FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2920229655> ?p ?o ?g. }

• W2920229655 abstract "Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component. We recently identified a novel SLE susceptibility locus near RASGRP1 , which governs the ERK/MAPK kinase cascade and B-/T-cell differentiation and development. However, precise causal RASGRP1 functional variant(s) and their mechanisms of action in SLE pathogenesis remain undefined. Our goal was to fine-map this locus, prioritize genetic variants according to likely functionality, experimentally validate the contribution of three SNPs to SLE risk, and experimentally determine their biochemical mechanisms of action. We performed a meta-analysis across six Asian and European cohorts (9,529 cases; 22,462 controls), followed by in silico bioinformatic and epigenetic analyses to prioritize potentially functional SNPs. We experimentally validated the functional significance and mechanism of action of three SNPs in cultured T-cells. Meta-analysis identified 18 genome-wide significant (p<5×10 −8 ) SNPs, mostly concentrated in two haplotype blocks, one intronic and the other intergenic. Epigenetic fine-mapping, allelic, eQTL and imbalance analyses predicted three transcriptional regulatory regions with four SNPs (rs7170151, rs11631591-rs7173565, and rs9920715) prioritized for functional validation. Luciferase reporter assays indicated significant allele-specific enhancer activity for intronic rs7170151 and rs11631591-rs7173565 in T-lymphoid (Jurkat) cells, but not in HEK293 cells. Following up with EMSA, mass spectrometry and ChIP-qPCR, we detected allele-dependent interactions between heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and rs11631591. Furthermore, inhibition of hnRNP-K in Jurkat and primary T-cells downregulated RASGRP1 and ERK/MAPK signaling. Comprehensive association, bioinformatics, and epigenetic analyses yielded putative functional variants of RASGRP1 , which were experimentally validated. Notably, intronic variant (rs11631591) is located in a cell type-specific enhancer sequence, where its risk allele binds to the hnRNP-K protein and modulates RASGRP1 expression in Jurkat and primary T-cells. As risk allele dosage of rs11631591 correlates with increased RASGRP1 expression and ERK activity, we suggest that this SNP may underlie SLE risk at this locus." @default.
• W2920229655 created "2019-03-11" @default.
• W2920229655 creator A5005705284 @default.
• W2920229655 creator A5016196423 @default.
• W2920229655 creator A5037133689 @default.
• W2920229655 creator A5041631463 @default.
• W2920229655 creator A5050470793 @default.
• W2920229655 creator A5055714761 @default.
• W2920229655 creator A5070001341 @default.
• W2920229655 creator A5077439703 @default.
• W2920229655 creator A5080107163 @default.
• W2920229655 creator A5089717413 @default.
• W2920229655 creator A5090013988 @default.
• W2920229655 date "2019-03-06" @default.
• W2920229655 modified "2023-09-23" @default.
• W2920229655 title "Mechanistic characterization of RASGRP1 variants identifies an hnRNP K-regulated transcriptional enhancer contributing to SLE susceptibility" @default.
• W2920229655 cites W1533942137 @default.
• W2920229655 cites W1544291870 @default.
• W2920229655 cites W1831401007 @default.
• W2920229655 cites W1963911710 @default.
• W2920229655 cites W1973062929 @default.
• W2920229655 cites W1983347147 @default.
• W2920229655 cites W1989590412 @default.
• W2920229655 cites W2004966039 @default.
• W2920229655 cites W2008989169 @default.
• W2920229655 cites W2010160850 @default.
• W2920229655 cites W2010789111 @default.
• W2920229655 cites W2012790485 @default.
• W2920229655 cites W2013128876 @default.
• W2920229655 cites W2020699105 @default.
• W2920229655 cites W2023342647 @default.
• W2920229655 cites W2025848946 @default.
• W2920229655 cites W2025943989 @default.
• W2920229655 cites W2026119296 @default.
• W2920229655 cites W2027820229 @default.
• W2920229655 cites W2029149519 @default.
• W2920229655 cites W2029530775 @default.
• W2920229655 cites W2031580483 @default.
• W2920229655 cites W2033202128 @default.
• W2920229655 cites W2036198235 @default.
• W2920229655 cites W2041656884 @default.
• W2920229655 cites W2051756496 @default.
• W2920229655 cites W2060012727 @default.
• W2920229655 cites W2063815548 @default.
• W2920229655 cites W2067673709 @default.
• W2920229655 cites W2070527591 @default.
• W2920229655 cites W2074656730 @default.
• W2920229655 cites W2075157322 @default.
• W2920229655 cites W2082793267 @default.
• W2920229655 cites W2085435814 @default.
• W2920229655 cites W2090627427 @default.
• W2920229655 cites W2100760640 @default.
• W2920229655 cites W2101280135 @default.
• W2920229655 cites W2103028313 @default.
• W2920229655 cites W2103707875 @default.
• W2920229655 cites W2103801060 @default.
• W2920229655 cites W2104116111 @default.
• W2920229655 cites W2106175900 @default.
• W2920229655 cites W2112543488 @default.
• W2920229655 cites W2119566098 @default.
• W2920229655 cites W2123411711 @default.
• W2920229655 cites W2133009026 @default.
• W2920229655 cites W2133520037 @default.
• W2920229655 cites W2135199713 @default.
• W2920229655 cites W2141820415 @default.
• W2920229655 cites W2143050295 @default.
• W2920229655 cites W2144693784 @default.
• W2920229655 cites W2146932422 @default.
• W2920229655 cites W2148015985 @default.
• W2920229655 cites W2151782442 @default.
• W2920229655 cites W2152406028 @default.
• W2920229655 cites W2152804961 @default.
• W2920229655 cites W2161633633 @default.
• W2920229655 cites W2163486415 @default.
• W2920229655 cites W2163749231 @default.
• W2920229655 cites W2168930986 @default.
• W2920229655 cites W2172123794 @default.
• W2920229655 cites W2176574121 @default.
• W2920229655 cites W2213964557 @default.
• W2920229655 cites W2234772738 @default.
• W2920229655 cites W2259938310 @default.
• W2920229655 cites W2267505920 @default.
• W2920229655 cites W2312682365 @default.
• W2920229655 cites W2313488052 @default.
• W2920229655 cites W2324665822 @default.
• W2920229655 cites W2468339236 @default.
• W2920229655 cites W2474656875 @default.
• W2920229655 cites W2514270659 @default.
• W2920229655 cites W2531349095 @default.
• W2920229655 cites W2534647638 @default.
• W2920229655 cites W2539721631 @default.
• W2920229655 cites W2553059833 @default.
• W2920229655 cites W2553838260 @default.
• W2920229655 cites W2734534935 @default.
• W2920229655 cites W2770331714 @default.
• W2920229655 cites W2780710194 @default.
• W2920229655 cites W2794458614 @default.
• W2920229655 cites W2808272893 @default.
• W2920229655 cites W2950020758 @default.
• W2920229655 cites W4253982802 @default.

• next