Achalasia: will genetic studies provide insights?

Gockel, Henning R.; Schumacher, Johannes; Gockel, Ines; Lang, Hauke; Haaf, Thomas; Nöthen, Markus M.

doi:10.1007/s00439-010-0874-8

Cited by 83 publications

(65 citation statements)

References 155 publications

(157 reference statements)

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Section: Introductionmentioning

confidence: 99%

“…1 Although the cause of this neuronal degeneration is mainly unknown, autoimmune processes seem to be involved in individuals with a genetic susceptibility. 1 Most recently, an insertion of eight amino acids in the cytoplasmic tail of HLA-DQβ1 and two amino acid substitutions in the extracellular part of HLA-DQα1 and HLA-DQβ1 have been identified as being independently disease associated. 2 Although on the cellular level the function of the identified achalasia risk variants remains speculative, the findings show that the HLA-DQ receptor and thereby autoimmune processes represent a major risk factor for idiopathic achalasia.…”

Section: Introductionmentioning

confidence: 99%

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The HLA-DQβ1 insertion is a strong achalasia risk factor and displays a geospatial north–south gradient among Europeans

et al. 2016

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Idiopathic achalasia is a severe motility disorder of the esophagus and is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. Most recently, we identified an eight-amino-acid insertion in the cytoplasmic tail of HLA-DQβ1 as strong achalasia risk factor in a sample set from Central Europe, Italy and Spain. Here, we tested whether the HLA-DQβ1 insertion also confers achalasia risk in the Polish and Swedish population. We could replicate the initial findings and the insertion shows strong achalasia association in both samples (Poland P = 1.84 × 10 − 04 , Sweden P = 7.44 × 10 − 05 ). Combining all five European data sets -Central Europe, Italy, Spain, Poland and Sweden -the insertion is achalasia associated with P combined = 1.67 × 10 − 35 . In addition, we observe that the frequency of the insertion shows a geospatial north-south gradient. The insertion is less common in northern (around 6-7% in patients and 2% in controls from Sweden and Poland) compared with southern Europeans (~16% in patients and 8% in controls from Italy) and shows a stronger attributable risk in the southern European population. Our study provides evidence that the prevalence of achalasia may differ between populations.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The HLA-DQβ1 insertion is a strong achalasia risk factor and displays a geospatial north–south gradient among Europeans

et al. 2016

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“…[2][3][4] Genetic factors are likely to be important in its pathogenesis as supported by occasional familial aggregation, concordance among monozygotic twins and reports on association between achalasia and Hirshsprung's disease, a similar condition with genetic basis. [5][6][7] Esophageal aperistalsis and incomplete lower esophageal sphincter (LES) relaxation, the characteristic features of achalasia, result from degeneration of the ganglion cells in the myenteric plexus. 8 Abnormal esophageal function in patients with achalasia is due to loss of inhibitory innervation.…”

Section: Introductionmentioning

confidence: 99%

Achalasia Is Associated With eNOS4a4a, iNOS22GA, and nNOS29TT Genotypes: A Case-control Study

Singh

Ghoshal

Misra

et al. 2015

J Neurogastroenterol Motil

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Background/AimsAchalasia is known to result from degeneration of inhibitory neurons, which are mostly nitrinergic. Characteristic features of achalasia include incomplete lower esophageal sphincter (LES) relaxation and esophageal aperistalsis. Nitric oxide (NO), produced by NO synthase (NOS), plays an important role in peristalsis and LES relaxation. Therefore, we evaluated genetic polymorphisms of NOS gene isoforms (endothelial NOS [eNOS], inducible NOS [iNOS], and neuronal NOS [nNOS]) in patients with achalasia and healthy subjects (HS). MethodsConsecutive patients with achalasia (diagnosed using esophageal manometry) and HS were genotyped for 27-base pair (bp) eNOS variable number of tandem repeats (VNTR), iNOS22G/A (rs1060826), nNOS C/T (rs2682826) polymorphisms by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP), respectively. Results Among ConclusionsAchalasia is associated with eNOS4a4a, iNOS22GA, and nNOS29TT genotypes. This may suggest that polymorphisms of eNOS, iNOS, and nNOS genes are risk factors for achalasia.

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“…It has been postulated that the PTPN22-allele 1858T promotes an autoimmune response that results in chronic inflammation and the associations with some autoimmune conditions have already been established. A gender-specific association has been observed between the T allele of C1858T and achalasia in female patients (20,21).…”

Section: Discussionmentioning

confidence: 95%

“…A cluster consisting of varied autoimmune diseases has been linked to achalasia: myasthenia gravis, polymyositis, autoimmune thyroid disease, among others, contributing to the argument that autoimmunity may be a cause for some idiopathic achalasia (17)(18)(19). A further achalasia candidate gene selected based on its involvement in autoimmunity is the protein of tyrosine phosphatase N22 gene (PTPN22) on chromosome 1p13 (20). PTPN22 encodes a lymphoid-specific phosphatase (LYP) that downregulates T-cell activation.…”

Section: Discussionmentioning

confidence: 99%

Achalasia and thyroid disease: possible autoimmune connection?

Quidute

Freitas²,

Lima³

et al. 2012

Arq Bras Endocrinol Metab

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SUMMARYMany cases have been published showing a co-existence of autoimmune thyroid diseases (AITDs) and other autoimmune diseases. About a quarter of patients with achalasia have a concurrent thyroid disease, most commonly associated with hypothyroidism. Although relatively rare, the association of achalasia and hyperthyroidism requires attention. The physiopathology of Grave's Disease (GD) involves B-and T-mediator lymphocytes, which have an affinity for known thyroid antigens: thyroglobulin, thyroid-peroxidase, and thyrotrophin receptor. Currently, however, the real physiopathogenesis of achalasia continues to be unknown. Some important findings are suggestive of an autoimmune mechanism: significant infiltration of the myoenteric plexus by monocytes, presence of the class II-Human Histocompatibility Complex DQwl antigen and antibodies to myoenteric neurons. The present case reports a patient who, despite testing negative for Chagas' disease, had achalasia, progressed to developing significant wasting and worsening of his quality of life, was later diagnosed with hyperthyroidism. After endoscopic esophageal dilatation and radioiodine ablation of the thyroid gland, there was great improvement in the patient clinical condition. Arq Bras Endocrinol Metab. 2012;56(9):677-82 SUMáRioMuitos casos têm sido publicados mostrando uma coexistência entre as doenças autoimunes da tireoide (DAIT) e outras doenças autoimunes. Cerca de um quarto dos pacientes com acalasia têm doenças da tireoide concomitantemente, sendo a mais comum a associação com hipotireoidismo. Apesar de ser relativamente rara, a associação da acalasia e hipertireoidismo requer atenção. A fisiopatologia da doença de Graves (DG) envolve os linfócitos B e T-mediados, os quais têm afinidade pelos antígenos da tireoide: tireoglobulina, tireoperoxidase e receptor de tireotrofina. Atualmente, a real fisiopatogenia da acalasia continua desconhecida. No entanto, alguns importantes achados em análise são sugestivos de mecanismo autoimune: infiltração significativa do plexo mioentérico pelos monócitos, presença do antígeno-DQwl do Complexo Humano de Histocompatibilidade classe II e presença de anticorpos contra neurô-nios mioentéricos. Este presente caso aborda um paciente que, apesar de testes negativos para doença de Chagas, tem acalasia que progrediu para o desenvolvimento de significativa perda ponderal e piora da sua qualidade de vida, posteriormente, diagnosticado com hipertireoidismo. Após dilatação endoscópica esofágica e ablação da glândula tireoide com radioiodo, houve grande melhora na condição clínica do paciente. Arq Bras Endocrinol Metab. 2012;56(9):677-82

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Achalasia: will genetic studies provide insights?

Cited by 83 publications

References 155 publications

The HLA-DQβ1 insertion is a strong achalasia risk factor and displays a geospatial north–south gradient among Europeans

The HLA-DQβ1 insertion is a strong achalasia risk factor and displays a geospatial north–south gradient among Europeans

Achalasia Is Associated With eNOS4a4a, iNOS22GA, and nNOS29TT Genotypes: A Case-control Study

Achalasia and thyroid disease: possible autoimmune connection?

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