Abstract
We performed linkage analysis on families with rheumatoid arthritis, stratifying by ethnic origin. We compared results using either Kong and Cox nonparametric LOD scores or MOD score analysis using the software GeneHunter MODSCORE. We first applied SNPLINK to remove markers showing excess linkage disequilibrium from the SNPs in the Illumina IV SNP Linkage panel. In this analysis there were 659 self-reported Caucasian families and 29 self-reported Hispanic families in the NARAC collection. Chromosome 19 yielded MOD scores > 3.00 in the Hispanic group, while chromosomes 2, 6, 7, 11, and XY had MOD scores > 3.00 in the Caucasian group. We performed simulation studies to evaluate the empirical distribution of the MOD score for autosomal loci separately in Hispanics and Caucasians. Results showed genome-wide significant evidence for linkage in Caucasians for chromosomes 2q and 6p, but no significant evidence for any linkages in the Hispanics, including little evidence for linkage to chromosome 6p in this group. An examination of the difference of phenotypes in two ethnic groups suggested significantly earlier mean age of onset, higher percentage of anti-cyclic citrullinated peptide positive people, and lower percentage of affected people carrying shared epitopes in Hispanics than those in Caucasians. A larger sample size of the Hispanic group is needed to identify linkage regions.
Highlights
Rheumatoid arthritis (RA) is a complex genetic disease with possible genetic heterogeneity among different ethnic groups [1]
We evaluated the phenotypes between the two groups to compare their ages of onset, rheumatoid factor (RF)-IgM and anti-CCP levels and the percentage of affected individuals carrying shared epitopes
Best fitting models from MOD score analyses corresponding to maximal MOD scores of 1.50 or greater are provided in Table 2 for Caucasians and Hispanics, even though they often lead to excess predicted prevalence of the disease
Summary
Rheumatoid arthritis (RA) is a complex genetic disease with possible genetic heterogeneity among different ethnic groups [1]. We performed a genome-wide single-nucleotide polymorphism (SNP) analysis of NARAC (North American Rheumatoid Arthritis Consortium) Caucasian families and identified two new loci at 2q33 and 11p12, in addition to confirming evidence for linkage in the HLA region (Kong and Cox LOD score of 16.14) [2]. We applied standard linkage analysis methods as well as the MOD score approach to this same set of Caucasian families as well as to a set of Hispanic families to compare evidence of linkage to RA in these two groups. The MOD score method provides estimates of the penetrance for putative disease-susceptibility loci, while conditioning on the disease status, adjusting for ascertainment of the families. The distribution of the MOD score test statistic is complex, and we have performed extensive simulations to obtain empirical p-values
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