From single gene to phenotype: questioning a discrete gene in explaining phenotype diversity

The great diversity of phenotypes across organisms raises the question of how it emerged from the digital DNA sequence. Often the question is summarized as ‘how many genes do we really need?’ The benefit of answering this is readily apparent; particularly since sequencing the genome, research has sought the origin of normative and pathological phenotypes in our genes. However, in response, the literature will retort that neither the number of genes nor the size of the genome make robust predictions about phenotype complexity or diversity. For example, a common sea flea, Daphnia pulex, has ~31,000 genes, compared with our ~23,000. Given the gene-centric state of current biology, the questions these comparisons advance about the power of the gene are disconcerting. The remit of what follows is to address the value of quantifying genes to explain the phenotype. The heterogeneous nature of gene definitions in the literature necessitates brief discussion of gene ontology. Following this, I will discuss how function emerges from the transcript, and the resultant translated functional product. However, questioning the power of the gene should be taken in tandem with questioning its scope; this discussion will end on a brief survey of the proportion of the phenotype that should readily be attributed to non-DNA inheritance information, which highlights the need or systems-based approaches to phenotype variability.ReiDoCrea. Departamento de Psicología Social. Universidad de Granada

Genetic susceptibility, elevated blood pressure and risk of atrial fibrillation:A Mendelian randomization study

Background: Whether elevated blood pressure (BP) is a modifiable risk factor for atrial fibrillation (AF) is not established. We tested (1) whether the association between BP and risk of AF is causal, (2) whether it varies according to individual’s genetic susceptibility for AF, and (3) the extent to which specific BP-lowering drugs are expected to reduce this risk. Methods: First, causality of association was assessed through two-sample Mendelian randomization, using data from two independent genome-wide association studies that included a total of one million European population. Second, the UK Biobank data of 329,237 participants at baseline was used to study the effect of BP on AF according to genetic susceptibility of developing AF. Third, a possible treatment effect with major BP-lowering drug classes on AF risk was predicted through genetic variants in genes encode the therapeutic targets of each drug class. Estimated drug effects were compared with effects on incident coronary heart disease, for which direct trial evidence exists. Results: The two-sample Mendelian randomization analysis indicated that, on average, exposure to a higher systolic BP increased the risk of AF by 19% (odds ratio per each 10-mm Hg [OR]: 1.19 [1.12 to 1.27]). This association was replicated in the UK biobank using individual participant data. However, in a further genetic risk-stratified analysis, there was evidence for a linear gradient in the relative effects of systolic BP on AF; while there was no conclusive evidence of an effect in those with low genetic risk, a strong effect was observed among those with high genetic susceptibility for AF. The comparison of predicted treatment effects using genetic proxies for three main drug classes (angiotensin-converting enzyme inhibitors, beta-blockers and calcium channel blockers) suggested similar average effects for the prevention of atrial fibrillation and coronary heart disease. Conclusions: The effect of elevated BP on the risk of AF is likely to be causal, suggesting that BP-lowering treatment may be effective in AF prevention. However, average effects masked clinically important variations, with a more pronounced effect in individuals with high genetic susceptibility risk for AF

Electronic alerts for acute kidney injury across primary and secondary care

Problem In 2009 the National Confidential Enquiry into Patient Outcome and Death suggested only 50% of patients with acute kidney injury (AKI) receive good standards of care. In response National Health Service (NHS) England mandated the use of electronic AKI alerts within secondary care. However, we recognised AKI is not just a secondary care problem, where primary care has a crucial role to play in prevention, early detection and management as well as post-AKI care. Methods AKI alerts were implemented in primary and secondary care services for a population of 480 000. Comparisons were made in AKI incidence, peak creatinine following AKI and renal recovery in the years before and after using Byar’s approximation (95% CI). Intervention A complex quality improvement initiative was implemented based on the design and integration of an AKI alerting system within laboratory information management systems for primary and secondary care, with an affixed URL for clinicians to access a care bundle of AKI guidelines on safe prescribing, patient advice and early contact with nephrology. Results The intervention was associated with an 8% increase in creatinine testing (n=32 563). Hospital acquired AKI detection increased by 6%, while community acquired AKI detection increased by 3% and AKI stage 3 detected in primary care fell by 14%. The intervention overall had no effect on AKI severity but did improve follow-up testing and renal recovery. Importantly hospital AKI 3 recoveries improved by 22%. In a small number of AKI cases, the algorithm did not produce an alert resulting in a reduction in follow-up testing compared with preintervention levels. Conclusion The introduction of AKI alerts in primary and secondary care, in conjunction with access to an AKI care bundle, was associated with higher rates of repeat blood sampling, AKI detection and renal recovery. Validating accuracy of alerts is required to avoid patient harm

Genetic predisposition to metabolically unfavourable adiposity and prostate cancer risk:A Mendelian randomization analysis

BACKGROUND The associations of adiposity with aggressive prostate cancer risk are unclear. Using two-sample Mendelian randomization, we assessed the association of metabolically unfavourable adiposity (UFA), favourable adiposity (FA) and for comparison body mass index (BMI), with prostate cancer, including aggressive prostate cancer. METHODS We examined the association of these genetically predicted adiposity-related traits with risk of prostate cancer overall, aggressive and early onset disease using outcome summary statistics from the PRACTICAL consortium (including 15,167 aggressive cases). RESULTS In inverse-variance weighted models, there was little evidence that genetically predicted one standard deviation higher UFA, FA and BMI were associated with aggressive prostate cancer [OR: 0.85 (95% CI:0.61-1.19), 0.80 (0.53-1.23) and 0.97 (0.88-1.08), respectively]; these associations were largely consistent in sensitivity analyses accounting for horizontal pleiotropy. There was no strong evidence that genetically determined UFA, FA or BMI were associated with overall prostate cancer or early age of onset prostate cancer. CONCLUSIONS We did not find differences in the associations of UFA and FA with prostate cancer risk, which suggest that adiposity is unlikely to influence prostate cancer via the metabolic factors assessed; however, these did not cover some aspects related to metabolic health that may link obesity with aggressive prostate cancer, which should be explored in future studies

Blood pressure lowering and risk of new-onset type 2 diabetes:an individual participant data meta-analysis

Background Blood pressure lowering is an established strategy for preventing microvascular and macrovascular complications of diabetes, but its role in the prevention of diabetes itself is unclear. We aimed to examine this question using individual participant data from major randomised controlled trials. Methods We performed a one-stage individual participant data meta-analysis, in which data were pooled to investigate the effect of blood pressure lowering per se on the risk of new-onset type 2 diabetes. An individual participant data network meta-analysis was used to investigate the differential effects of five major classes of antihypertensive drugs on the risk of new-onset type 2 diabetes. Overall, data from 22 studies conducted between 1973 and 2008, were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We included all primary and secondary prevention trials that used a specific class or classes of antihypertensive drugs versus placebo or other classes of blood pressure lowering medications that had at least 1000 persons-years of followup in each randomly allocated arm. Participants with a known diagnosis of diabetes at baseline and trials conducted in patients with prevalent diabetes were excluded. For the one-stage individual participant data meta-analysis we used stratified Cox proportional hazards model and for the individual participant data network meta-analysis we used logistic regression models to calculate the relative risk (RR) for drug class comparisons. Findings 145 939 participants (88 500 [60.6%] men and 57 429 [39.4%] women) from 19 randomised controlled trials were included in the one-stage individual participant data meta-analysis. 22 trials were included in the individual participant data network meta-analysis. After a median follow-up of 4.5 years (IQR 2.0), 9883 participants were diagnosed with new-onset type 2 diabetes. Systolic blood pressure reduction by 5 mm Hg reduced the risk of type 2 diabetes across all trials by 11% (hazard ratio 0.89 [95% CI 0.84-0.95]). Investigation of the effects of five major classes of antihypertensive drugs showed that in comparison to placebo, angiotensin-converting enzyme inhibitors (RR 0.84 [95% 0.76-0.93]) and angiotensin II receptor blockers (RR 0.84 [0.76-0.92]) reduced the risk of new-onset type 2 diabetes; however, the use of beta blockers (RR 1.48 [1.27-1.72]) and thiazide diuretics (RR 1.20 [1.07-1.35]) increased this risk, and no material effect was found for calcium channel blockers (RR 1.02 [0.92-1.13]). Interpretation Blood pressure lowering is an effective strategy for the prevention of new-onset type 2 diabetes. Established pharmacological interventions, however, have qualitatively and quantitively different effects on diabetes, likely due to their differing off-target effects, with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers having the most favourable outcomes. This evidence supports the indication for selected classes of antihypertensive drugs for the prevention of diabetes, which could further refine the selection of drug choice according to an individual's clinical risk of diabetes

Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study

Bilirubin, an endogenous antioxidant, may play a protective role in cancer development. We applied two-sample Mendelian randomization to investigate whether genetically raised bilirubin levels are causally associated with the risk of ten cancers (pancreas, kidney, endometrium, ovary, breast, prostate, lung, Hodgkin's lymphoma, melanoma, and neuroblastoma). The number of cases and their matched controls of European descent ranged from 122,977 and 105,974 for breast cancer to 1200 and 6417 for Hodgkin's lymphoma, respectively. A total of 115 single-nucleotide polymorphisms (SNPs) associated (p < 5 × 10-8) with circulating total bilirubin, extracted from a genome-wide association study in the UK Biobank, were used as instrumental variables. One SNP (rs6431625) in the promoter region of the uridine-diphosphoglucuronate glucuronosyltransferase1A1 (UGT1A1) gene explained 16.9% and the remaining 114 SNPs (non-UGT1A1 SNPs) explained 3.1% of phenotypic variance in circulating bilirubin levels. A one-standarddeviation increment in circulating bilirubin (≈ 4.4 µmol/L), predicted by non-UGT1A1 SNPs, was inversely associated with risk of squamous cell lung cancer and Hodgkin's lymphoma (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.73-0.99, P 0.04 and OR 0.64, 95% CI 0.42-0.99, p 0.04, respectively), which was confirmed after removing potential pleiotropic SNPs. In contrast, a positive association was observed with the risk of breast cancer after removing potential pleiotropic SNPs (OR 1.12, 95% CI 1.04-1.20, p 0.002). There was little evidence for robust associations with the other seven cancers investigated. Genetically raised bilirubin levels were inversely associated with risk of squamous cell lung cancer as well as Hodgkin's lymphoma and positively associated with risk of breast cancer. Further studies are required to investigate the utility of bilirubin as a low-cost clinical marker to improve risk prediction for certain cancers