A. P. Rochford

Abstract Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health 1 . This is compounded by the limited efficacy of available treatments 1 and high failure rates during drug development 2 , 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 arteritis 3–6 —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 signatures 7 , 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.

Abstract Increasing global rates of autoimmune and inflammatory disease present a burgeoning threat to human health 1 . This is compounded by the limited efficacy of available treatments 1 and high failure rates during drug development 2 – underscoring an urgent need to better understand disease mechanisms. Here we show how genetics could address this challenge. By investigating an intergenic haplotype on chr21q22, independently linked to inflammatory bowel disease (IBD), ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis 3–6 , we discover that the causal gene, ETS2 , is a master regulator of inflammatory responses in human macrophages and delineate how the risk haplotype increases ETS2 expression. Genes regulated by ETS2 were prominently expressed in affected tissues from chr21q22-associated diseases and more enriched for IBD GWAS hits than almost all previously described pathways. Overexpressing ETS2 in resting macrophages produced an activated effector state that phenocopied intestinal macrophages from IBD 7 , with upregulation of multiple drug targets including TNFα and IL-23. Using a database of cellular signatures 8 , we identify drugs that could modulate this pathway and validate the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo . Together, this highlights the potential for common genetic associations to improve both the understanding and treatment of human disease.

Abstract Introduction Nutrition and hydration are essential components of hospital inpatient care. Inadequate provision has been shown to be linked to poorer outcome. We performed a cross-sectional study of nutritional care in a London teaching hospital. Method Data collection was undertaken in October 2021 across two medical wards. Data for demographics; morbidity factors including: Charlson Comorbidity index (CCI), length of stay (LoS), cognitive score (AMTS); nutrition parameters and their recorded accuracy including: weight, ‘MUST’ score, fluid balance, food chart, and evidence of dietetic referral and review were examined. Results 52 patients were assessed [male 24/52 (46.15%), median age 80.5 (IQR 61.75–85.25, range 30–98)]. The median CCI score was 5, corresponding to 21.36% estimated 10-year mortality, with median LoS of 8 days (IQR 3–15.25). AMTS was recorded in 12/52 (23.08%). Variable recording of nutrition parameters was observed (weight: 57.69%, ‘MUST’ score 23.1%, fluid balance 63.5%, food chart 15.4%). Only 54.6% of the recorded fluid balance charts were clinically accurate. Where oral nutritional supplement (ONS) was prescribed, 57.1% (8/14) of patients had not received a dietetic review. Upon comparison the care of the elderly ward demonstrated a significantly higher accuracy of fluid balance chart (60% vs 46%, p < 0.001). Discussion Supporting patients to meet nutrition and hydration goals is a core component of clinical care. Our results demonstrate that nutrition and hydration care is poorly documented across several parameters, and by inference, poorly delivered irrespective of age, co-morbidity or cognitive impairment. Less than 1/3 of patients had a formal nutrition screen suggesting that identification of patients at risk of malnutrition should be the priority for future work. An electronic health record allows easy access to data that can be used for improvement. As an achievable first step, an improvement in awareness of nutritional scores, such as MUST, will be important in identification of malnutrition.