A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Benefit of Sequential Audit Cycles in Improving Management of Vitamin D Deficiency in the HIV Infected Paediatric Population

Aims Lifelong HIV infection has an unknown impact on bone health in children. In view of this, we aimed to improve management of vitamin D deficiency. Methods Three audits over 8 years (2009-2017) were performed with interventions introduced intermittently in an effort to improve vitamin D deficiency. The interventions included education, a change in vitamin D dose and brand to increase compliance and a shift to nursing led management. Results The most striking result was the eradication of patients with deficient vitamin D levels (<25nmol/L) in 2017. In 2009 and 2015, 15% and 9% were deficient. In the earlier two studies, only 15% had 'sufficient' (>50nmol) vitamin D levels. This increased to 71% in 2017. 10% of patients had levels greater than >120nmol/L, increasing risk of vitamin D toxicity. 67% of patients with insufficient vit D (25-50nmol/L) were prescribed a stat high dose vitamin D (120,000 IU) to help avoid adherence issues. Conclusions Sequential audits along with a shift to nurse led management were the most likely reasons for sustained improvement. Similar projects in all medical departments could improve clinical outcomes.