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

<div><h3>Background</h3><p>TNFα 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 TNFα inhibitors in patients with rheumatoid arthritis (RA).</p> <h3>Methodology and Principal Findings</h3><p>In the DANBIO Registry we identified 237 TNFα inhibitor naïve 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 INDELS potentially related to RA and treatment response using the GeneVa® (Compugen) <em>in silico</em> 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 Fisher’s 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: 1.99–10.09, p = 7.211×10⁻⁵) and with EULAR good response vs. moderate/no response (OR = 4.54, 95% CI: 2.29–8.99, p = 3.336×10⁻⁶). A microsatellite within the syntaxin binding protein 6 (STXBP6) was associated with EULAR good response vs. no response (OR = 4.01, 95% CI: 1.92–8.49, p = 5.067×10⁻⁵).</p> <h3>Conclusion</h3><p>Genetic variations within CD6 and STXBP6 may influence response to TNFα inhibitors in patients with RA.</p> </div

Allele distribution of the CGEN-40003 amplicon according to EULAR response.

<p>The Y-axis indicates percentage of patients. The X-axis indicates EULAR response (good, moderate, none). The colored boxes indicate the size (base pair) of the longest allele.</p

Association between genotype and EULAR good response versus EULAR no response.

*<p>Odds ratio for EULAR good response being 512 positive; #adjusted p-value;</p>**<p>Odds ratio for EULAR good response when both alleles are ≤280;</p>***<p>after correction for dependency.</p

Association between genotype and EULAR good response versus EULAR moderate response/no response.

*<p>Odds ratio for EULAR good response being 512 positive,</p>***<p>after correction for dependency.</p

Demographic and clinical characteristics at baseline.

<p>Values are given as median (range) or number (percentage of total).</p>#<p>3 patients had missing smoking status.</p>##<p>115 patients had missing anti-CCP values.</p

Possible tests imposing a 10% genotype group size condition in the 156 patients with either EULAR good response or no response.

<p>Possible tests imposing a 10% genotype group size condition in the 156 patients with either EULAR good response or no response.</p