Steve Eyre | PubMed Health

PubMed2006

Investigation of genetic variation across the protein tyrosine phosphatase gene in patients with rheumatoid arthritis in the UK.

OBJECTIVE: To investigate single-nucleotide polymorphisms (SNPs) across the PTPN22 gene region in a UK cohort of patients with rheumatoid arthritis (RA), to look for evidence of disease associations independent of the well-characterised R620W variant (rs2476601). METHODS: 951 RA cases in the UK satisfying American Rheumatism Association (ARA) criteria and 448 population controls were genotyped for 11 SNPs across the PTPN22 gene region using the Sequenom MassArray MassEXTEND technology. Allele, genotype and estimated haplotype frequencies of cases and controls were compared. RESULTS: In addition to the R620W (rs2476601) SNP, three SNPs were associated with RA in this study. The sole haplotype on which the associated T allele of R620W occurred was associated with RA; no other haplotypes showed a significant difference in frequencies between RA cases and controls. CONCLUSION: In contrast with a study of American patients with RA no evidence of association with PTPN22 independent of the well-characterised R620W variant was found, suggesting that in these patients this variant alone explains the association with the PTPN22 gene.

Alleles↗

PubMed2004

Whole-genome scan, in a complex disease, using 11,245 single-nucleotide polymorphisms: comparison with microsatellites.

Despite the theoretical evidence of the utility of single-nucleotide polymorphisms (SNPs) for linkage analysis, no whole-genome scans of a complex disease have yet been published to directly compare SNPs with microsatellites. Here, we describe a whole-genome screen of 157 families with multiple cases of rheumatoid arthritis (RA), performed using 11,245 genomewide SNPs. The results were compared with those from a 10-cM microsatellite scan in the same cohort. The SNP analysis detected HLA*DRB1, the major RA susceptibility locus (P=.00004), with a linkage interval of 31 cM, compared with a 50-cM linkage interval detected by the microsatellite scan. In addition, four loci were detected at a nominal significance level (P<.05) in the SNP linkage analysis; these were not observed in the microsatellite scan. We demonstrate that variation in information content was the main factor contributing to observed differences in the two scans, with the SNPs providing significantly higher information content than the microsatellites. Reducing the number of SNPs in the marker set to 3,300 (1-cM spacing) caused several loci to drop below nominal significance levels, suggesting that decreases in information content can have significant effects on linkage results. In contrast, differences in maps employed in the analysis, the low detectable rate of genotyping error, and the presence of moderate linkage disequilibrium between markers did not significantly affect the results. We have demonstrated the utility of a dense SNP map for performing linkage analysis in a late-age-at-onset disease, where DNA from parents is not always available. The high SNP density allows loci to be defined more precisely and provides a partial scaffold for association studies, substantially reducing the resource requirement for gene-mapping studies.

Arthritis, Rheumatoid↗