Endocrine, Metabolic, Cardiovascular and Immunological Aspects of Sex Chromosome Abnormalities in Relation to Genotype
NCT ID: NCT05425953
Last Updated: 2023-11-29
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
320 participants
OBSERVATIONAL
2022-06-13
2025-05-01
Brief Summary
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Patients participate in questionaries, dexa-scan of bones, fibroscan of liver, ultra sound of testicles and blood will be analyzed for organ specific blood work as well as immunological and coagulation components.
Detailed Description
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Hypotheses:
1. The methylome and transcriptome of SCAs is altered compared to karyotypical normal female and males, and a unique methylation profile and RNA expression profile is seen for the different SCAs subgroups.
2. The methylation profile and the RNA expression profile show temporal alterations.
3. The DNA methylation profile and the RNA expression profile are tissue-specific.
3\. The phenotype and the increased risk of diseases seen in patients with SCAs are associated with the altered RNA-expression and DNA methylation profile.
Materials: Blood, fat, muscle, skin, buccal swaps, urine, will be collected from 60 klinefelter, 60 Turner syndrome patient, 20: 47, XXX and 20: 47, XYY and 80 male and female matched controls.
Methods:
Analysis of DNA-methylation using Whole Genome Bisulfite Sequencing (WGBS). Genomic DNA will be bisulfite-converted and sequenced on an Illumina Novaseq System. Sequence data pre-processors of software pipeline MethylStar. Analyzed using R.
Gene expression analysis (RNA) RNA will be cleaned and sequenced with a sequence depth of 30 million reads. Processing of sequence data using FastQC (quality control), HISAT2 (mapping) and featureCounts (gene-expression). Differences in gene-expression will be analyzed in R.
The extracted biopsies will be dissociated to singular cells RNA from these singular cells will be individually sequenced. For miRNA analysis we will isolate small non-coding RNAs and analyze these by next generation sequencing. Chromatin re-modelling can be analyzed through "footprints" left by histones on DNA-strand. Mapping of footprints along the whole X-chromosome is done using a single assay with chromatin-immunoprecipitation (CHIP) in combination med deep sequencing (chIPseq).
Genotype-Phenotype association analysis with weighted correlation network analysis (WGCNA) we will uncover the patterns in which genes behave and divide them into modules where genes react dependent of each other. These modules will afterwards be associated with the clinical data, enabling identification of the "hub" genes with the strongest associations to the phenotype.
These gene-modules, and the gene expression data itself, can furthermore be included in "deep-phenotyping" using artificial intelligence Perspectives A characterization of the methylome and transcriptome from different target tissue from patients with SCAs would not just be of significance to these patients but could lead to a larger understanding of similar diseases in patients without SCAs. Using SCAs as disease models and identify changes in DNA methylation and RNA-expression related to co-morbidity such as the metabolic syndrome, congenital heart disease or psychiatric diseases could increase the understanding of these diseases in general and potentially improve treatment in other patients groups with similar diseases.
In addition, the data collection will expand our biobank and will enable future research projects about SCAs.
Conditions
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Study Design
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CASE_CONTROL
CROSS_SECTIONAL
Study Groups
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Klinefelter syndrome
Patients with 47, XXY n=60
No intervention other than obtaining biopsies
Biopsies will be obtained.
Turner syndrom
Patients with 45, X n=60
No intervention other than obtaining biopsies
Biopsies will be obtained.
47, XXX
Patients with 47, XXX n=20
No intervention other than obtaining biopsies
Biopsies will be obtained.
47, XYY
Patients with 47, XYY n=20
No intervention other than obtaining biopsies
Biopsies will be obtained.
Male controls
Male controls n=80
No intervention other than obtaining biopsies
Biopsies will be obtained.
Female controls
Female controls n=80
No intervention other than obtaining biopsies
Biopsies will be obtained.
Interventions
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No intervention other than obtaining biopsies
Biopsies will be obtained.
Eligibility Criteria
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Inclusion Criteria
Exclusion Criteria
18 Years
90 Years
ALL
Yes
Sponsors
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Aarhus University Hospital
OTHER
University of Aarhus
OTHER
Responsible Party
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Principal Investigators
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Claus Gravholt, Prof
Role: STUDY_DIRECTOR
Aarhus University Hospital
Locations
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Aarhus university hospital
Aarhus, Region Midt, Denmark
Countries
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Central Contacts
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Facility Contacts
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References
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Roulot D, Degott C, Chazouilleres O, Oberti F, Cales P, Carbonell N, Benferhat S, Bresson-Hadni S, Valla D. Vascular involvement of the liver in Turner's syndrome. Hepatology. 2004 Jan;39(1):239-47. doi: 10.1002/hep.20026.
Gravholt CH, Chang S, Wallentin M, Fedder J, Moore P, Skakkebaek A. Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology. Endocr Rev. 2018 Aug 1;39(4):389-423. doi: 10.1210/er.2017-00212.
de Vos WM, Tilg H, Van Hul M, Cani PD. Gut microbiome and health: mechanistic insights. Gut. 2022 May;71(5):1020-1032. doi: 10.1136/gutjnl-2021-326789. Epub 2022 Feb 1.
Berglund A, Viuff MH, Skakkebaek A, Chang S, Stochholm K, Gravholt CH. Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: a nationwide cohort study. Orphanet J Rare Dis. 2019 Jan 14;14(1):16. doi: 10.1186/s13023-018-0976-2.
Gravholt CH, Juul S, Naeraa RW, Hansen J. Prenatal and postnatal prevalence of Turner's syndrome: a registry study. BMJ. 1996 Jan 6;312(7022):16-21. doi: 10.1136/bmj.312.7022.16.
Elsheikh M, Hodgson HJ, Wass JA, Conway GS. Hormone replacement therapy may improve hepatic function in women with Turner's syndrome. Clin Endocrinol (Oxf). 2001 Aug;55(2):227-31. doi: 10.1046/j.1365-2265.2001.01321.x.
Gravholt CH, Poulsen HE, Ott P, Christiansen JS, Vilstrup H. Quantitative liver functions in Turner syndrome with and without hormone replacement therapy. Eur J Endocrinol. 2007 Jun;156(6):679-86. doi: 10.1530/EJE-07-0070.
Ahmed S, Spence JD. Sex differences in the intestinal microbiome: interactions with risk factors for atherosclerosis and cardiovascular disease. Biol Sex Differ. 2021 May 17;12(1):35. doi: 10.1186/s13293-021-00378-z.
Org E, Mehrabian M, Parks BW, Shipkova P, Liu X, Drake TA, Lusis AJ. Sex differences and hormonal effects on gut microbiota composition in mice. Gut Microbes. 2016 Jul 3;7(4):313-322. doi: 10.1080/19490976.2016.1203502. Epub 2016 Jun 29.
Other Identifiers
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EMKI SCA
Identifier Type: -
Identifier Source: org_study_id