genetics of rheumatoid arthritis in some arab states
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Genetics of Rheumatoid Arthritis in some Arab States
Thurayya Arayssi M.DWeill Cornell Medical College-Qatar
May 2012
Welcome
Objectives of the Meeting
• To review study design• To discuss study details• To familiarize investigators with study
procedure• To assess the needs of the collaborating
centers for a successful study
Aims of the Study
1. Enroll and Collect DNA on at least 2000 RA cases and 2000 controls
2. Assess for the defined RA risk alleles by genotyping a subset of 500 seropositive cases and 500 controls
3. Sequence the whole exome in a large consanguineous family to discover inherited recessive protein coding mutations that cause RA.
Figure 2: Common alleles associated with risk of RA. Timeline of discovery of common alleles from candidate gene and genome-wide studies. These RA risk alleles have not yet been tested among individuals of Arab ancestry.
Common Alleles Associated with RA Risk
T-Cell Activation NF Kappa B pathwayHLA DRB1:involved in MHC molecule–based antigen presentation and responsible for self-peptide selection and T-cell repertoire
REL:Proto-oncogene member of the NF-κB family that regulates leukocyte activation and survival
PTPN22:Lymphocyte-specific nonreceptor tyrosine phosphatase involved in regulation of activation threshold of lymphocyte
TNFAIP3:Signaling protein and negative regulator of TNF-α–induced NF-κB activation
AFF3:Transcription factor for lymphoid development TRAF1:Regulator of TNF-α–receptor superfamily signaling (e.g., to NF-κB and JNK)
CD28:Costimulatory molecule for T-cell activation Other pathwaysCD40:Costimulatory molecule that enhances interactions between T and B cells and increases auto- antibody production
BLK:B-lymphoid tyrosine kinase involved in B-cell receptor signaling and B-cell development
CTLA4:Costimulation suppressor that regulates interactions between T cells and antigen-presenting cells
CCL21
IL2RA:High-affinity receptor for interleukin-2 on lymphocyte subsets
FCGR2A
IL2:Cytokine that regulates activation of T cells, particularly regulatory T cells
PADI4:Enzyme that converts arginine to citrulline, creating autoantigens in rheumatoid arthritis
IL-21:Cytokine that regulates differentiation of T cells, particularly Th17, and activation of B cells
PRDM1
PRKCQ, STAT4, TAGAP:Member of the protein kinase C family that regulates T-cell and macrophage activation; Transducer of cytokine signals that regulate proliferation, survival, and differentiation of lymphocytes; Rho-GTPase enzyme involved in T-cell activation
TNFRSF14
NEJM, 365;23nejm.orgdecember 8, 2011
Studies from the Middle East
• Largest study by Dr. Kazkaz:– A dose effect was observed between the SE copy
number and• risk of RA (OR 1 vs 0 copies = 1.6; OR 2 vs 0 = 15.3) • radiographic joint destruction (OR 1 vs 0 = 2.2; OR 2 vs
0 = 9.9)
Our study
• Genome Wide Association Study (GWAS) that will test for >30 identified risk alleles identified in European and North American populations
Patients Inclusion Criteria
• Self reported Arab ancestry• Age > 18• RA diagnosed per the ACR criteria• Ability to provide informed consent• Otherwise no exclusion criteria
Case log
ControlsInclusion Criteria
• Self reported Arab Ancestry• Absence of an underlying autoimmune
disorder• Able to provide an informed consent• 1:1 matching for age ( 10 year range), gender
and reported ancestry
Control log
Projected number of patients/center
Total patient visits and expected RA patients at each collaborating center Country Approximate number of
clinic visits per yearAnticipated number of RA patients enrolled in the study per year
Jordan 2620 350 (13%)Kingdom of Saudi Arabia 1500 100 ( 7%)Lebanon 3000 300 (10%)Qatar 3500 130 (4%)United Arab Emirates 1600 250 (15%)
We are committed to 1000 patients and 1000 controls in the first year
Data collection( 10-15 minutes)
• Clinical Data – Demographic and clinical data questionnaire– Ancestry questionnaire
• All data entry will be electronic via survey gizmo
1. Demographic Questionnaire2. Ethnicity Questionnaire
Blood Collection(30 Minutes)
• Blood collection kits pre-labeled shipped to center according to a preset schedule
• 10 cc of blood to be collected in EDTA tubes• Tube to be inverted 8-10 times• Blood to be transferred to cryovials, precoded• Blood to be frozen immediately at -80 C
1. Shipment form2. Blood collection form
Shipment
• Samples will then be shipped, on dry-ice, according to a preset timeline, to WCMC-Q for DNA extraction
Shipment lecture
Documentation
• Linking patients to samples• Anonymization• Recruitment strategy
Eligibility Criteria met
Patient signs two original informed consent forms
and entered into the study
Pre-prepared labels affixed to consent forms
Questionnaires filled electronically by PI or
representative
Patient to blood drawing station
10 cc of blood drawn and stored according to SOP
Blood shipped to WCMC-Q per preset schedule
Patient refuses to sign ICF Patient d/c
Technical problems
•Use paper format•Lable with provided lables•Send electronically within 24 hours
Patient refuses blood draw
Document in log sheet
Log sheet sent monthly basis
WORKFLOW
Study TimelineAims 3/12-9/12 9/12-3/13 3/13-9/13 9/13-3/14 3/14-9/14 9/14-3/15
Set-upRecruitment
Famliy/exomeGenotype
Analysis
1000 patients 1000 patients
Sequencing Analysis
Questions
Genetics of Rheumatoid Arthritis in some Arab States
Thurayya Arayssi M.DWeill Cornell Medical College-Qatar
May 2012
What is Next?
September 1 2012
First Patient to be recruited
June-September 2012
• Testing the system– Use suvery Gizmo to trouble shoot– Assess your site for readiness• Identify responsibilities ( Responsibility log to be sent)• -80 Freezer, racks, back up electricity and space
availability• Pipettes• Shipping agency and the requirements for shipping
blood outside the country• Recruitment plan
June-September 2012June and July
• SOP will be sent to each Center to standardize and facilitate the work
• Weekly Skype calls in June to trouble shoot according to a preset schedule
• Monthly Skype calls thereafter or as requested by each center
June-September 2012August
• Mid August- – Reminder documents, webcasts sent to centers– Skype calls for each Center to finalize needs prior
to “first patient in”
Communication Plans
• Monthly Skype Calls
• Quarterly Newsletter• Update on recruitment• Trouble shooting• Emerging issues to all centers
• Meeting preset at the ACR and ? EULAR
Future Plans
• Searching for families with multiple members with RA
• Metabolomics
THANK YOU
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