Genetic evidence has supported a protective effect of cerebral angiotensin converting enzyme (ACE) against Alzheimer’s disease (AD). However, it is unclear whether this is mediated through blood pressure and extends to other neurodegenerative diseases. We performed genetic colocalization investigating an effect of cortical ACE expression on AD risk. We further investigated whether any effect of ACE expression is mediated through changes in blood pressure, and whether effects extend to Parkinson’s disease, small vessel disease or cognitive function. There was genetic evidence supporting a protective effect of cortical ACE expression on AD risk. Although higher cortical ACE expression was associated with higher blood pressure, there was no strong evidence to support that its association with AD was mediated through blood pressure, nor that ACE expression affected risk of other neurodegenerative traits. Genetic evidence supports protective effects of cerebral ACE expression on AD, but not other neurodegenerative outcomes.

Artificial intelligence (AI) will impact many aspects of clinical pharmacology including drug discovery and development, clinical trials, personalised medicine, pharmacogenomics, pharmacovigilance and clinical toxicology. The rapid progress of AI in healthcare means clinical pharmacologists should have an understanding of AI and its implementation into clinical practice. As with any new therapy or health technology, it is imperative that AI tools are subject to robust and stringent evaluation to ensure that they enhance clinical practice in a safe and equitable manner. This review serves as an introduction to AI for the clinical pharmacologist, highlighting current applications, aspects of model development and issues surrounding evaluation and deployment. The aim of this article is to empower clinical pharmacologists to embrace and lead on the safe and effective use of AI within healthcare.

Abstract Interleukin 6 (IL-6) is a circulating cytokine that is implicated in a range of inflammatory diseases. However, the broad effects of IL-6 receptor (IL-6R) signalling on other circulating cytokines is not known. Using summary-level data from genome-wide association studies, we leveraged genetic variants that proxy IL-6R signalling in two-sample Mendelian randomization analyses to investigate effects on levels of 40 circulating cytokines. Increased genetically proxied IL-6R signalling was associated with reduced levels of 10 circulating interleukins, chemokines, and growth factors. The findings from this study support feedback effects of IL-6R signalling on reducing levels of a range of circulating cytokines and identify compensatory mechanisms that may be modulating its inflammatory effects. These results provide novel insight into the mechanisms by which IL-6R signalling may be contributing to inflammatory and autoimmune diseases.

Inhibition of interleukin 6 (IL-6) signalling has been proposed as a potential cardioprotective strategy for patients with chronic kidney disease (CKD) but the direct renal effects of IL-6 inhibition are not established. A Mendelian randomization (MR) study was performed to investigate the association of genetically proxied inhibition of IL-6 signalling with estimated glomerular filtration rate (eGFR), CKD and blood urea nitrogen (BUN). Inverse variance weighted MR was used as the main analysis, with sensitivity analyses performed using simple median, weighted median and MR-Egger methods. There was no evidence for an association of genetically proxied inhibition of IL-6 signalling (scaled per unit decrease in natural log transformed C-reactive protein) with log eGFR (0.002, 95% confidence interval -0.004 – 0.008), BUN (0.088, 95% confidence interval -0.003 – 0.019) and CKD (odds ratio 1.018, 95% confidence interval 0.899 – 1.153). These findings suggest that inhibition of IL-6 signalling is unlikely to have a direct effect on renal function.