Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


An International Collaboration for the Genetic Fine Mapping of 8,000 Rheumatoid Arthritis Cases and 12,000 Controls Refines Associations to Known Loci, Indicates Multiple Independent Affects and Reveals Novel Associations.

Eyre1,  Stephen, Bowes2,  John, Barton3,  Anne, Raychaudhuri4,  Soumya, Amos5,  Christopher, Diogo4,  Dorothee, Lee6,  Annette T.

University of Manchester, Manchester, United Kingdom
Arthritis Research UK, Manchester, United Kingdom
Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom
Brigham and Women's Hospital, Boston, MA
Houston, TX
Feinstein Institute Med Rsch, Manhasset, NY
Karolinska Institutet, Stockholm, Sweden
Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden
Feinstein Institute Medical Reschearch, Manhasset, NY

Background/Purpose:

Genome wide association studies (GWAS) have been tremendously successful in identifying loci associated with a range of traits and disorders. Indeed, there are over 240 confirmed susceptibility loci reported for nine autoimmune diseases alone. One task now is to take these findings and translate them into clinical utility. The first step in this is to elucidate the genetic architecture of the loci in each disease with fine mapping experiments. These are expected to localise the association signal, indicate whether multiple, independent genetic affects are present and may point to the casual gene.

Methods:

The aim of this study was to fine map loci significantly associated with autoimmune disease in a large cohort of 10,000 rheumatoid arthritis (RA) cases and 14,000 controls using the custom Illumina Immunochip. The Immunochip was designed by a consortium of researchers investigating 12 autoimmune diseases and represents all known genetic variation from dbSNP, 1kG and sequencing projects for approximately 200 validated loci.The genotyping for the RA samples was performed in multiple centres and therefore all raw genotyping data was collated centrally for combined clustering and analysis. The data was first re-clustered and after applying strict QC metrics (98% SNP and 98% sample) the samples were subjected to further pruning for relatedness and ancestral outliers.

Results:

In the initial analysis we have examples of re-focusing of the strongest association signal (e.g. 2q11), evidence for multiple independent associations within a locus (e.g. PADI4, PTPN22) and associations to previously unconfirmed RA loci (e.g. IRAK1, IRF8).Within the 2q11 locus the peak of associations has moved 76kb to now lie within the AFF3 gene. The PADI4 gene has, for the first time, been robustly associated with RA in a Caucasian population (p = 7×10-8). There is also evidence for two independent affects in this region, one of which is correlated with the variant previously reported to be associated with RA in Japanese populations. In addition we have preliminary evidence that there may be 2 independent associations around the PTPN22 locus. The second affect is centred on the RSBN1/PHTF1 genes, a region previously implicated with PsA. We also have preliminary evidence of genome-wide significant (p<5×10-8) associations to IRF8, a gene previously associated with Multiple Sclerosis, and to a region on ChrX incorporating IRAK1, a loci previously associated with systemic lupus erythematosus. This is the first evidence of a significant association with a locus on ChrX with RA.

Conclusion:

Although GWAS studies have underpinned a dramatic advance in our understanding of the genetic architecture of rheumatoid arthritis it is clear that large scale fine mapping efforts, such as this, will be necessary to better interpret the complexity of the results and translate the findings into clinicsal utility.

To cite this abstract, please use the following information:
Eyre, Stephen, Bowes, John, Barton, Anne, Raychaudhuri, Soumya, Amos, Christopher, Diogo, Dorothee, et al; An International Collaboration for the Genetic Fine Mapping of 8,000 Rheumatoid Arthritis Cases and 12,000 Controls Refines Associations to Known Loci, Indicates Multiple Independent Affects and Reveals Novel Associations. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1677
DOI:

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