Impact of genetic polymorphisms on the pathogenesis of idiopathic achalasia: Association with IL33 gene variant

Palmieri, Orazio; Bossa, Fabrizio; Latiano, Tiziana; Corritore, Giuseppe; Santo, Ermelinda De; Martino, Giuseppina; Merla, Antonio; Valvano, Maria Rosa; Cuttitta, Antonello; Mazza, Tommaso; Annese, Vito; Andriulli, Angelo

doi:10.1016/j.humimm.2014.01.004

Cited by 11 publications

(9 citation statements)

References 54 publications

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“…Previous GWAS identified associations of BD with SNPs in the intergenic region between IL23R and IL12RB2 4 5 . IL23R is also a susceptibility locus for a number of inflammatory and immune-linked diseases, including inflammatory bowel disease 13 , psoriasis 14 , psoriatic arthritis 15 , ankylosing spondylitis 16 , acute anterior uveitis 17 , Vogt-Koyanagi-Harada syndrome 18 , and idiopathic achalasia 19 . These findings suggest that up-regulation of IL23R is involved in the pathogenesis of BD.…”

Section: Resultsmentioning

confidence: 99%

Microarray and whole-exome sequencing analysis of familial Behçet’s disease patients

Okuzaki

Yoshizaki

Tanaka

et al. 2016

Sci Rep

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Behçet’s disease (BD), a chronic systemic inflammatory disorder, is characterized by recurrent oral and genital mucous ulcers, uveitis, and skin lesions. We performed DNA microarray analysis of peripheral blood mononuclear cell (PBMC) mRNA from 41 Japanese BD patients and revealed elevated levels of interleukin (IL) 23 receptor (IL23R) mRNA in many BD patients. DNA sequencing around a SNV (Rs12119179) tightly linked to BD revealed an elevated frequency of the C genotype, consistent with a previous report that IL23R is a susceptibility locus for BD. Notably, four of these BD patients are members of familial BD; a whole-exome sequencing (WES) of these BD patients identified 19 novel single-nucleotide variations (SNVs) specific to these patients. They include heterozygous SNVs in the genes encoding IL-1 receptor-associated kinase 4 (IRAK4), nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 14 (NRP14) and melanoma antigen-encoding gene E2 (MAGEE2); IRAK4 harbors a missense mutation, whereas NRP14 and MAGEE2 harbor nonsense mutations. These SNVs may serve as genetic markers that characterize BD.

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Section: Resultsmentioning

confidence: 99%

Microarray and whole-exome sequencing analysis of familial Behçet’s disease patients

Okuzaki

Yoshizaki

Tanaka

et al. 2016

Sci Rep

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“…Moreover, genetic studies have recently identified HLA alleles 7 8 9 10 11 and single nucleotide polymorphisms in the PTPN22 12 , IL10 13 , IL23R 14 , VIPR1 15 , c- kit 16 , IL33 17 , and LTA/TNFα 18 genes associated with the condition. Recently, a systematic association study 19 , performed on the Immunochip 20 , identified genetic risk factors for achalasia within the HLA-DQ receptor, thereby confirming a key role for immune-mediated processes in the pathogenesis of the disease.…”

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confidence: 99%

Gene expression of muscular and neuronal pathways is cooperatively dysregulated in patients with idiopathic achalasia

Palmieri

Mazza

Merla

et al. 2016

Sci Rep

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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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“…These cases have been mostly seen in the paediatric population [16,17]. Multiple genetic mutations, such as nitric oxide synthase 1 gene (NOS1), VIP receptor 1, IL23R, IL10 promoter, IL 33, and protein tyrosine phosphatase non-receptor 22 (PTPN22), proved to be related to the development of achalasia [18][19][20][21][22][23][24]. Mutations in the AAAS gene on chromosome 12q13, encoding the nuclear pore protein ALADIN, lead to triple A syndrome (TAS), also known as Allgrove syndrome, which is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima [25].…”

Section: Introductionmentioning

confidence: 99%

Present insight on achalasia – from diagnosis to treatment

Dziedzic

Nowak

Zgodziński

et al. 2019

J Pre Clin Clin Res.

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Introduction. Achalasia is a most frequent primary motility disorder of the oesophagus with the prevalence of 10/100,000 individuals, with no gender predominance. Due to its rare occurrence, at the early stages may be erroneously diagnosed, leading to progression of disease and delayed treatment. Objectives. The main aim of the review is to depict current data about achalasia, including pathogenesis, diagnosis, and possible treatment modalities, particularly the latest, minimally invasive technique: per-oral endoscopic myotomy (POEM). State of knowledge. The ethology of achalasia remains unknown, although autoimmune, viral or neurodegenerative causes may be considered triggers of the disease. In some cases, achalasia may be secondary to other conditions (e.g. malignancy, Chagas disease). Typical symptoms of achalasia are dysphagia (for both liquids and solids), regurgitations, heartburn and weight loss. The diagnosis is based on endoscopy, oesophageal high-resolution manometry (HRM) and X-ray with barium swallow. Therapies used in the treatment of achalasia focus on improving food passage by reducing LES pressure. These procedures include pharmacologic treatment, pneumatic balloon dilation, Heller myotomy and endoscopic myotomy. POEM was first introduced in humans by Inoue in 2008. Recent studies have revealed excellent short-term outcome of POEM with no serious complications. Conclusion. Achalasia is an incurable disease; however, available therapies can effectively reduce patients` symptoms. Further evaluation may lead to the establishment of tailored-to-patient treatment, and it is believed that POEM will become a gold standard for treatment of achalasia.

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Impact of genetic polymorphisms on the pathogenesis of idiopathic achalasia: Association with IL33 gene variant

Cited by 11 publications

References 54 publications

Microarray and whole-exome sequencing analysis of familial Behçet’s disease patients

Microarray and whole-exome sequencing analysis of familial Behçet’s disease patients

Gene expression of muscular and neuronal pathways is cooperatively dysregulated in patients with idiopathic achalasia

Present insight on achalasia – from diagnosis to treatment

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