LAUSR

Background Although pharmacogenetic studies of TNF inhibitors (TNFi) response presented the estimates of high heritability, only few loci with suggestive weak common association as biomarkers for TNFi response have been identified. Objectives We aimed to identify novel functional rare variants associated with response to etanercept using targeted exon sequencing in Korea. Methods Disease activity scores were assessed at baseline and after 6 months in 156 Korean RA patients who started etanercept due to moderate or high disease activity. We analysed targeted exon sequencing data of 399 genes selected from a multifaceted approach. We conducted a single-marker association test (MAF ≥1%) and a gene-based analysis [optimal sequence kernel association test (SKAT-O)] of rare variants (MAF <1%). In addition, we performed gene set analyses of TNF pathway genes. Results We identified that clinical factors seem to influence the therapeutic good response of etanercept including male, high disease activity score at baseline, BMI. After stringent quality control, we analysed 14 024 variants of 399 genes in 156 RA patients. We identified two novel significant functional SNPs [rs16942564, rs61734378 (exon of AKAP13)] associated with response to etanercept, surpassing study-wide significant threshold (p<3.0 × 10−5) in single variant association tests. Using a gene-based approach, we found two genes with nominal burden signals (p<0.001) which did not reach study-wide significance. In the gene set enrichment test, we found no evidence for enrichment of association at genes involved in the TNF pathway. Conclusions We were unable to identify rare coding variants with large effect of 399 targeted genes. Our study suggests that rare coding variants of RA risk associated genes do not contribute to heritability of response to etanercept therapy. Disclosure of Interest None declared