Rhe Ar

Rheumatoid Arthritis: 

Rheumatoid Arthritis GAW 15 Problem 2 Shuyan Wan

Project Overview (1): 

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

Project Overview (2): 

Project Overview (2) Sex difference: preponderance of females to males-3:1. Mean age of onset: in the 50s with considerable variability and occasional presentation in the teenage years.

Implicated genes: 

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.

Environmental Cofactors: 

Environmental Cofactors Smoking: 2-fold increased risk—those have a shared epitope allele and also have elevated levels of anti-CCP.

Data from Study Centers: 

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

Data Categories : 

Data Categories

Family Size: 

Family Size NARAC: 4~32; (average ~10) France: 4~13; (average ~6) Canada: mostly 4 and 1 family of size 7. (average 4) UK: 4~9; (average 5)

Phenotype Data: 

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.

Data Format and Preprocessing: 

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.

Initial Genome Scan France chrom1: 

Initial Genome Scan France chrom1

France-chrom2-NPL score: 

France-chrom2-NPL score

France-chrom6: 

France-chrom6

NARAC-MSdata: 

NARAC-MSdata NPL scores for chrom 2, 4 and 5 are less than 2.

Research Questions: 

Research Questions Construct confidence intervals for putative locus by asymptotic method and simulation method—with 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.