Deriving mechanisms of immune-mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is most enriched for immune-mediated disease SNPs. This enabled the effects of candidate SNPs to be examined in a relevant cellular context and generated testable hypotheses into disease mechanisms. To illustrate the power of this approach, we investigated a locus that has been linked to six immunemediated diseases but cannot be fine-mapped. By studying the lead expression-modulating SNP, we uncovered an NF-jB-driven regulatory circuit which constrains T-cell activation through the dynamic formation of a super-enhancer that upregulates TNFAIP3 (A20), a key NF-jB inhibitor. In activated T cells, this feedback circuit is disrupted-and super-enhancer formation prevented-by the risk variant at the lead SNP, leading to unrestrained T-cell activation via a molecular mechanism that appears to broadly predispose to human autoimmunity.

Trust is an important factor in improving the performance of the healthcare system. This study aimed to develop a validated scale to measure trust in the public healthcare system. We adopted a sequential exploratory mixed study design, with developmental and testing phases. In the developmental phase, the construct of "healthcare system trust" was conceptualised and items were generated on the basis of information from a review of the literature on trust, in-depth interviews and a review of other scales. Exploratory factor analysis was employed for item reduction. In the testing phase, the reliability and validity measures were established. The face validity, content validity and construct validity of the scale were assessed. The final scale was a Likert-type scale with 23 items, 16 of which measured trust in the healthcare providers and 7, in healthcare institutions. The scale is a valid and reliable tool for measuring trust in the public healthcare system.

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Deriving mechanisms of immune-mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by linkage disequilibrium. To determine whether causal variants could be identified via their functional effects, we adapted a massively-parallel reporter assay for use in primary CD4 T-cells, key effectors of many immune-mediated diseases. Using the results to guide further study, we provide a generalisable framework for resolving disease mechanisms from non-coding associations -illustrated by a locus linked to 6 immune-mediated diseases, where the lead functional variant causally disrupts a super-enhancer within an NF-κB-driven regulatory circuit, triggering unrestrained T-cell activation. Keywords MPRA, primary T cells, TNFAIP3, super-enhancer, GWAS 7Shan, X. et al. Deficiency of PTEN in Jurkat T cells causes constitutive localization of Itk to the plasma membrane and hyperresponsiveness to CD3 stimulation. Mol Cell Biol 20, 6945-57 (2000).