CD6 and Syntaxin Binding Protein 6 Variants and Response to Tumor Necrosis Factor Alpha Inhibitors in Danish Patients with Rheumatoid Arthritis

abstract: ...Background TNF inhibitor therapy has greatly improved the treatment of patients with rheumatoid arthritis, however at least 30% do not respond. We aimed to investigate insertions and deletions (INDELS) associated with response to TNF inhibitors in patients with rheumatoid arthritis (RA). Methodology and Principal Findings In the DANBIO Registry we identified 237 TNF inhibitor nave patients with RA (81% women; median age 56 years; disease duration 6 years) who initiated treatment with infliximab (n=160), adalimumab (n=56) or etanercept (n=21) between 1999 and 2008 according to national treatment guidelines. Clinical response was assessed at week 26 using EULAR response criteria. Based on literature, we selected 213 INDELSpotentially related to RA and treatment response using the GeneVa (Compugen) in silico database of 350,000 genetic variations in the human genome. Genomic segments were amplified by polymerase chain reaction (PCR), and genotyped by Sanger sequencing or fragment analysis. We tested the association between genotypes and EULAR good response versus no response, and EULAR good response versus moderate/no response using Fishers exact test. At baseline the median DAS28 was 5.1. At week 26, 68 (29%) patients were EULAR good responders, while 81 (34%) and 88 (37%) patients were moderate and non-responders, respectively. A 19 base pair insertion within the CD6 gene was associated with EULAR good response vs. no response (OR=4.43, 95% CI: 1.9910.09, p=7.21110 5 ) and with EULAR good response vs. moderate/no response (OR=4.54, 95% CI: 2.298.99, p=3.33610 6 ). A microsatellite within the syntaxin binding protein 6 (STXBP6) was associated with EULAR good response vs. no response (OR=4.01, 95% CI: 1.928.49, p=5.06710 5 ). Conclusion Genetic variations within CD6 and STXBP6 may influence response to TNF inhibitors in patients with RA.

..., respectively. A 19 base pair insertion within the CD6 gene was associated with EULAR good response vs. no response (OR=4.43, 95% CI: 1.9910.09, p=7.21110 5 ) and with EULAR good response vs. moderate/no response (OR=4.54, 95% CI: 2.298.99, p=3.33610 6 ). A microsatellite within the syntaxin binding protein 6 (STXBP6) was associated with EULAR good response vs. no response (OR=4.01, 95% CI: 1.928.49, p=5.06710 5 ). Conclusion Genetic variations within CD6 and STXBP6 may influence response to TNF inhibitors

... positive; #adjusted p-value; ** Odds ratio for EULAR good response when both alleles are 280; *** after correction for dependency. CGEN-40003 CGEN-40003 represents a multi-allelic amplicon located within the syntaxin binding protein 6 (STXBP6) gene on chromosome 14. It has seven alleles ranging in lengths between 252 and 294 bp. The distribution of genotype within the 156 patients with either EULAR good response or EULAR no response is shown in Table 3 . Imposing the 10% group size condition, 8 tests

... EULAR response (good, moderate, none). The colored boxes indicate the size (base pair) of the longest allele. Discussion Our main finding is that INDELS within the CD6 gene and the STXBP6 gene are associated with EULAR response to TNF inhibitor treatment in patients with RA treated in routine care. During the last decade biologic therapies have greatly improved the treatment of patients with RA. Although highly effective, concerns remain about the variable response rates to TNF inhibitors, the high

..., and we found that patients with the longest CGEN-40003 alleles were more often classified as non- and moderate responders. The CGEN-40003 amplicon represents a 2 bp short repeat within the STXBP6 gene (syntaxin binding protein 6) on chromosome 14. The variation lies within a very long intron, approximately 10 Kbp away from the closest exon. This microsatellite is represented in dbSNP version 130 by several entries, for example rs10630160, rs34132743, rs35668825. The reference genome contains 17 TG

... transcription of the STXBP6 gene or be correlated with another variation in the region. STXBP6 is not a known RA susceptibility gene or biomarker of response to TNF inhibitors in patients with RA but in a previous microarray study of patients with RA treated with TNF inhibitors, STXBP6 was differentially expressed in responders compared to non responders [37] . STXBP6 is a syntaxin binding protein that binds to components of the SNARE complex which inhibits membrane fusions including phagocytosis [38] . Interestingly, a combined GWAS and replication study has recently identified 4 loci within STXBP6, ITGA4, MLZE and the MHC region associated with monocyte counts in a cohort of 14,792 Japanese individuals [39] . STXBP6 is suggested to play a role in the immune response by altering the ability of phagocytosis and antigen presentation of monocytes and macrophages [39] . In our primary analysis, we tested the allele frequency in patients with good EULAR response versus no EULAR response. Our basic assumption

... INDELS (such as microsatellites) might be more useful than SNPs [46] . In the present study, we did only test common INDELS with a length of maximum 500 bp. Rare INDELS >500 kb and other large genetic variations such as copy number variations, which are likely to be more deleterious, were not tested. In conclusion, we identified genetic variations within the CD6 and the STXBP6 genes associated with response to TNF inhibitors in a cohort of homogeneous Danish patients with RA. Future, prospective

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Gene: STXBP6 - syntaxin binding protein 6 (amisyn) - (NCBI)

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