The role of genetic factors in the aetiology of achalasia

Achalasia is rare motility disorder of the oesophagus of which the
pathofysiolofy is still lagerly unknown. There is a progressive destruction and
degeneration of the neurons in the myenteric plexus which causes aperistalsis
of the oesophageal body and dysrelaxation of the lower oesophagus sphincter
(LOS). The exact cause of the alterations in the myenteric plexus remains to be
determined. Genetic, infectious, neuodegenerative and autoimmune mechanisms
have all been suggested as possible etiological factors. Achalasia leads to
severe symptoms, the patients have an increased risk for development of
carcinoma of the oesophagus and currently treatment is purely palliative.
Therefore further insight into the aetiology of achalasia is important because
it can drive the search for new targets for therapy, diagnostics and prevention
of achalasia.

Accumulating data suggest a role for genetic factors in the pathofysiolgy of
achalasia. Studies have suggested that patients with achalasia may have a
certain genetic background that leads to an autoimmune response resulting in
the destruction of the neurons. It is likely that the genetic background of
achalasia shows a similar pattern to that of other rare diseases with a
suspected autoimmune aetiology such as systemic scleroderma. Furthermore an
increased risk for development of achalasia has been observed in monozygotic
twins and siblings of patients with achalasia. The observation that there is an
increased risk of developing achalasia in certain genetic disorders supports,
together with the other data, the hypothesis that certain genetic factors play
an important role in the development of achalasia. Therefore it is important to
do further research into genetic variants that are possible associated with
achalasia which also leads to further insight into the aetiology of the
disease.

Primary:
- To identify causal genetic variants and proteomes involved in achalasia and
to study their relevance

Secundary:
- To build-up a large scale harmonized biobank of achalasia patients, based on
combining existing and new data from the European and Non-European centres.
- To perform large scale genetic studies to identify the most likely causal
common and rare genetic variants for achalasia.
- To study the functional relevance of identified genetic variants in achalasia
using genomics and proteomics.
- To integrate genetic, genomics and proteomics into clinical phenotypes and
course of the disease.

A prospective observational study, in a multicentre setting.

The study subjects will donate once 20 mL of venous blood by means of a
standard venapuncture. A venapuncture for blood withdrawal is a safe procedure
and routinely performed in the clinical setting, with rarely any serious
complications. There is no serious risk attachted. Small complications are a
bleeding or a puncture hematoma for which no treatment is necessary. In rare
cases patients get an infection or a thrombophlebitis after a venapuncture,
which seldom needs treatment. The venapuncture will be performed by a trained
nurse or physician who are qualified to perform venapunctures and therefore
complication will be kept to a minimum.

Study subjects that undergo a surgical or endoscopic myotomy for the treatment
of achalasia will be asked to give informed consent for taking 6 biopsies of
the oesophageal muscle layers during the procedure. The duration of the myotomy
will not be extended due to the biopsy. Taking biopsies during a surgical or
endoscopic myotomy is a regular performed procedure and rarely gives
complications. A qualified and trained surgeon or gastroenterologist will take
the biopsies. A rare but potentially severe risk of a biopsy is a perforation.
In most cases a perforation can be treated expectatively, directly during the
procedure or endoscopically. In a minority of cases, surgery has to be
performed to close the perforation. Another very rare risk of an oesophageal
biopsy is a bleeding, which can be treated directly during the procedure or
endoscopically.

Furthermore participants will be asked to complete a questionnaire for
demographic and clinical data, which isn't associated with any risks.

From the blood samples of the study subjects, DNA and plasma will be isolated.
A Genome Wide Association analysis (GWAS) and Next-Generation Sequencing will
be performed on the DNA and proteomics on the plasma. The biopsies of the
oesophageal muscle layers will also be used for proteomics. The DNA analysis
enables the sequencing of the entire genome and in that way information will be
obtained that contains all coding regions, exones of each participant. Not all
variants in all exones will be evaluated, the results in patients with
achalasia will be compared to one another in order to find variants in genes
they have in common. Therefore the chance for unexpected findings is small but
it still exists. It may be that variants are found in genes that are not only
associated to achalasia but are also associated with an increased chance of
developing another disorder. Participants are informed about this, and need to
agree to be informed about such results if the findings have significant
consequences for their health and care. Participants will only be informed
about disorders that can be influenced by medical interventions or
interventions into their life style. An increased risk in developing disorders
that cannot be prevented by medical or life style intervention will not be
reported to the participants. Study subjects who refuse to be informed about
such factors cannot participate in the study. So, in conclusion study subjects
are at risk, because the whole DNA is analysed, that certain medical
information is coming up that they wouldn't have known otherwise. However, the
risk is relatively small.

The risks of the additional acts and studies are minimal for the study
subjects. The results of the study have no consequences for the participants
and don't influence the treatment or the prognosis of the disease. The study
can provide new insights in the aetiology of achalasia and possibly offer new
targets for therapy and diagnosis, which may benefit all patients with
achalasia in the future. Because the risks for the study subjects in this study
are minimal and the results of the study can give valuable, new information
about the aetiology of achalasia it is justified to perform this study.