ASSOCIATION OF GENES INVOLVED IN ANTIGEN PRESENTATION AND PROCESSING IN AS

W.P. Maksymowych, R.D. Inman, D.D. Gladman, N. Roslin, L. Peddle, P. RahmanRheumatology, University of Alberta, Edmonton; Rheumatology, University of Toronto, Toronto; Rheumatology, Memorial University of Newfoundland, St. Johns, CanadaObjectives: Alterations in antigen processing has been proposed to play a significant role in the pathogenesis of ankylosing spondylitis. This contention is further supported by the recent association of ARTS1 gene and AS (Nat Genet Nov 2007). The ARTS1 protein is involved in trimming peptides to the optimal length for MHC Class 1 presentation. We assessed 13 coding SNPs from 5 genes involved in antigen processing (ARTS1, TAP1, TAP2, LMP2, and LMP7) in a Canadian AS cohort to address the possibility of gene interactions in disease susceptibility.Methods: In total there were 888 AS cases and 927 controls, comprised from three AS centers in Canada (472 cases and 451 controls from Alberta; 138 cases and 392 controls from Newfoundland; 278 cases and 114 controls from Toronto). Most AS patients were Caucasians of North European descent and satisfied the modified New York Classification Criteria. The healthy, unrelated controls were of similar ethnicity to the cases. Associations were performed using UNPHASED 3.0.12 which employs an allelic likelihood ratio test.Results: Evidence for association between AS and antigen processing genes are noted in table 1. Significant associations were noted for the ARTS1 variants (3 SNPs) and TAP2 variants (2 SNPs) and one LMP2 variant. Analysis of the individual cohorts demonstrated associations only in the Alberta population although the direction of allelic frequencies were the same in all 3 cohorts. Therefore this most likely reflects the smaller sample sizes in the Newfoundland and Toronto cohorts. Gene Marker Allele Case Freq Control Freq P-Value ARTS1 rs27044 G 0.2900 0.2733 0.2716 ARTS1 rs10050860 T 0.1704 0.2089 0.0036 ARTS1 rs30187 T 0.3973 0.3383 0.0004 ARTS1 rs26618 C 0.2468 0.2407 0.6753 ARTS1 rs26653 C 0.3310 0.2870 0.0047 ARTS1 rs3734016 A 0.0458 0.0606 0.0532 TAP2 rs241447 G 0.2893 0.2547 0.0230 TAP2 rs4148876 T 0.0594 0.0916 0.0004 TAP2 rs2228396 A 0.0758 0.0903 0.1247 TAP2 rs1800454 A 0.1368 0.1403 0.7699 TAP1 rs1057141 G 0.1608 0.1417 0.1202 LMP2 rs17587 A 0.2554 0.2878 0.0349 LMP7 rs2071543 A 0.1490 0.1595 0.3916 Conclusion: Our data indicate that genetic variation in the ARTS1, TAP2 and LMP2 genes is associated with AS. Possible multiplicative and cumulative effects of genetic variation at multiple loci now need to be formally evaluated.References: Wellcome Trust Case Control Consortium and Australo-Anglo-American Spondylitis Consortium. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants Nature Genetics 2007: 39 (11): 1329-37Citation: Ann Rheum Dis, volume 67, supplement II, year 2008, page 59Session: Abstract Session: Straight talk on SpA; therapies, outcome, genes and sex