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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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Wu XY, Liu ZQ, Wang Y, Chen WF, Gao PT, Li QL, Zhou PH. The etiology of achalasia: An immune-dominant disease. J Dig Dis 2021; 22:126-135. [PMID: 33583137 DOI: 10.1111/1751-2980.12973] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 02/06/2023]
Abstract
There is accumulating evidence suggesting that an autoimmune component is involved in esophageal achalasia. An increase in immune cells, cytokines, chemokines, and autoimmune antibodies in serum and infiltration of immune cells in tissues support the view that immune-mediated inflammation is a crucial pathogenesis of inhibitory neuron degeneration in the lower esophageal sphincter. Infection of viruses such as the herpes virus family has been suspected of provoking the autoimmune reaction. Meanwhile, previous reports on immunogenetics have proposed that specific risk alleles on the human leukocyte antigen complex define the susceptible population to achalasia. In this study we reviewed current knowledge regarding the immune-related factors of achalasia, including immunology, viral infection and immunogenetic variations.
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Affiliation(s)
- Xing Yue Wu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical College, Fudan University, Shanghai, China
| | - Zu Qiang Liu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yun Wang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Feng Chen
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ping Ting Gao
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Quan Lin Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ping Hong Zhou
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
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An original Eurasian haplotype, HLA-DRB1*14:54-DQB1*05:03, influences the susceptibility to idiopathic achalasia. PLoS One 2018; 13:e0201676. [PMID: 30092016 PMCID: PMC6084941 DOI: 10.1371/journal.pone.0201676] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 07/19/2018] [Indexed: 01/04/2023] Open
Abstract
Idiopathic achalasia is a relatively infrequent esophageal motor disorder for which major histocompatibility complex (MHC) genes are well-identified risk factors. However, no information about HLA-achalasia susceptibility in Mexicans has previously been reported. We studied a group of 91 patients diagnosed with achalasia and 234 healthy controls with Mexican admixed ancestry. HLA alleles and conserved extended haplotypes were analyzed using high-resolution HLA typing based on Sanger and next-generation sequencing technologies. Admixture estimates were determined using HLA-B and short tandem repeats. Results were analyzed by non-parametric statistical analysis and Bonferroni correction. P-values < 0.05 were considered significant. Patients with achalasia had 56.7% Native American genes, 24.7% European genes, 16.5% African genes and 2.0% Asian genes, which was comparable with the estimates in the controls. Significant increases in the frequencies of alleles DRB1*14:54 and DQB1*05:03 and the extended haplotypes DRB1*14:54-DQB1*05:03 and DRB1*11:01-DQB1*03:01, even after Bonferroni correction (pC<0.05), were found in the achalasia group compared to those in the controls. Concluding, the HLA class II alleles HLA-DRB1*14:54:01 and DQB1*05:03:01 and the extended haplotype are risk factors for achalasia in mixed-ancestry Mexican individuals. These results also suggest that the HLA-DRB1*14:54-DQB1*05:03 haplotype was introduced by admixture with European and/or Asian populations.
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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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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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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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Latiano A, Palmieri O, Bossa F, Latiano T, Corritore G, De Santo E, Martino G, Merla A, Valvano MR, Cuttitta A, Mazza T, Annese V, Andriulli A. Impact of genetic polymorphisms on the pathogenesis of idiopathic achalasia: Association with IL33 gene variant. Hum Immunol 2014; 75:364-369. [PMID: 24468584 DOI: 10.1016/j.humimm.2014.01.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 01/03/2014] [Accepted: 01/14/2014] [Indexed: 02/06/2023]
Abstract
AIM To investigate the association of single nucleotide polymorphisms (SNPs) of genes involved in the regulation of immune responses, IL33, IL1RL1, IL23R, and IL10, with idiopathic achalasia in an Italian cohort of patients. MATERIALS AND METHODS A panel of eleven polymorphisms were genotyped in 116 unrelated idiopathic achalasic patients and 371 healthy subjects, by using TaqMan genotyping assays. RESULTS Significant differences of allele (P=0.0065, OR=1.59, CI=1.14-2.22) and genotype (P=0.0097, OR=1.74, CI=1.14-2.65) frequencies of the IL33 rs3939286 variant were found between achalasic patients and controls. No association of the other investigated SNPs was detected. No differences in genotype and allele distribution were found with respect to clinical characteristics of patients. CONCLUSION We provide for the first time an association between the risk of developing idiopathic achalasia and IL-33 variant, underling the role of cytokines and inflammatory mediators on the pathogenesis of the disease.
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Affiliation(s)
- Anna Latiano
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, San Giovanni Rotondo, Italy.
| | - Orazio Palmieri
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, San Giovanni Rotondo, Italy
| | - Fabrizio Bossa
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, San Giovanni Rotondo, Italy
| | - Tiziana Latiano
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, San Giovanni Rotondo, Italy
| | - Giuseppe Corritore
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, San Giovanni Rotondo, Italy
| | - Ermelinda De Santo
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, San Giovanni Rotondo, Italy
| | - Giuseppina Martino
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, San Giovanni Rotondo, Italy
| | - Antonio Merla
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, San Giovanni Rotondo, Italy
| | - Maria Rosa Valvano
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, San Giovanni Rotondo, Italy
| | - Antonello Cuttitta
- IRCCS 'Casa Sollievo della Sofferenza', Unit of General Surgery 2nd and Thoracic Surgery, San Giovanni Rotondo, Italy
| | - Tommaso Mazza
- IRCCS 'Casa Sollievo della Sofferenza', Bioinformatics Unit, San Giovanni Rotondo, Italy
| | - Vito Annese
- Gastroenterology Unit 2, AOU Careggi Hospital, Florence, Italy
| | - Angelo Andriulli
- IRCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, San Giovanni Rotondo, Italy
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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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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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Gockel HR, Schumacher J, Gockel I, Lang H, Haaf T, Nöthen MM. Achalasia: will genetic studies provide insights? Hum Genet 2010. [PMID: 20700745 DOI: 10.1007/s00439-010-0874-8.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Despite increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia and its association with well-defined genetic syndromes suggest the involvement of genetic factors. Mutant mouse models display gastrointestinal disturbances that are similar to those observed in achalasia patients. The candidate gene approach has revealed some promising results; however, it has not established conclusive links to specific genes so far. The aim of this review was to summarize current knowledge of the genetics of achalasia. We also discuss the extent to which our understanding of achalasia is likely to be enhanced through future molecular genetic research.
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Affiliation(s)
- Henning R Gockel
- Department of General and Abdominal Surgery, Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany
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12
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Gockel HR, Schumacher J, Gockel I, Lang H, Haaf T, Nöthen MM. Achalasia: will genetic studies provide insights? Hum Genet 2010; 128:353-64. [PMID: 20700745 DOI: 10.1007/s00439-010-0874-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2010] [Accepted: 08/02/2010] [Indexed: 12/15/2022]
Abstract
Despite increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia and its association with well-defined genetic syndromes suggest the involvement of genetic factors. Mutant mouse models display gastrointestinal disturbances that are similar to those observed in achalasia patients. The candidate gene approach has revealed some promising results; however, it has not established conclusive links to specific genes so far. The aim of this review was to summarize current knowledge of the genetics of achalasia. We also discuss the extent to which our understanding of achalasia is likely to be enhanced through future molecular genetic research.
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Affiliation(s)
- Henning R Gockel
- Department of General and Abdominal Surgery, Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany
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13
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de León AR, de la Serna JP, Santiago JL, Sevilla C, Fernández-Arquero M, de la Concha EG, Nuñez C, Urcelay E, Vigo AG. Association between idiopathic achalasia and IL23R gene. Neurogastroenterol Motil 2010; 22:734-8, e218. [PMID: 20367798 DOI: 10.1111/j.1365-2982.2010.01497.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Idiopathic achalasia is a primary esophageal motor disorder of unknown etiology. Different evidences have been reported in support of achalasia as the result of an autoimmune and inflammatory process leading to neuronal cell loss. According to this, idiopathic achalasia has been significantly associated with specific alleles of the human leukocyte antigen system class II, although few reports studying association with other loci can be found in the literature. Recent studies have shown association of a non-synonymous polymorphism within the IL23R gene with different chronic inflammatory disorders, including Barrett's esophagus. The purpose of this study was to assess whether the IL23R coding variant Arg381Gln polymorphism is involved in susceptibility to idiopathic achalasia. METHODS We performed a case-control study including 262 patients with idiopathic achalasia and 802 healthy subjects, all of them white Spaniards. Achalasia patients were diagnosed on the basis of clinical, radiographic, endoscopic, and manometric criteria. All samples were genotyped for the IL23R Arg381Gln polymorphism using TaqMan technology. KEY RESULTS The minor allele of the Arg381Gln polymorphism was significantly increased in patients compared with healthy controls (OR = 1.46, 95% CI = 1.01-2.11, P = 0.036). This association seems to be specific to male patients with disease onset after 40 years (OR = 2.33, 95% CI = 1.29-4.16, P = 0.002). CONCLUSIONS & INFERENCES Our results suggest a role of IL23R in idiopathic achalasia predisposition and extend the evidence of the general influence of this gene in autoimmune and inflammatory diseases.
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Affiliation(s)
- A R de León
- Gastroenterology Department, Hospital Clínico San Carlos, Madrid, Spain
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14
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Suggested association of NOS2A polymorphism in idiopathic achalasia: no evidence in a large case-control study. Am J Gastroenterol 2009; 104:1326-7. [PMID: 19337240 DOI: 10.1038/ajg.2009.72] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Abstract
Achalasia, a motor disorder of the esophagus, is characterized by myenteric plexitis leading to neuronal loss. Cytotoxic T cells, isolated from the lower esophageal sphincter of achalasia patients, respond to human herpes virus-1 (HSV-1) with gamma-IFN (and to a lesser extent IL-2) production and clonal proliferation. In addition, HSV-1 DNA was demonstrated in the vast majority of patients, but also in controls. These exciting data suggest that achalasia is an immune-mediated inflammatory disease in which a (latent) infection with HSV-1 leads to persistent immune activation and self-destruction of esophageal neurons, most likely in genetic susceptible subjects only.
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16
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Latiano A, De Giorgio R, Volta U, Palmieri O, Zagaria C, Stanghellini V, Barbara G, Mangia A, Andriulli A, Corinaldesi R, Annese V. HLA and enteric antineuronal antibodies in patients with achalasia. Neurogastroenterol Motil 2006; 18:520-525. [PMID: 16771767 DOI: 10.1111/j.1365-2982.2006.00772.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The aetiopathogenesis of primary achalasia is largely unknown, although an immunogenetic predisposition is suspected. To establish whether a correlation exists among possible aetiological factors, including class II human leucocyte antigen (HLA) alleles and autoantibodies to enteric neurones, and clinical features of patients with achalasia, a total of 60 patients and 200 healthy subjects were typed by high-resolution HLA-DQ and HLA-DR alleles. Circulating antineuronal antibodies were investigated by using indirect immunofluorescence on enteric neurones of rat ileum and colon and immunoblotting assay in a subset of achalasic patients and in all controls. The DQB1*0502 and DQB1*0601 alleles were significantly increased in patients with achalasia compared with controls (P < 0.03, P < 0.001, respectively). Moreover a negative correlation with the DQB1*0201 allele was found (P = 0.016). As a whole, 14 of 60 (23.3%) achalasia patients were carriers of HLA risk alleles, and 10 of 41 (24.4%) presented antineuronal antibodies. No significant correlation among HLA risk alleles, antineuronal antibodies and clinical features was found. In achalasia, no correlation exists among HLA alleles, antineuronal antibodies and clinical features. However, given the association between achalasia and HLA-DQ1, further research is needed to clarify the role of HLA antigens and antineuronal antibodies in this disease.
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Affiliation(s)
- A Latiano
- U.O. Gastroenterologia, Ospedale CSS-IRCCS, San Giovanni Rotondo, Italy
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Gockel I, Bohl JRE, Doostkam S, Eckardt VF, Junginger T. Spectrum of histopathologic findings in patients with achalasia reflects different etiologies. J Gastroenterol Hepatol 2006; 21:727-33. [PMID: 16677160 DOI: 10.1111/j.1440-1746.2006.04250.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND The etiology of achalasia is still unknown. The aim of the present study was to elucidate its underlying pathologies and their chronology by investigation of esophageal specimens in patients undergoing surgery (esophageal resection or myotomy) for achalasia. METHODS In 17 patients with achalasia, histopathologic examinations of the esophageal wall focussing on the myenteric plexus were performed. Preoperative diagnosis was based on clinical evaluation, esophagogastroscopy, barium esophagogram in all, and esophageal manometry in eight patients. The median age at the time of surgery was 54 years (range: 14-78 years). In eight cases, the complete esophageal, body and in nine cases a smooth muscle biopsy including parts of the myenteric plexus from the distal part of the esophagus (high pressure zone) was available. The tissue specimens were fixed in formalin and embedded in paraffin. The staining procedures were hematoxylin and eosin (HE), Elastica van Gieson (EvG), and periodic acid-Schiff (PAS) reaction. Immunohistochemical examinations were performed with antibodies against B and T lymphocytes, neurofilament, protein gene-related product (PGP 9.5), S-100 protein, myosin, desmin, smooth muscle actin and substance P. RESULTS In 13 of 17 patients, a significant reduction of the number of intramural ganglion cells was present. Common findings were a severe fibrosis of the smooth muscle layer (10/17) and obvious myopathic changes of the smooth muscle cells (5/17). Staining for B and T lymphocytes found signs of inflammation in mucosal and muscular areas. Three patients exhibited a marked invasion of eosinophilic granulocytes of the muscularis propria (eosinophilia). Esophageal carcinoma had developed in three patients (squamous cell carcinoma in two and carcinoma in situ in another patient with Barrett's esophagus and high-grade dysplasia). Severe inflammatory reactions (neural, eosinophilic and mucosal) dominated in patients with a longstanding history of achalasia (>10 years) as well as a marked endomysial fibrosis. CONCLUSIONS The histopathological investigations of the esophageal wall in 17 patients undergoing esophageal resection or myotomy for achalasia suggest that the reduction of intramural ganglion cells might be a secondary change, probably due to inflammation triggered by autoimmune mechanisms or a chronic degenerative process of the central and/or peripheral part of the vagal nerve. The primary lesion could also be a severe myopathy of the smooth muscle cells.
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Affiliation(s)
- Ines Gockel
- Department of General and Abdominal Surgery, Johannes Gutenberg University of Mainz, Mainz, Germany.
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18
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Fernández L, Núñez C, Mendoza JL, Urcelay E, Fernández-Arquero M, Taxonera C, Díaz-Rubio M, de la Concha EG, Martínez A. A recombined haplotype in the major histocompatibility region contains a cluster of genes conferring high susceptibility to ulcerative colitis in the Spanish population. Inflamm Bowel Dis 2005; 11:785-91. [PMID: 16116311 DOI: 10.1097/01.mib.0000179210.96025.23] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND The most consistently described associations in ulcerative colitis (UC) have been with human leukocyte antigen (HLA) class II alleles. Our aim was to look for associations among distinct genetic polymorphisms in the major histocompatibility complex (MHC) that might play a role in determining the susceptibility to UC and especially to the extensive form of the disease. METHODS A case-control study was performed with a total of 253 patients with UC and 315 healthy controls recruited from a single Spanish center. All the samples and 4 cell lines carrying DRB1*0103 or DRB1*1501 alleles were typed for the HLA-DRB1 class II gene and for a panel of HLA class III markers (D6S273, BAT_2, TNFa, b, c, d, e, IKBL+738, MICA). RESULTS The frequency of the alleles DRB1*0103, IKBL+738(C) (extending our previous results) and BAT_2-8 (newly typed) was increased in patients compared with controls (P=0.00001, odds ratio [OR]=5.90; P=0.002, OR=2.42; and P=0.0001, OR=3.04, respectively), and these associations were greatest in patients with extensive disease compared with patients with distal disease (P=0.02, OR=2.53; P=0.002, OR=3.06; and P=0.03, OR=2.08, respectively). The allelic combination DRB1*0103/D6S273-5/BAT_2-8/TNFa11b4c1d3e3/IKBL+738(C)/MICA5.1 that includes the telomeric class III markers of the 7.1 ancestral haplotype is highly increased in patients with UC (P=0.0001, OR=10.57), especially in those with the extensive form of the disease (P=0.02, OR=3.41 extensive versus distal). CONCLUSIONS The above-mentioned pattern, most likely formed by recombination of the telomeric fragment of the MHC 7.1 ancestral haplotype, seems to be the most important genetic determinant of susceptibility to the extensive form of UC in our population.
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Affiliation(s)
- Laura Fernández
- Department of Clinical Immunology, Hospital Clínico San Carlos, Madrid, Spain
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Kountouras J, Zavos C, Chatzopoulos D. Apoptosis and autoimmunity as proposed pathogenetic links between Helicobacter pylori infection and idiopathic achalasia. Med Hypotheses 2005; 63:624-9. [PMID: 15325006 DOI: 10.1016/j.mehy.2004.04.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2004] [Accepted: 04/06/2004] [Indexed: 12/14/2022]
Abstract
Achalasia is a disorder of the oesophagus characterised by increased lower oesophageal sphincter (LOS) tone, lack of LOS relaxation with swallowing and aperistalsis of the body of the oesophagus. The aetiology and pathogenesis of idiopathic achalasia are still unclear, although a viral cause, genetic influences (associations with HLA loci) and autoimmune processes have been postulated. Degeneration and significant loss of nerve fibres, associated with an inflammatory infiltrate of the myenteric plexus in idiopathic achalasia, provide evidence of an immune mediated destruction of the myenteric plexus, possibly through apoptotic process. This concept is reinforced by the concomitant appearance of achalasia and Guillain-Barré syndrome (GBS) and/or Parkinson's disease, where inappropriate initiation of apoptosis has been proposed to underlie the neuronal attrition. In the same respect, Helicobacter pylori (H. pylori) infection has been associated with gastric autoimmunity, and patients infected with H. pylori have been shown to possess autoantibodies that cross-react with antigens expressed on the gastric mucosa. Furthermore, H. pylori is thought to be associated with the development of autoimmune sequelae observed in peripheral neuropathies and GBS, where autoantibodies to specific neural targets have been found to impair native neural function by inducing nerve tissue damage, possibly by apoptosis. Taken together, we assume that H. pylori infection might be a pathogenetic factor of achalasia through induction of autoimmunity and apoptosis. Whether eradication of H. pylori infection may indirectly offer benefit to the pathophysiology of idiopathic achalasia by ameliorating the apoptotic loss of ganglion cells and their axons in the oesophageal wall remains to be elucidated.
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Affiliation(s)
- Jannis Kountouras
- Department of Gastroenterology, 2nd Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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Martínez A, Gual L, Fernández-Arquero M, Nogales A, Ferreira A, Garcia-Rodriguez MC, Fontan G, de la Concha Ed EG. Epistatic effects occurring among susceptibility and protective MHC genes in IgA deficiency. Genes Immun 2003; 4:316-20. [PMID: 12761569 DOI: 10.1038/sj.gene.6363955] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Immunoglobulin A deficiency (IgAD), the most prevalent primary immunodeficiency in Caucasian populations, shows strong evidence of polygenic inheritance with several associated genes being located in the major histocompatibility complex (MHC). Our aims were to determine which previously described MHC associations were primary and not secondary to a decrease or an increase in other MHC haplotype frequencies, to study the genetic interactions between all disease-associated MHC haplotypes and, finally, to ascertain the relative importance of protection vs susceptibility. A relative predispositional effect (RPE) study showed that in addition to the primary positive association of IgAD with HLA-DRB1*0102, DR3/TNFa2b3, and DR7 carrying haplotypes, DRB1*1501 was a marker of a primary protective factor in the Spanish population. Our data also indicate that the combined presence in an individual of two MHC susceptibility haplotypes notably increases the predisposition to the disease and that DRB1*1501 positive haplotypes eliminate the susceptibility conferred by any other MHC haplotype.
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Affiliation(s)
- A Martínez
- Department of Immunology, Hospital Clinico San Carlos, Madrid, Spain
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Hidalgo-Tenorio C, Sabio JM, Jaimez L, Jiménez-Alonso J. Achalasia, angioedema and systemic lupus erythematosus. Lupus 2002; 10:831-2. [PMID: 11789498 DOI: 10.1177/096120330101001115] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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