Abstract 1170: Genome Wide Linkage Scan of 748 Affected Sibling Pair Families with Rheumatoid Arthritis Using the Illumina Linkage IV Set of ~5,600 SNP Markers
P Gregersen, W Chen, A Lee, M Seldin, W Li, M Kern, S Remmers, L Criswell, D Kastner, C Amos

In RA, a genetic susceptibility locus has been strongly linked to chromosome 6 in the HLA region, corresponding to the shared epitope locus and other genes associated with immune function. However, other loci have been identified on other chromosomes, though with less compelling evidence based on conventional methods. Comparative genome screening for variability in single nucleotide polymorphisms (SNPs) among affected sibling pairs has emerged as a powerful tool for examining loci of genetic susceptibility. Newer technologies, such as the use of chips containing libraries of SNP markers can be used to perform genome wide linkage scans accurately and inexpensively. Here, Gregersen et al use the Illumina method to perform genome linkage scans on affected sibling pairs collected in the North American Rheumatoid Arthritis Consortium (NARAC).

Methods: NARAC contains DNA samples from the parents and affected siblings of 748 multiplex families with RA. For this analysis, complete genome wide linkage scans were performed using the Illumina linkage set of 5,600 SNP markers in the 888 affected sibling pairs from these 748 multiplex families.

Results: As expected, a broad linkage peak was identified on chromosome 6p, centered on the HLA region. However, the breadth and strength of this linkage area suggests that multiple loci on this chromosome outside of the HLA region may also participate in RA susceptibility. Additional susceptibility loci with strong linkage associations were identified on chromosomes 2, 4, 5 (two loci), 10, 11, and 18. The locus on chromosome 11 was highly associated with anti-CCP antibodies.

Conclusions: Other than the well-known HLA locus on chromosome 6, multiple other chromosomes demonstrate strong associations with RA susceptibility on complete genome wide linkage scanning using a large data bank of SNP markers.

Editorial Comment: These are exciting results using a powerful new tool for studying the genetic contribution to disease causation. These results await confirmation and locus mapping to identify the nature of the genes involved. Obviously, not all of the genes located within the loci identified here will be confirmed to play a role in the pathogenesis of RA. However, it is highly likely that genes previously not thought to play any role in the initiation or maintenance of the immune response in RA will gain new importance. Further, novel therapeutic targets have the potential to be identified. Besides the obvious advantage of being able to appreciate the full range of potential susceptibility genes in RA, perhaps an even greater advantage of investigations of this type is knowing where susceptibility genes are not located.

All information contained within the Johns Hopkins Arthritis Center website is intended for educational purposes only. Physicians and other health care professionals are encouraged to consult other sources and confirm the information contained within this site. Consumers should never disregard medical advice or delay in seeking it because of something they may have read on this website.