Human Genomics and Drug Development

Insights into the genetic basis of human disease are helping to address some of the key challenges in new drug development including the very high rates of failure. Here we review the recent history of an emerging, genomics-assisted approach to pharmaceutical research and development, and its relationship to Mendelian randomization (MR), a well-established analytical approach to causal inference. We demonstrate how human genomic data linked to pharmaceutically relevant phenotypes can be used for (1) drug target identification (mapping relevant drug targets to diseases), (2) drug target validation (inferring the likely effects of drug target perturbation), (3) evaluation of the effectiveness and specificity of compound-target engagement (inferring the extent to which the effects of a compound are exclusive to the target and distinguishing between on-target and off-target compound effects), and (4) the selection of end points in clinical trials (the diseases or conditions to be evaluated as trial outcomes). We show how genomics can help identify indication expansion opportunities for licensed drugs and repurposing of compounds developed to clinical phase that proved safe but ineffective for the original intended indication. We outline statistical and biological considerations in using MR for drug target validation (drug target MR) and discuss the obstacles and challenges for scaled applications of these genomics-based approaches

Neutrophil Counts and Initial Presentation of 12 Cardiovascular Diseases: A CALIBER Cohort Study

BACKGROUND: Neutrophil counts are a ubiquitous measure of inflammation, but previous studies on their association with cardiovascular disease (CVD) were limited by small numbers of patients or a narrow range of endpoints. OBJECTIVES: This study investigated associations of clinically recorded neutrophil counts with initial presentation for a range of CVDs. METHODS: We used linked primary care, hospitalization, disease registry, and mortality data in England. We included people 30 years or older with complete blood counts performed in usual clinical care and no history of CVD. We used Cox models to estimate cause-specific hazard ratios (HRs) for 12 CVDs, adjusted for cardiovascular risk factors and acute conditions affecting neutrophil counts (such as infections and cancer). RESULTS: Among 775,231 individuals in the cohort, 154,179 had complete blood counts performed under acute conditions and 621,052 when they were stable. Over a median 3.8 years of follow-up, 55,004 individuals developed CVD. Adjusted HRs comparing neutrophil counts 6 to 7 versus 2 to 3 × 10(9)/l (both within the 'normal' range) showed strong associations with heart failure (HR: 2.04; 95% confidence interval [CI]: 1.82 to 2.29), peripheral arterial disease (HR: 1.95; 95% CI: 1.72 to 2.21), unheralded coronary death (HR: 1.78; 95% CI: 1.51 to 2.10), abdominal aortic aneurysm (HR: 1.72; 95% CI: 1.34 to 2.21), and nonfatal myocardial infarction (HR: 1.58; 95% CI: 1.42 to 1.76). These associations were linear, with greater risk even among individuals with neutrophil counts of 3 to 4 versus 2 to 3 × 10(9)/l. There was a weak association with ischemic stroke (HR: 1.36; 95% CI: 1.17 to 1.57), but no association with stable angina or intracerebral hemorrhage. CONCLUSIONS: Neutrophil counts were strongly associated with the incidence of some CVDs, but not others, even within the normal range, consistent with underlying disease mechanisms differing across CVDs. (White Blood Cell Counts and Onset of Cardiovascular Diseases: a CALIBER Study [CALIBER]; NCT02014610)

Low eosinophil and low lymphocyte counts and the incidence of 12 cardiovascular diseases: a CALIBER cohort study

BACKGROUND: Eosinophil and lymphocyte counts are commonly performed in clinical practice. Previous studies provide conflicting evidence of association with cardiovascular diseases. METHODS: We used linked primary care, hospitalisation, disease registry and mortality data in England (the CALIBER (CArdiovascular disease research using LInked Bespoke studies and Electronic health Records) programme). We included people aged 30 or older without cardiovascular disease at baseline, and used Cox models to estimate cause-specific HRs for the association of eosinophil or lymphocyte counts with the first occurrence of cardiovascular disease. RESULTS: The cohort comprised 775 231 individuals, of whom 55 004 presented with cardiovascular disease over median follow-up 3.8 years. Over the first 6 months, there was a strong association of low eosinophil counts (<0.05 compared with 0.15-0.25×10(9)/L) with heart failure (adjusted HR 2.05; 95% CI 1.72 to 2.43), unheralded coronary death (HR 1.94, 95% CI 1.40 to 2.69), ventricular arrhythmia/sudden cardiac death and subarachnoid haemorrhage, but not angina, non-fatal myocardial infarction, transient ischaemic attack, ischaemic stroke, haemorrhagic stroke, subarachnoid haemorrhage or abdominal aortic aneurysm. Low eosinophil count was inversely associated with peripheral arterial disease (HR 0.63, 95% CI 0.44 to 0.89). There were similar associations with low lymphocyte counts (<1.45 vs 1.85-2.15×10(9)/L); adjusted HR over the first 6 months for heart failure was 2.25 (95% CI 1.90 to 2.67). Associations beyond the first 6 months were weaker. CONCLUSIONS: Low eosinophil counts and low lymphocyte counts in the general population are associated with increased short-term incidence of heart failure and coronary death. TRIAL REGISTRATION NUMBER: NCT02014610; results

The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.

A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown

Is a fatty liver (always or ever) bad for the heart?

This editorial refers to ‘Liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease: Mendelian randomization and meta-analysis of 279 013 individuals’†, by B.K. Lauridsen et al., on page 385 - https://doi.org/10.1093/eurheartj/ehx66

Cochrane corner: PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease

Introduction: Drug therapies targeted at the reduction of low-density lipoproteincholesterol (LDL-C) are mainstream in the treatment of cardiovascular disease (CVD) and particularly for the prevention of coronary heart disease. In patients who do not have a sufficient response to, or who do not tolerate traditional LDL-C-lowering therapies such as statins or ezetimibe, monoclonal antibodies (mAbs) against PCSK9 (PCSK9 inhibitors) may provide an alternative treatment. Non-mAb-based PCSK9 inhibitors such as inclisiran are also emerging but currently lack robust outcome data1 and their effects are not considered in the current review. In this synopsis, we summarise findings from a recent update of a Cochrane systematic review on the efficacy and safety of PCSK9 inhibitors.2 This article focuses on the effects on outcomes (CVD and total mortality), safety, and the quality of the evidence in studies of mAb PCSK9 inhibitors alirocumab and evolocumab. Most of the available studies compared PCSK9 mAb treatment against placebo (against a background of usual care including statin and or ezetimibe), with a smaller group of studies evaluating the effects of PCSK9 mAb directly against statins and/or ezetimibe (none of the trials compared PCSK9 exclusively against statin treatment). Methods: The following databases were systematically searched for suitable randomised controlled trials (RCTs): Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Web of Science, ClinicalTrials.gov and the International Clinical Trials Registry Platform. Parallel-group and factorial RCTs with at least 24 weeks of follow-up were eligible; due to discontinuation of bococizumab and RG7652, studies examining these mAbs were excluded in this update. Summary of findings The 24 selected randomised trials (60 997 participants, box 1) predominantly included high-risk patients, for example, by enrolling patients with non-optimal LDL-C concentration despite treatment with statins or ezetimibe, or with a history of CVD. The study sample included 1879 who had familial hypercholesterolaemia (FH) (22% of the alirocumab participants and 38% of the evolocumab participants who provided information on FH status), and 18 908 (31%) with a diagnosis of type 2 diabetes mellitus (T2DM) at baseline (32% in alirocumab and 34% evolocumab trials; out of participants with reported T2DM status). Of the included patients, 4590 had no history of CVD (10% of the alirocumab patients and 7% of the evolocumab participants). Alirocumab was evaluated in 18 trials and evolocumab in 6 trials. Comparisons were made against placebo in 18 trials, ezetimibe and/or statins in 6 trials. Tables 1 and 2 display the key results of the meta-analysis for both PCSK9 inhibitors compared with placebo and with statins and/or ezetimibe, respectively

Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin D.

Mendelian randomization (MR) studies use genetic variants mimicking the influence of a modifiable exposure to assess and quantify a causal association with an outcome, with an aim to avoid problems with confounding and reverse causality affecting other types of observational studies

Regulation of pancreatic cancer aggressiveness by stromal stiffening

No abstract available

Lipid lowering and Alzheimer's disease risk: a Mendelian randomization study

Objective: To examine whether genetic variation affecting the expression or function of lipid-lowering drug targets isassociated with Alzheimer disease (AD) risk, to evaluate the potential impact of long-term exposure to correspondingtherapeutics.Methods: We conducted Mendelian randomization analyses using variants in genes that encode the protein targets ofseveral approved lipid-lowering drug classes: HMGCR (encoding the target for statins), PCSK9 (encoding the target forPCSK9 inhibitors, eg, evolocumab and alirocumab), NPC1L1 (encoding the target for ezetimibe), and APOB (encodingthe target of mipomersen). Variants were weighted by associations with low-density lipoprotein cholesterol (LDL-C)using data from lipid genetics consortia (n up to 295,826). We meta-analyzed Mendelian randomization estimates forregional variants weighted by LDL-C on AD risk from 2 large samples (total n = 24,718 cases, 56,685 controls).Results: Models for HMGCR, APOB, and NPC1L1 did not suggest that the use of related lipid-lowering drug classeswould affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase ADrisk in both of the AD samples (combined odds ratio per standard deviation lower LDL-C inducible by the drug tar-get = 1.45, 95% confidence interval = 1.23–1.69). This risk increase was opposite to, although more modest than, thedegree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition.Interpretation: We did not identify genetic support for the repurposing of statins, ezetimibe, or mipomersen for ADprevention. Notwithstanding caveats to this genetic evidence, pharmacovigilance for AD risk among users of PCSK9inhibitors may be warranted