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.


Genome-Wide Association Study and Comparison of Risk Alleles for Rheumatoid Arthritis in An Isolated Dutch Population.

Nitiham1,  Joanne, Taylor1,  Kimberly E., Aulchenko2,  Yurii S., Oostra2,  Ben, Plenge3,  Robert M., Huizinga4,  Tom W.J., Gregersen5,  Peter K.

University of California, San Francisco, San Francisco, CA
Erasmus Medical Center, Rotterdam, Netherlands
Brigham and Women's Hospital, Boston, MA
Leiden University Medical Center, Leiden, Netherlands
Feinstein Institute Medical Reschearch, Manhasset, NY

Background/Purpose:

Rheumatoid arthritis (RA) is a genetically complex autoimmune disease causing severe disability through joint destruction and deformity. Alleles of the of the HLA-DRB1 locus in the major histocompatibility complex (MHC) have long been known to increase risk of RA; recent genome-wide association studies (GWAS) have resulted in over 30 established loci associated with RA risk. However, effects of these loci are small and much of the heritability of RA is not explained. Isolated populations offer a unique opportunity for the study of genetic diseases, as certain disease-causing alleles may be enriched in such populations.

Methods:

We performed Illumina 660W genotyping on 201 RA cases and 100 healthy controls from a genetically-isolated Dutch population, and utilized Illumina 317K genotyping on another 500 healthy controls from the isolate. After strict quality control, SNPs were imputed up to the HapMap2 using MACH, and SNPs retained with quality score > 0.8 and RSQ > 0.3. We also obtained genotypes for known RA risk SNPs from 2 cohorts: anti-CCP+ or RF+ cases (5,539) and healthy controls (20,169) from a pan-European study, and anti-CCP+ cases (157) and healthy controls (702) from a non-isolated Dutch population. First, we compared 49 RA risk SNPs in our anti-CCP+ cases (131) and controls (555) to those from the pan-European study, and to a subset of SNPs typed in the Dutch non-isolate. Second, we performed a GWAS of our full cohort using the software ProbABEL in order to account for imputed genotype probabilities and relatedness in the population. New SNP associations will be investigated in replication cohorts.

Results:

Although 17 (35%) of the RA risk SNPs had evidence of different background (control) frequencies (p<0.01), only 6 SNPs had evidence of heterogeneity of odds ratios (ORs) (phet<0.1) between the isolate and pan-European cohorts. A SNP of gene TNFRSF14/MMEL1 had a significantly stronger protective effect in the isolate, OR=0.62 (95% CI 0.44–0.87) versus OR=0.89 (0.85–0.94), phet= 0.037. Comparison to the Dutch non-isolate supported that differences are due to isolate membership versus Dutch ancestry. In our GWAS, in spite of the relatively small size of this study, 58 SNPs in the MHC reached genome-wide significance (p < 5×10-8), with the top hit as expected in the HLA-DRB1-HLA-DQA1 region. In addition there were 31 regions outside of the MHC with at least two signals with p<5×10-8, which have not been implicated previously.

Conclusion:

For most established RA risk alleles this isolated Dutch population has similar risk distributions to that of a pan-European cohort, with some exceptions. Our GWAS has identified additional loci with preliminary evidence of association with RA in this population.

To cite this abstract, please use the following information:
Nitiham, Joanne, Taylor, Kimberly E., Aulchenko, Yurii S., Oostra, Ben, Plenge, Robert M., Huizinga, Tom W.J., et al; Genome-Wide Association Study and Comparison of Risk Alleles for Rheumatoid Arthritis in An Isolated Dutch Population. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2162
DOI:

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