Aortic Aneurysm Clinical Trial
Official title:
X-chromosome Inactivation, Epigenetics and the Transcriptome
The human genetic material consists of 46 chromosomes of which two are sex chromosomes. The
sex-chromosome from the mother is the X and from the father the Y-chromosome. Hence a male
consist of one Y and one X chromosome and a female of 2 X-chromosomes. Alterations in the
number of sex-chromosomes and in particular the X-chromosome is fundamental to the
development of numerous syndromes such as Turner syndrome (45,X), Klinefelter syndrome
(47,XXY), triple X syndrome (47,XXX) and double Y syndrome (47,XYY). Despite the obvious
association between the X-chromosome and disease only one gene has been shown to be of
significance, namely the short stature homeobox gene (SHOX). Turner syndrome is the most
well characterized and the typical diseases affecting the syndrome are:
- An Increased risk of diseases where one's own immune system reacts against one's own
body (autoimmune diseases) and where the cause of this is not known; For example
diabetes and hypothyroidism.
- Increased risk of abortion and death in uteri
- Underdeveloped ovaries with the inability to produce sex hormones and being infertile.
- Congenital malformations of the major arteries and the heart of unknown origin.
- Alterations in the development of the brain, especially with respect to the social and
cognitive dimensions.
- Increased incidence obesity, hypertension, diabetes and osteoporosis.
In healthy women with to normal X-chromosomes, the one of the X-chromosomes is switched off
(silenced). The X-chromosome which is silenced varies from cell to cell. The silencing is
controlled by a part of the X-chromosome designated XIC (X-inactivation center). The
inactivation/silencing of the X-chromosome is initiated by a gene named Xist-gene (the X
inactivation specific transcript).This gene encodes specific structures so called lincRNAs
(long intervening specific transcripts) which are very similar to our genetic material (DNA)
but which is not coding for proteins. The final result is that women are X-chromosome
mosaics with one X-chromosome from the mother and the other X from the father. However,
numerous genes on the X-chromosome escape this silencing process by an unknown mechanism.
Approximately two third of the genes are silenced, 15 % avoid silencing and 20 percent are
silenced or escape depending on the tissue of origin.
The aforementioned long non-protein-coding parts of our genetic material (LincRNAs) are
abundant and produced in large quantities but their wole as respect to health and disease
need further clarification. Studies indicate that these LincRNAs interact with the protein
coding part of our genetic material modifying which genes are translated into proteins and
which are not. During this re-modelling there is left foot prints on the genetic material
which can indicate if it is a modification that results in silencing or translation of the
gene. It is possible to map these foot prints along the entire X-chromosome using molecular
techniques like ChIP (Chromatin immunoprecipitation) and ChIP-seq (deep sequencing).
The understanding achieved so far as to the interplay between our genetic material and
disease has arisen from genetic syndromes which as the X-chromosome syndromes are relatively
frequent and show clear manifestations of disease giving the researcher a possibility to
identify genetic material linked to the disease. Turner and Klinefelter syndrome are, as the
remaining sex chromosome syndromes, excellent human disease models and can as such help to
elaborate on processes contributing to the development of diseases like diabetes,
hypothyroidism, main artery dilation and ischemic heart disease.
The purpose of the study is to:
1. Define the changes in the non-coding part of the X-chromosome.
2. Identify the transcriptome (non-coding part of the X-chromosome)as respect to the RNA
generated from the X-chromosome.
3. Identify changes in the coding and non-coding parts of the X-chromosome which are
specific in relation to Turner syndrome and which can explain the diseases seen in
Turner syndrome.
4. Study tissue affected by disease in order to look for changes in the X-chromosome with
respect to both the coding and non-coding part of the chromosome.
6. Determine if certain genes escape X-chromosome silencing and to establish if this is
associated with the parent of origin.
Status | Completed |
Enrollment | 110 |
Est. completion date | January 2016 |
Est. primary completion date | October 2015 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | Both |
Age group | 18 Years to 80 Years |
Eligibility |
Controls should fore fill the criteria below Inclusion Criteria: - Healthy - Age matched Exclusion Criteria: - Any chronic or acute illness thought to influence the outcome measures |
Observational Model: Cohort, Time Perspective: Cross-Sectional
Country | Name | City | State |
---|---|---|---|
Denmark | Department of Endocrinology and Internal medicine | Aarhus |
Lead Sponsor | Collaborator |
---|---|
University of Aarhus | AP Moeller Foundation, Lundbeck Foundation, The Korning Foundation Denmark |
Denmark,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | DNA-methylation of CpG-islands. | mapping DNA-methylations of CpG-islands | Once | No |
Primary | Histone modifications | Permissive and repressive histone modifications on the X-chromosome | Once | No |
Primary | mRNA and nonRNA | identification of the entire transcriptome including both mRNA and non-coding RNAs (lincRNA as well as miRNA)from the X-chromosome | Once | No |
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