Ignite Creation Date:
2024-05-06 @ 2:52 AM
Last Modification Date:
2024-10-26 @ 11:24 AM
Study NCT ID:
NCT02146872
Status:
UNKNOWN
Last Update Posted:
2014-05-26
First Post:
2014-05-02
Brief Title:
Premature Coronary Artery Disease - Clinical and Molecular Genetic Aspects
Sponsor:
Aarhus University Hospital Skejby
Organization:
Aarhus University Hospital Skejby
Study Overview
Official Title:
Premature Coronary Artery Disease - Clinical and Molecular Genetic Aspects
Status:
UNKNOWN
Status Verified Date:
2014-05
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PIHS
Brief Summary:
Since finishing the sequencing of the human genome in 2003 genetic research in coronary artery disease CAD and other complex traits have developed dramatically Recent genome-wide association studies have identified a considerable number of common genetic variants each associated with the disease This has led to a new understanding but also to the discovery of new therapeutical targets However each of the variants discovered only have minor effects on disease development and even the pooling of the variants only explains a minor percentage of the total heritability It has been evident that rare or private mutations probably play a great role in the genetic architecture of CAD especially among young and severely affected patients These may only be identified by sequencing Therefore the investigators hypothesize that the use of exome sequencing the read-off of the entire protein-coding regions of the genome and linkage analysis in families of extreme phenotype cases will identify disease-causing genetic variants From the West Denmark Heart Registry the investigators will enroll a minimum of 120 patients with atherosclerosis who have undergone a coronary artery revascularization procedure before the age of 40 to participate in study part 1 A pedigree analysis will be performed and cardiovascular CVD risk factors and current preventive treatment will be evaluated 1 degree relatives aged 30-65 years who are free of CAD are invited to participate in study 2 CVD risk factors are evaluated as well as a CT coronary angiogram is performed to quantify the degree of asymptomatic coronary atherosclerosis Families from study 1 and 2 who are considered severely affected by atherosclerosis evaluated on a basis of family size number of affected and severity of disease will be selected for exome sequencing Other relevant family members will be included as well as their CVD risk factors will be evaluated Exome sequencing will be performed and variants found will be filtered on a basis of frequency linkage analysis gene position existing knowledge and in-silico prediction tools Possible findings will be validated by Sanger-sequencing and causality of new variants will subsequently be sought to be proven by relevant experimental studies
Detailed Description:
Purposes Study part 1 Quantify the occurrence of risk factors of atherosclerosis among patients with very premature CAD in the Central Denmark Region and investigate to what degree patients are treated according to national guidelines
Study part 2 Investigate the occurrence of CAD among middle-aged 1st degree relatives of established patients having very premature CAD
Study part 3 Evaluate possible genetic risk factors in families with a high CAD prevalence using exome sequencing analysis
Hypotheses Hypothesis 1 Patients with very premature CAD have modifiable risk factors which are inadequately treated relative to current national guidelines
Hypothesis 2 The occurrence of very premature CAD is associated with familial accumulation of the disease
Hypothesis 3 The use of exome sequencing in selected families with phenotypic severe premature CAD will identify disease-causing genetic variants
Method Study part 1 Patients suffering from premature CAD who have had a percutaneous coronary intervention PCI or coronary artery bypass graft operation CABG done before the age of 40 years will be selected from the West Denmark Heart Registry VDHD Specifically patients treated at Aarhus University Hospital AUH in Skejby for myocardial infarction MI stable or unstable angina pectoris in the period of January 1st 2007 - December 31st 2013 will be recruited and the occurrence of registered risk factors be evaluated sample indicates app 170 patients per year After informed consent is obtained they will participate in this research study Participants will be interviewed in the cardiac outpatient clinic at the Dep of Cardiology AUH Skejby The following information about cardiovascular risk factors will be collected family history of atherosclerosis a pedigree analysis will be performed and cases of diagnosed CVD will be identified prior medical history ie hypertension dyslipidemia diabetes chronic kidney disease vascular disease smoking status and number of pack years alcohol consumption and vascular symptoms ie angina pectoris intermittent claudication Gathered information will be compared to the registered information in patient records and VDHD In addition information about localization of the invasive treatment the degree of CAD and the latest estimate of the left ventricular ejection fraction LVEF will be collated All patients will be examined regarding height and weight abdominal girth and a blood sample is collected An automated office blood pressure measurement Bp-TRU device will be performed Levels of creatinine e-GFR total cholesterol LDL cholesterol HDL cholesterol triglycerides and HbA1c will be measured Further a blood sample will be saved for prospective DNA analysis below The investigators will evaluate to what degree the treatment targets have been met in accordance with national guidelines Analysis will be corrected to reflect changes in these treatment guidelines which have occurred in recent years
Study part 2 Patients from study 1 index patients are requested to establish contact to 1st degree relatives between 30 and 65 years of age for the purpose of participating in Study part 2 The form of contact follows regular department guidelines for contact to family members 1st degree relatives who give their informed consent will be included in study part 2 participants Patient records from participants who are diagnosed with atherosclerosis will be obtained Exclusion criteria will be former diagnosis of CAD by CTCA or percutaneous transluminal coronary angiography chronic atrial fibrillation renal failure e-GFR 30mlmin obesity BMI 30 is indicative but body geometry plays a role former allergic contrast reaction and pregnancy A traditional risk profile and blood samples will be collected as in study part 1 Prior to the CTCA LVEF is estimated by echocardiography A CTCA is performed according to the standard protocol in the department Initially the CT-scan is performed without contrast in order to estimate the coronary calcification by Agatstons method Afterwards a scan is performed with 70 ml of iodine-containing contrast ECG modulation and radiation-reduced protocols will be used so that an average participant 70 kg may expect to receive a radiation dose below 3 mSv The analysis of the contrast study will focus on automated- and semi-automated plaque quantification Non-cardiac findings will be described according to department standard procedures by the Dep of Radiology AUH Skejby and medical intervention performed as clinically indicated
Study part 3 Families from study part 1 and 2 who are considered severely affected by atherosclerosis evaluated on a basis of family size number of affected and severity of disease will be selected Family members index patients 1st degree relatives and if relevant also their 1st degree relatives who consentwill be included in study part 3 Contact with relatives who have not yet participated in the project will be attempted as in study part 2 A traditional risk profile and a blood sample for DNA analysis exome sequencing will be requested if it has not already been obtained The analysis takes place at Department of Molecular Medicine MOMA AUH Skejby who have the required equipment software and laboratory expertise in performing the tests as well as the bioinformatic analysis First genomic DNA is purified and fragmented to a size of 200-500 base pairs Illumina TruSeq libraries to be used with the exome sequencing will be produced at a Caliper Sciclone-robot where the exome enrichment with Nimblegens EZ in solution Exome v3 kit will also take place The dataanalysis will be taking place at MOMA under the guidance of the MOMA staff First sequences will be trimmed and aligned to the humane genome Second alignments will be fine-tuned before variants will be called including single nucleotide variants and insertionsdeletions of various size The interpretation of the data will be taking place in the software program Cartagenia which gives access to an abundance of public and commercial databases and also offers the opportunity of integrating private databases Variants will be filtered on a basis of frequency gene position existing knowledge and different in-silico prediction tools Possible significant findings will be validated by Sanger sequencing
Statistical analysis At the found genotypes from study part 3 coupling analysis is performed to identify regions in the genome shared by disease-affected individuals The use of pedigree analysis and coupling analysis substantially reduce the candidate intervals in the genome thereby increasing the statistical power to identify disease-causing variants even in small families Because the precise genetic architecture and family structure of the included families is not known exact calculation of statistical power will not be possible In case of a dominant monogenetic disease a filtration only based on localization coupling reduces the potential variants by app 80 within a pair of affected siblings and by more than 95 for monogenetic recessive diseases if affected individuals from inbred families
Research Biobank A research biobank will be established under The Institute of Clinical Medicine Health Aarhus University A sample of 2x4 ml BD Vacutainer K3E 72mg Ref 368860 and 1x4ml BD Vacutainer SST II Advance Ref 367957 blood from all participants in studies 1-3 will be submitted to the biobank for further analysis The sampling is performed at AUH Skejby or a glass and a return envelope will sent to the patient for the drawing of blood by their family physician The sample is cryo-preserved and exome sequencing is performed on the participants of study part 3 The biobank will be carried on after the project has ended for the purpose of future research In case of future analysis on the preserved material The Research Ethics Committee and the participant if still alive will be noticed before hand Permission to store the biological material will be applied continuously according to specified intervals by The Danish Data Protection Agency All participants may demand their biological material destroyed at any time
Study part 2 Investigate the occurrence of CAD among middle-aged 1st degree relatives of established patients having very premature CAD
Study part 3 Evaluate possible genetic risk factors in families with a high CAD prevalence using exome sequencing analysis
Hypotheses Hypothesis 1 Patients with very premature CAD have modifiable risk factors which are inadequately treated relative to current national guidelines
Hypothesis 2 The occurrence of very premature CAD is associated with familial accumulation of the disease
Hypothesis 3 The use of exome sequencing in selected families with phenotypic severe premature CAD will identify disease-causing genetic variants
Method Study part 1 Patients suffering from premature CAD who have had a percutaneous coronary intervention PCI or coronary artery bypass graft operation CABG done before the age of 40 years will be selected from the West Denmark Heart Registry VDHD Specifically patients treated at Aarhus University Hospital AUH in Skejby for myocardial infarction MI stable or unstable angina pectoris in the period of January 1st 2007 - December 31st 2013 will be recruited and the occurrence of registered risk factors be evaluated sample indicates app 170 patients per year After informed consent is obtained they will participate in this research study Participants will be interviewed in the cardiac outpatient clinic at the Dep of Cardiology AUH Skejby The following information about cardiovascular risk factors will be collected family history of atherosclerosis a pedigree analysis will be performed and cases of diagnosed CVD will be identified prior medical history ie hypertension dyslipidemia diabetes chronic kidney disease vascular disease smoking status and number of pack years alcohol consumption and vascular symptoms ie angina pectoris intermittent claudication Gathered information will be compared to the registered information in patient records and VDHD In addition information about localization of the invasive treatment the degree of CAD and the latest estimate of the left ventricular ejection fraction LVEF will be collated All patients will be examined regarding height and weight abdominal girth and a blood sample is collected An automated office blood pressure measurement Bp-TRU device will be performed Levels of creatinine e-GFR total cholesterol LDL cholesterol HDL cholesterol triglycerides and HbA1c will be measured Further a blood sample will be saved for prospective DNA analysis below The investigators will evaluate to what degree the treatment targets have been met in accordance with national guidelines Analysis will be corrected to reflect changes in these treatment guidelines which have occurred in recent years
Study part 2 Patients from study 1 index patients are requested to establish contact to 1st degree relatives between 30 and 65 years of age for the purpose of participating in Study part 2 The form of contact follows regular department guidelines for contact to family members 1st degree relatives who give their informed consent will be included in study part 2 participants Patient records from participants who are diagnosed with atherosclerosis will be obtained Exclusion criteria will be former diagnosis of CAD by CTCA or percutaneous transluminal coronary angiography chronic atrial fibrillation renal failure e-GFR 30mlmin obesity BMI 30 is indicative but body geometry plays a role former allergic contrast reaction and pregnancy A traditional risk profile and blood samples will be collected as in study part 1 Prior to the CTCA LVEF is estimated by echocardiography A CTCA is performed according to the standard protocol in the department Initially the CT-scan is performed without contrast in order to estimate the coronary calcification by Agatstons method Afterwards a scan is performed with 70 ml of iodine-containing contrast ECG modulation and radiation-reduced protocols will be used so that an average participant 70 kg may expect to receive a radiation dose below 3 mSv The analysis of the contrast study will focus on automated- and semi-automated plaque quantification Non-cardiac findings will be described according to department standard procedures by the Dep of Radiology AUH Skejby and medical intervention performed as clinically indicated
Study part 3 Families from study part 1 and 2 who are considered severely affected by atherosclerosis evaluated on a basis of family size number of affected and severity of disease will be selected Family members index patients 1st degree relatives and if relevant also their 1st degree relatives who consentwill be included in study part 3 Contact with relatives who have not yet participated in the project will be attempted as in study part 2 A traditional risk profile and a blood sample for DNA analysis exome sequencing will be requested if it has not already been obtained The analysis takes place at Department of Molecular Medicine MOMA AUH Skejby who have the required equipment software and laboratory expertise in performing the tests as well as the bioinformatic analysis First genomic DNA is purified and fragmented to a size of 200-500 base pairs Illumina TruSeq libraries to be used with the exome sequencing will be produced at a Caliper Sciclone-robot where the exome enrichment with Nimblegens EZ in solution Exome v3 kit will also take place The dataanalysis will be taking place at MOMA under the guidance of the MOMA staff First sequences will be trimmed and aligned to the humane genome Second alignments will be fine-tuned before variants will be called including single nucleotide variants and insertionsdeletions of various size The interpretation of the data will be taking place in the software program Cartagenia which gives access to an abundance of public and commercial databases and also offers the opportunity of integrating private databases Variants will be filtered on a basis of frequency gene position existing knowledge and different in-silico prediction tools Possible significant findings will be validated by Sanger sequencing
Statistical analysis At the found genotypes from study part 3 coupling analysis is performed to identify regions in the genome shared by disease-affected individuals The use of pedigree analysis and coupling analysis substantially reduce the candidate intervals in the genome thereby increasing the statistical power to identify disease-causing variants even in small families Because the precise genetic architecture and family structure of the included families is not known exact calculation of statistical power will not be possible In case of a dominant monogenetic disease a filtration only based on localization coupling reduces the potential variants by app 80 within a pair of affected siblings and by more than 95 for monogenetic recessive diseases if affected individuals from inbred families
Research Biobank A research biobank will be established under The Institute of Clinical Medicine Health Aarhus University A sample of 2x4 ml BD Vacutainer K3E 72mg Ref 368860 and 1x4ml BD Vacutainer SST II Advance Ref 367957 blood from all participants in studies 1-3 will be submitted to the biobank for further analysis The sampling is performed at AUH Skejby or a glass and a return envelope will sent to the patient for the drawing of blood by their family physician The sample is cryo-preserved and exome sequencing is performed on the participants of study part 3 The biobank will be carried on after the project has ended for the purpose of future research In case of future analysis on the preserved material The Research Ethics Committee and the participant if still alive will be noticed before hand Permission to store the biological material will be applied continuously according to specified intervals by The Danish Data Protection Agency All participants may demand their biological material destroyed at any time
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 13517433 | OTHER | Aarhus University PhD application number | None |