471 Integrated psoriasis GWAS and eQTL analysis reveals risk-associated genetic control of TRAF3IP2-AS1 expression in activated CD8 T-cells
نویسندگان
چکیده
We performed an international meta-GWAS of psoriasis, increasing effective sample size by 3.4-fold. Using COJO, we identified 191 independent psoriasis loci at genome-wide (GW) significance (179 outside the MHC). conducted eQTL analysis 1,195 strand-specific RNA-seq libraries passing QC (MQ30, ∼25M reads/sample) from 9 FACS-purified immune cell types (CD4/CD8, CLA-/CLA+, and 0h/24 h CD3-CD28-activated T-cells; also resting mDC) 153 genotyped individuals, yielding 9,091 significant (p<5x10-3) cis-eQTLs mapping to 179 non-MHC 95% Bayesian credible sets. Here focus on TRAF3IP2 encoding Act1, adaptor that transduces signals through IL-17R. COJO found 14 risk for this region (2 potentially protein-altering 12 regulatory). The lead protein-coding variant, rs33980500 C/T Act1 D10N, is top GWAS hit with a posterior probability 1.00 unconditional analysis. have shown rs33980500-T increases promotes Th17 expansion. lncRNA TRAF3IP2-AS1 in activated CD8 T-cells, but not CD4 or T-cells. In contrast, cis-eQTL itself were markedly reduced after T-cell activation. Moreover, best signal T-cells (rs11153301, p=2.9x10-6) GW-significant (p=3.7x10-8) conditioning D10N. allele rs11153301-T results expression recent study (J Immunol 206:2353) describes inhibitory effect protein level IL-17 signaling. Notably, expanded implicates cluster noncoding variants near IL17RA (p=3.9x10-9), which encodes key subunit IL-17R targeted brodalumab, highly treatment. These suggest acts as brake via its effects signaling
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ژورنال
عنوان ژورنال: Journal of Investigative Dermatology
سال: 2022
ISSN: ['1523-1747', '0022-202X']
DOI: https://doi.org/10.1016/j.jid.2022.05.480