery University Federico II, Naples, Italy
| | - Alessandra D’Alessandro
- Gastroenterology Unit, Department of
Clinical Medicine and Surgery University Federico II, Naples, Italy
| | - Giovanni Zaninotto
- Imperial College-St Mary’s Hospital,
Department of Academic Surgery, London, UK
| | - Vito Annese
- Unit of Gastroenterology SOD2, Azienda
Ospedaliera Universitaria, Careggi, Firenze, Italy
| | - Raffaella Petruzzelli
- Department of Biochemistry and Medical
Biotechnology, University Federico II, Naples, Italy
| | - Paola Izzo
- Department of Biochemistry and Medical
Biotechnology, University Federico II, Naples, Italy
| | - Rossana Sepulveres
- Department of Biochemistry and Medical
Biotechnology, University Federico II, Naples, Italy
| | - Dario Bruzzese
- Department of Public Health, University
Federico II, Naples, Italy
| | - Giuseppe Esposito
- Department of Physiology and
Pharmacology, “La Sapienza” University of Rome, Italy
| | - Rosario Cuomo
- Gastroenterology Unit, Department of
Clinical Medicine and Surgery University Federico II, Naples, Italy
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11
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Furuzawa-Carballeda J, Torres-Landa S, Valdovinos M&A, Coss-Adame E, Martín del Campo LA, Torres-Villalobos G. New insights into the pathophysiology of achalasia and implications for future treatment. World J Gastroenterol 2016; 22:7892-7907. [PMID: 27672286 PMCID: PMC5028805 DOI: 10.3748/wjg.v22.i35.7892] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 07/06/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
Idiopathic achalasia is an archetype esophageal motor disorder, causing significant impairment of eating ability and reducing quality of life. The pathophysiological underpinnings of this condition are loss of esophageal peristalsis and insufficient relaxation of the lower esophageal sphincter (LES). The clinical manifestations include dysphagia for both solids and liquids, regurgitation of esophageal contents, retrosternal chest pain, cough, aspiration, weight loss and heartburn. Even though idiopathic achalasia was first described more than 300 years ago, researchers are only now beginning to unravel its complex etiology and molecular pathology. The most recent findings indicate an autoimmune component, as suggested by the presence of circulating anti-myenteric plexus autoantibodies, and a genetic predisposition, as suggested by observed correlations with other well-defined genetic syndromes such as Allgrove syndrome and multiple endocrine neoplasia type 2 B syndrome. Viral agents (herpes, varicella zoster) have also been proposed as causative and promoting factors. Unfortunately, the therapeutic approaches available today do not resolve the causes of the disease, and only target the consequential changes to the involved tissues, such as destruction of the LES, rather than restoring or modifying the underlying pathology. New therapies should aim to stop the disease at early stages, thereby preventing the consequential changes from developing and inhibiting permanent damage. This review focuses on the known characteristics of idiopathic achalasia that will help promote understanding its pathogenesis and improve therapeutic management to positively impact the patient’s quality of life.
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12
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Gene expression of muscular and neuronal pathways is cooperatively dysregulated in patients with idiopathic achalasia. Sci Rep 2016; 6:31549. [PMID: 27511445 PMCID: PMC4980661 DOI: 10.1038/srep31549] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 07/11/2016] [Indexed: 02/07/2023] Open
Abstract
Idiopathic achalasia is characterized by the absence of peristalsis secondary to loss of neurons in the myenteric plexus that hampers proper relaxation of the lower esophageal sphincter. Achalasia can be considered a multifactorial disorder as it occurs in related individuals and is associated with HLA class II genes, thereby suggesting genetic influence. We used microarray technology and advanced in-silico functional analyses to perform the first genome-wide expression profiling of mRNA in tissue samples from 12 achalasia and 5 control patients. It revealed 1,728 differentially expressed genes, of these, 837 (48.4%) were up-regulated in cases. In particular, genes participating to the smooth muscle contraction biological function were mostly up-regulated. Functional analysis revealed a significant enrichment of neuronal/muscular and neuronal/immunity processes. Upstream regulatory analysis of 180 genes involved in these processes suggested TLR4 and IL18 as critical key-players. Two functional gene networks were significantly over-represented: one involved in organ morphology, skeletal muscle system development and function, and neurological diseases, and the other participating in cell morphology, humoral immune response and cellular movement. These results highlight on pivotal genes that may play critical roles in neuronal/muscular and neuronal/immunity processes, and that may contribute to the onset and development of achalasia.
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13
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Esposito D, Maione F, D’Alessandro A, Sarnelli G, De Palma GD. Endoscopic treatment of esophageal achalasia. World J Gastrointest Endosc 2016; 8:30-39. [PMID: 26839644 PMCID: PMC4724029 DOI: 10.4253/wjge.v8.i2.30] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Revised: 11/26/2015] [Accepted: 12/13/2015] [Indexed: 02/05/2023] Open
Abstract
Achalasia is a motility disorder of the esophagus characterized by dysphagia, regurgitation of undigested food, chest pain, weight loss and respiratory symptoms. The most common form of achalasia is the idiopathic one. Diagnosis largely relies upon endoscopy, barium swallow study, and high resolution esophageal manometry (HRM). Barium swallow and manometry after treatment are also good predictors of success of treatment as it is the residue symptomatology. Short term improvement in the symptomatology of achalasia can be achieved with medical therapy with calcium channel blockers or endoscopic botulin toxin injection. Even though few patients can be cured with only one treatment and repeat procedure might be needed, long term relief from dysphagia can be obtained in about 90% of cases with either surgical interventions such as laparoscopic Heller myotomy or with endoscopic techniques such pneumatic dilatation or, more recently, with per-oral endoscopic myotomy. Age, sex, and manometric type by HRM are also predictors of responsiveness to treatment. Older patients, females and type II achalasia are better after treatment compared to younger patients, males and type III achalasia. Self-expandable metallic stents are an alternative in patients non responding to conventional therapies.
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14
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Abstract
Idiopathic achalasia is a primary esophageal motor disorder characterized by loss of esophageal peristalsis and insufficient lower esophageal sphincter relaxation in response to deglutition. Patients with achalasia commonly complain of dysphagia to solids and liquids, bland regurgitation often unresponsive to an adequate trial of proton pump inhibitor, and chest pain. Weight loss is present in many, but not all patients. Although the precise etiology is unknown, it is often thought to be either autoimmune, viral immune, or neurodegenerative. The diagnosis is based on history of the disease, barium esophagogram, and esophageal motility testing. Endoscopic assessment of the gastroesophageal junction and gastric cardia is necessary to rule out malignancy. Newer diagnostic modalities such as high resolution manometry help in predicting treatment response in achalasia based on esophageal pressure topography patterns identifying three phenotypes of achalasia (I-III) and outcome studies suggest better treatment response with types I and II compared to type III. Although achalasia cannot be permanently cured, excellent outcomes are achieved in over 90 % of patients. Current medical and surgical therapeutic options (pneumatic dilation, endoscopic and surgical myotomy, and pharmacologic agents) aim at reducing the LES pressure and facilitating esophageal emptying by gravity and hydrostatic pressure of retained food and liquids. Either graded pneumatic dilatation or laparoscopic surgical myotomy with a partial fundoplication are recommended as initial therapy guided by patient age, gender, preference, and local institutional expertise. The prognosis in achalasia patients is excellent. Most patients who are appropriately treated have a normal life expectancy but the disease does recur and the patient may need intermittent treatment.
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Affiliation(s)
| | - Hannah P Kim
- Department of Internal Medicine, Nashville, TN, USA
| | | | - Michael F Vaezi
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA.
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15
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Abstract
Achalasia is a kind of esophageal motility disorder, and it is mainly characterized by loss of the peristalsis of the esophagus during swallowing and insufficient lower esophageal sphincter (LES) relaxation. Primary achalasia is mainly due to the lack of inhibitory nerve fibers in the esophageal myenteric nerve plexus. However, the exact pathogenesis of the disease is still clear. This paper reviews recent progress in understanding the pathogenesis of achalasia.
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16
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Wouters MM, Lambrechts D, Becker J, Cleynen I, Tack J, Vigo AG, Ruiz de León A, Urcelay E, Pérez de la Serna J, Rohof W, Annese V, Latiano A, Palmieri O, Mattheisen M, Mueller M, Lang H, Fumagalli U, Laghi L, Zaninotto G, Cuomo R, Sarnelli G, Nöthen MM, Vermeire S, Knapp M, Gockel I, Schumacher J, Boeckxstaens GE. Genetic variation in the lymphotoxin-α (LTA)/tumour necrosis factor-α (TNFα) locus as a risk factor for idiopathic achalasia. Gut 2014; 63:1401-1409. [PMID: 24259423 DOI: 10.1136/gutjnl-2013-304848] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Idiopathic achalasia is a rare motor disorder of the oesophagus characterised by neuronal loss at the lower oesophageal sphincter. Achalasia is generally accepted as a multifactorial disorder with various genetic and environmental factors being risk-associated. Since genetic factors predisposing to achalasia have been poorly documented, we assessed whether single nucleotide polymorphisms (SNPs) in genes mediating immune response and neuronal function contribute to achalasia susceptibility. METHODS 391 SNPs covering 190 immune and 67 neuronal genes were genotyped in an exploratory cohort from Central Europe (589 achalasia patients, 794 healthy volunteers (HVs)). 24 SNPs (p<0.05) were validated in an Italian (160 achalasia patients, 278 HVs) and Spanish cohort (281 achalasia patients, 296 HVs). 16 SNPs in linkage disequilibrium (LD) with rs1799724 (r(2)>0.2) were genotyped in the exploratory cohort. Genotype distributions of patients (1030) and HVs (1368) were compared using Cochran-Armitage trend test. RESULTS The rs1799724 SNP located between the lymphotoxin-α (LTA) and tumour necrosis factor-α (TNFα) genes was significantly associated with achalasia and withstood correction for testing multiple SNPs (p=1.17E-4, OR=1.41 (1.18 to 1.67)). SNPs in high LD with rs1799724 were associated with achalasia. Three SNPs located in myosin-5B, adrenergic receptor-β-2 and interleukin-13 (IL13) showed nominally significant association to achalasia that was strengthened by replication. CONCLUSIONS Our study provides evidence for rs1799724 at the LTA/TNFα locus as a susceptibility factor for idiopathic achalasia. Additional studies are needed to dissect which genetic variants in the LTA/TNFα locus are disease-causing and confirm other variants as potential susceptibility factors for achalasia.
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Affiliation(s)
- Mira M Wouters
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Diether Lambrechts
- Vesalius Research Center, VIB, Leuven University, Leuven, Belgium Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium
| | - Jessica Becker
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Isabelle Cleynen
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Ana G Vigo
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Antonio Ruiz de León
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Elena Urcelay
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Julio Pérez de la Serna
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Wout Rohof
- Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands
| | - Vito Annese
- Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy Unit of Gastroenterology SOD2, Azienda Ospedaliera Universitaria, Careggi, Firenze, Italy
| | - Anna Latiano
- Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy
| | - Orazio Palmieri
- Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy
| | - Manuel Mattheisen
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany Institute for Genomic Mathematics, University of Bonn, Bonn, Germany Department of Biostatistics, Harvard School of Public Health, Boston, USA
| | - Michaela Mueller
- Department of Gastroenterology, German Clinic of Diagnostics, Wiesbaden, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany
| | - Uberto Fumagalli
- Department of Gastroenterology, Humanitas Clinical and Research Center-Istituto Clinico Humanitas IRCCS, Milan, Italy
| | - Luigi Laghi
- Department of Gastroenterology, Humanitas Clinical and Research Center-Istituto Clinico Humanitas IRCCS, Milan, Italy
| | - Giovanni Zaninotto
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Rosario Cuomo
- Gastroenterology Unit, Department of Clinical and Experimental Medicine, Federico II University, Napoli, Italy
| | - Giovanni Sarnelli
- Gastroenterology Unit, Department of Clinical and Experimental Medicine, Federico II University, Napoli, Italy
| | - Markus M Nöthen
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Séverine Vermeire
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Michael Knapp
- Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
| | - Ines Gockel
- Department of General, Visceral and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany
| | - Johannes Schumacher
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Guy E Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
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17
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Evsyutina YV, Trukhmanov AS, Ivashkin VT. Family case of achalasia cardia: Case report and review of literature. World J Gastroenterol 2014; 20:1114-1118. [PMID: 24574786 PMCID: PMC3921537 DOI: 10.3748/wjg.v20.i4.1114] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Revised: 09/07/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
Achalasia cardia is an idiopathic disease that occurs as a result of inflammation and degeneration of myenteric plexi leading to the loss of postganglionic inhibitory neurons required for relaxation of the lower esophageal sphincter and peristalsis of the esophagus. The main symptoms of achalasia are dysphagia, regurgitation, chest pain and weight loss. At present, there are three main hypotheses regarding etiology of achalasia cardia which are under consideration, these are genetic, infectious and autoimmune. Genetic theory is one of the most widely discussed. Case report given below represents an inheritable case of achalasia cardia which was not diagnosed for a long time in an 81-year-old woman and her 58-year-old daughter.
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18
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Abstract
Achalasia is a rare motility disorder of the oesophagus characterised by loss of enteric neurons leading to absence of peristalsis and impaired relaxation of the lower oesophageal sphincter. Although its cause remains largely unknown, ganglionitis resulting from an aberrant immune response triggered by a viral infection has been proposed to underlie the loss of oesophageal neurons, particularly in genetically susceptible individuals. The subsequent stasis of ingested food not only leads to symptoms of dysphagia, regurgitation, chest pain, and weight loss, but also results in an increased risk of oesophageal carcinoma. At present, pneumatic dilatation and Heller myotomy combined with an anti-reflux procedure are the treatments of choice and have comparable success rates. Per-oral endoscopic myotomy has recently been introduced as a new minimally invasive treatment for achalasia, but there have not yet been any randomised clinical trials comparing this option with pneumatic dilatation and Heller myotomy.
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Affiliation(s)
- Guy E Boeckxstaens
- Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospital Leuven, Catholic University of Leuven, Leuven, Belgium.
| | - Giovanni Zaninotto
- Department of Surgical and Gastroenterological Sciences, University of Padova, UOC General Surgery, Sts Giovanni e Paolo Hospital, Venice, Italy
| | - Joel E Richter
- Division of Digestive Diseases and Nutrition, Joy McCann Culverhouse Center for Esophageal and Swallowing Disorders, University of South Florida Morsani College of Medicine, Tampa, FL, USA
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Sarnelli G, D’Alessandro A, Pesce M, Palumbo I, Cuomo R. Genetic contribution to motility disorders of the upper gastrointestinal tract. World J Gastrointest Pathophysiol 2013; 4:65-73. [PMID: 24244875 PMCID: PMC3829454 DOI: 10.4291/wjgp.v4.i4.65] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 08/09/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023] Open
Abstract
Motility disorders of the upper gastrointestinal tract encompass a wide range of different diseases. Esophageal achalasia and functional dyspepsia are representative disorders of impaired motility of the esophagus and stomach, respectively. In spite of their variable prevalence, what both diseases have in common is poor knowledge of their etiology and pathophysiology. There is some evidence showing that there is a genetic predisposition towards these diseases, especially for achalasia. Many authors have investigated the possible genes involved, stressing the autoimmune or the neurological hypothesis, but there is very little data available. Similarly, studies supporting a post-infective etiology, based on an altered immune response in susceptible individuals, need to be validated. Further association studies can help to explain this complex picture and find new therapeutic targets. The aim of this review is to summarize current knowledge of genetics in motility disorders of the upper gastrointestinal tract, addressing how genetics contributes to the development of achalasia and functional dyspepsia respectively.
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20
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Ghoshal UC, Daschakraborty SB, Singh R. Pathogenesis of achalasia cardia. World J Gastroenterol 2012; 18:3050-7. [PMID: 22791940 PMCID: PMC3386318 DOI: 10.3748/wjg.v18.i24.3050] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2011] [Revised: 10/11/2011] [Accepted: 04/28/2012] [Indexed: 02/06/2023] Open
Abstract
Achalasia cardia is one of the common causes of motor dysphagia. Though the disease was first described more than 300 years ago, exact pathogenesis of this condition still remains enigmatic. Pathophysiologically, achalasia cardia is caused by loss of inhibitory ganglion in the myenteric plexus of the esophagus. In the initial stage, degeneration of inhibitory nerves in the esophagus results in unopposed action of excitatory neurotransmitters such as acetylcholine, resulting in high amplitude non-peristaltic contractions (vigorous achalasia); progressive loss of cholinergic neurons over time results in dilation and low amplitude simultaneous contractions in the esophageal body (classic achalasia). Since the initial description, several studies have attempted to explore initiating agents that may cause the disease, such as viral infection, other environmental factors, autoimmunity, and genetic factors. Though Chagas disease, which mimics achalasia, is caused by an infective agent, available evidence suggests that infection may not be an independent cause of primary achalasia. A genetic basis for achalasia is supported by reports showing occurrence of disease in monozygotic twins, siblings and other first-degree relatives and occurrence in association with other genetic diseases such as Down’s syndrome and Parkinson’s disease. Polymorphisms in genes encoding for nitric oxide synthase, receptors for vasoactive intestinal peptide, interleukin 23 and the ALADIN gene have been reported. However, studies on larger numbers of patients and controls from different ethnic groups are needed before definite conclusions can be obtained. Currently, the disease is believed to be multi-factorial, with autoimmune mechanisms triggered by infection in a genetically predisposed individual leading to degeneration of inhibitory ganglia in the wall of the esophagus.
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Nuñez C, García-González MA, Santiago JL, Benito MS, Mearín F, de la Concha EG, de la Serna JP, de León AR, Urcelay E, Vigo AG. Association of IL10 promoter polymorphisms with idiopathic achalasia. Hum Immunol 2011; 72:749-52. [PMID: 21641950 DOI: 10.1016/j.humimm.2011.05.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2010] [Revised: 04/18/2011] [Accepted: 05/13/2011] [Indexed: 12/21/2022]
Abstract
Idiopathic achalasia is an esophageal motor disorder of unknown etiology. A wealth of evidence supports the concept that achalasia is an immune-mediated disease. According to this evidence, achalasia has been significantly associated with specific alleles of the human leukocyte antigen class II, PTPN22 and IL23R. Several studies have demonstrated association of the IL10 gene with different inflammatory disorders. Our aim was to evaluate the role of functional IL10 promoter polymorphisms in susceptibility to idiopathic achalasia. A case-control study was performed with the -1082, -819, and -592 IL10 promoter polymorphisms in 282 patients and 529 controls and in an independent replication set of 75 patients and 575 controls. The GCC haplotype of the IL10 promoter was reported to be associated with a lower risk of achalasia in the discovery sample (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.64-0.98, p = 0.029). This association was validated in a replication set (OR = 0.69, 95% CI = 0.48-1.00, p = 0.04). In the combined analysis no heterogeneity was observed between the 2 sample sets and the GCC haplotype was significantly associated with the disease (OR(MH) = 0.76, 95% CI = 0.63-0.91, p = 0.003). Our results provide the first evidence for an association between IL10 promoter polymorphisms and idiopathic achalasia, suggesting that the interleukin-10 cytokine may contribute to the pathogenesis of this disease.
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Affiliation(s)
- Concepción Nuñez
- Clinical Immunology Department, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain
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