Brief Report:The Role of Rare Protein-Coding Variants in Anti–Tumor Necrosis Factor Treatment Response in Rheumatoid Arthritis

In many rheumatoid arthritis (RA) patients, disease is controlled with anti-tumor necrosis factor (anti-TNF) biologic therapies. However, in a significant number of patients, the disease fails to respond to anti-TNF therapy. We undertook the present study to examine the hypothesis that rare and low-frequency genetic variants might influence response to anti-TNF treatment. We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry who were treated with anti-TNF. After quality control, 690 genes were included in the analysis. We applied single-variant association and gene-based association tests to identify variants associated with anti-TNF treatment response. In addition, given the key mechanistic role of TNF, we performed gene set analyses of 27 TNF pathway genes. We identified 14,420 functional variants, of which 6,934 were predicted as nonsynonymous 2,136 of which were further predicted to be "damaging." Despite the fact that the study was well powered, no single variant or gene showed study-wide significant association with change in the outcome measures disease activity or European League Against Rheumatism response. Intriguingly, we observed 3 genes, of 27 with nominal signals of association (P  < 0.05), that were involved in the TNF signaling pathway. However, when we performed a rigorous gene set enrichment analysis based on association P value ranking, we observed no evidence of enrichment of association at genes involved in the TNF pathway (Penrichment  = 0.15, based on phenotype permutations). Our findings suggest that rare and low-frequency protein-coding variants in TNF signaling pathway genes or other genes do not contribute substantially to anti-TNF treatment response in patients with R

Brains in Space II - Brain research at the German Aerospace Center's (DLR) Short Arm Human Centrifuge: Products in Practice

Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein- coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3x10(-21)), A928V (rs35018800, OR = 0.53, P = 1.2x10(-9)), and I684S (rs12720356, OR = 0.86, P = 4.6x10(-7)). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, P-omnibus = 6x10(-18)), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; P-omnibus = 0.005). Finally, in a phenome-wide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases

<i>TYK2</i> protein-coding variants identified by exon-sequencing of RA cases and controls.

<p>Using dense genotyping, we demonstrate that three <i>TYK2</i> protein-coding variants predicted to be damaging, P1104A, A928V, and I684S, protect against RA (highlighted in red). By exon-sequencing in 1,118 RA cases and 1,118 controls, we identified 23 additional missense variants predicted to be damaging (PolyPhen-2 and SIFT), with no strong evidence of association to RA in gene-based association tests. The <i>TYK2</i> coding exons, the protein domains, and the minor allele count (MAC) of the rare variants (MAC<5) in cases and controls are shown.</p

Results from stepwise conditional analysis of the <i>TYK2</i> locus.

<p>We fine-mapped the <i>TYK2</i> locus using Immunochip data available for 7,222 ACPA+ RA cases and 15,870 controls (MAF>0). (A) In the meta-analysis, the best signal of association was at the <i>TYK2</i> missense variant P1104A (rs34536443).(B) Conditional on P1104A, the best signal of association was at the <i>TYK2</i> missense variant A928V (rs35018800). (C) Conditional on P1104A and A928V variants, the best signal of association is at the <i>TYK2</i> missense variant I684S (rs12720356). (D) Conditional on the 3 RA-protective variants in <i>TYK2</i>, we observed no additional signal of association at the locus (best signal is rs3176768, P = 0.01). P-values from meta-analyses of logistic regressions results from 6 Immunochip collections are shown. The three <i>TYK2</i> missense variants predicted to be damaging and independently associated with RA risk are highlighted in green.</p