The cause of rheumatoid arthritis is unknown, and the number and importance of genetic factors outside the Major Histocompatibility Complex (MHC) on chromosome 6 are obscure. The North American Rheumatoid Arthritis Consortium (NARAC) has been formed to comprehensively address this question using a variety of strategies including affected sib pair analysis and transmission disequilibrium testing. The consortium consists of ten collaborating centers which will mount a coordinated national effort to identify and collect 800 affected sibling pairs with rheumatoid arthritis. Well-defined sibling pairs with RA will be collected by eight of the ten cooperating centers. Entry into the study will depend on standardized criteria, documented by fact to face clinical evaluation of every sib pair, hand x-rays read by a single radiologist, and centralized serological testing. Where possible, parents and unaffected siblings will be collected. A centralized clinical database, DNA, serum, and cell bank will be established for all affected sibling pairs and family members. The consortium will utilize allele methods for genome wide screening to establish whether genetic regions outside the MHC are linked to susceptiblity to RA. Screening for candidate genetic regions will be done by an analysis of allele sharing using a panel of highly polymorphic microsatellite markers spaced at 10-15 cM intervals across the entire human genome. The large sample size should allow for the analysis of specific subgroups of sib pairs with phenotypes indicative of high genetic risk, namely early onset disease and male sex. When candidate regions are identified, the consortium will further analyze these regions by association based methods, including transmission disequilibrium testing with losely spaced markers in the genetic regions of interest. The consortium expects to identify 5 to 10 candidate regions of interest. By using closely spaced polymorphic markers in these regions, the consortium expects to be able to define haplotypes tha can be tested for their association with disease susceptibility for RA by transmission disequilibrium testing. At UAB we propose to identify and collect 200 of the proposed 800 siblings pairs. We will also perform HLA oligotyping of all of the patients identified. Although the multicenter study is open to patients from all ethnic groups, at UAB emphasis will be placed on collecting families of African-American origin due to the relatively low frequency of this ethnic group in the populations served by the other collaborating centers.
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