A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases

Abstract

Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with lambdaHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P<.005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement in significance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.

Figures

Figure 1

Results from affected sib-pair tests implemented by SIBPAL. The negative logarithm of the P values are plotted against the markers by chromosomal position. For markers on the X chromosome, the analysis was performed using the MLOD method from ASPEX; for this chromosome, too, the negative logarithm of the P values are plotted against the chromosomal position of the markers.

Figure 2

Results of the ASM analysis (GeneHunterPlus), under the Kong and Cox exponential model. Only the five chromosomes (1, 4, 12, 16, and 17) that show evidence of linkage in SIBPAL (P<.005) were considered for this analysis. The LOD scores are plotted against the chromosomal positions of the markers.