Rheumatoid Arthritis

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Rheumatoid Arthritis

• GAW 15 Problem 2
• Shuyan Wan

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Project Overview (1)

• Goal to identify genetic factors that predispose
  for rheumatoid arthritis (RA).
• RA a complex disease with moderately strong
  genetic component.
• Prevalence
• 0.8 in Caucasians
• 10 in Native American groups
• Rare in rural Africans

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Project Overview (2)

• Sex difference
• preponderance of females to males-31.
• Mean age of onset in the 50s
• with considerable variability and occasional
  presentation in the teenage years.

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Implicated genes

• HLA-DR alleles on 6p21 (also some evidence for
  haplotypic effects-class 1 region and central MHC
  with DR3)
• Specific autoantibodies
• IgM, anti-CCP (modulated by HLA-DR3), PTPN22
  (with R620W allele in rs2476601, rs1310182 or
  rs3789604)
• PADI4 encodes on chrom1p, 5q and 17
• CTLA4 on chrom 2q33.

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Environmental Cofactors

• Smoking
• 2-fold increased riskthose have a shared epitope
  allele and also have elevated levels of anti-CCP.

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Data from Study Centers

• The North American RA Consortium (NARAC)
• statgen/GAW15/NARAC/
• The European RA Consortium (ECRAF)
  statgen/GAW15/France/
• Canada
• statgen/GAW15/Canada
• UK
• statgen/GAW15/UK

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Data Categories
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Family Size

• NARAC 432 (average 10)
• France 413 (average 6)
• Canada mostly 4 and 1 family of size 7. (average
  4)
• UK 49 (average 5)

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(No Transcript)
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Phenotype Data

• NARAC including RA affection status, age
  onset,race,height,weight,antiCCP,DRB1_1,DRB1_2,
  etc.
• France and Canada only RA affection status.
• UK RA affection status, Cohort, Age
  Onset,Erosions,RFTiter,RFPast,DRB1_1,DRB1_2.

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Data Format and Preprocessing

• Comma-delimited files
• Map files with unit in Kosambi cM or bp
• Genotypes for typed individuals only.
• Need to make use of pheno file, .DAT and .MAP
  file to make linkage input files for genehunter
  or allegro, etc.
• Merlin and pedwipe to eliminate genotyping error
  and estimate marker allele frequency.

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Initial Genome Scan France chrom1
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France-chrom2-NPL score
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France-chrom6
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NARAC-MSdata

• NPL scores for chrom 2, 4 and 5 are less than 2.

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Research Questions

• Construct confidence intervals for putative locus
  by asymptotic method and simulation methodwith
  MS data from France/NARAC/UK.
• Candidate gene studies NARAC data. PTPN22-1519
  indept controls and 1393 cases.
• Association mapping NARAC data. 2300 dense SNPs
  with 460 cases and 460 controls.
• Quantitative Trait anti-CCP and IgM.