Abstract
In the present paper, we used the North American Rheumatoid Arthritis Consortium data provided for Genetic Analysis Workshop 15 Problem 2 to: 1) estimate the penetrances of PTPN22 and HLA-DRB1 and, 2) test the selected model of PTPN22 conditional on the rheumatoid factor status. To achieve these aims, we used the marker association segregation chi-square method, fitting simultaneously both genotype frequency and identical by descent distributions in a sample of 3690 White individuals from 604 nuclear families. A co-dominant model fitted the rs2476601 (R620W) single-nucleotide polymorphism (SNP) of the PTPN22 gene well, whereas a lack of fit for all models was observed for the HLA-DRB1 locus. Testing genetic models of rheumatoid arthritis that include the PTPN22 SNP in addition to the HLA-DRB1 locus did not affect the results, nor did subgroup analysis of PTPN22 conditional on the rheumatoid factor status. In conclusion, PTPN22 R620W SNP is a risk factor for rheumatoid arthritis. The genetic architecture of the HLA-DRB1 locus is highly complex, and more elaborate modeling of this locus is required.
Highlights
The HLA locus, and in particular several alleles of HLADRB1, have been associated with rheumatoid arthritis (RA) and other autoimmune disorders [1,2]
We report that a co-dominant model best fits the PTPN22 data and that stratification based on rheumatoid factor status did not modified the results
Lack of fit of identical by descent (IBD) data for HLA-DRB1 The estimated general population allele frequencies are 15%, 6%, 5%, and 74% for E1, E2, E3, and Ex, respectively. These frequencies are similar to those of the population recruited in France through the European Consortium on Rheumatoid Arthritis [7]
Summary
The HLA locus, and in particular several alleles of HLADRB1, have been associated with rheumatoid arthritis (RA) and other autoimmune disorders [1,2]. The specific alleles being implicated vary according to population. Reported set of alleles are DRB1*0101, 0102, 0401, 0404, 0405, 0408, and 1001 [2]. These alleles are either associated with severe forms of RA, or are weakly and sometime inconsistently associated with RA. Variability in disease expression is observed in individuals with the same HLA background, ranging from some being severely affected to others being unaffected [2]. HLA-DRB1 does not alone explain the genetic susceptibility to common forms of RA.
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