Biology subjects

Hingorani, A. D.

Publications and source records attributed to Hingorani, A. D..

4 recordsLinked to original sources

bioRxiv2018

Adjustment for index event bias in genome-wide association studies of subsequent events

Following numerous genome-wide association studies of disease susceptibility, there is increasing interest in genetic associations with disease prognosis, survival or other subsequent events. Such associations are vulnerable to index event bias, by which selection of subjects according to their disease status creates biased associations if common causes of incidence and prognosis are not accounted for. We propose a novel adjustment for index event bias using the residuals from the regression of genetic effects on prognosis on genetic effects on incidence. Our approach eliminates this bias when direct genetic effects on incidence and prognosis are independent, and otherwise reduces bias in realistic situations. In a study of idiopathic pulmonary fibrosis, we resolved a paradoxical association of the strong susceptibility gene MUC5B with increased survival, identifying instead a significant association with decreased survival. In re-analysis of a study of Crohns disease prognosis, four regions remained associated at genome-wide significance albeit with increased P-values.

epidemiology↗

bioRxiv2018

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

BackgroundWe characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.\n\nMethodsPublished and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Fourteen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration\n\nResultsThe PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95%CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95%CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95%CI 0.57; 1.22) for the GS, compared to 0.85 (95%CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95%CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimers disease - outcomes for which large-scale trial data were unavailable.\n\nConclusionsGenetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. Apparent discordance between genetic associations and trial outcome for T2DM might be explained lack by a of statistical precision, or differences in the nature and duration of genetic versus pharmacological perturbation of PCSK9.\n\nFundingThis research was funded by the British Heart Foundation (SP/13/6/30554, RG/10/12/28456, FS/18/23/33512), UCL Hospitals NIHR Biomedical Research Centre, by the Rosetrees and Stoneygate Trusts.\n\nCondensed abstractEvidence on the long-term efficacy and safety of therapeutic inhibition of PCSK9 is lacking. To explore potential long-term effects of PCSK9 inhibition, we characterised the phenotypic consequence of LDL-cholesterol lowering variants at the PCSK9 locus. A PCSK9 gene score comprising 4 SNPs recapitulated the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and risk of myocardial infarction, and was associated with an increased risk of type 2 diabetes. No associations with safety outcomes such as cancer, COPD, Alzheimers disease or atrial fibrillation were identified. Our findings suggest PCSK9 inhibition may be safe and effective during prolonged use.

genetics↗

bioRxiv2017

Flipping the odds of drug development success through human genomics

Drug development depends on accurately identifying molecular targets that both play a causal role in a disease and are amenable to pharmacological action by small molecule drugs or bio-therapeutics, such as monoclonal antibodies.\n\nErrors in drug target specification contribute to the extremely high rates of drug development failure.\n\nIntegrating knowledge of genes that encode druggable targets with those that influence susceptibility to common disease has the potential to radically improve the probability of drug development success.

genomics↗

bioRxiv2017

Metabolic profiling of adiponectin levels in adults: Mendelian randomization analysis

BackgroundAdiponectin, a circulating adipocyte-derived protein has insulin-sensitizing, anti-inflammatory, anti-atherogenic, and cardiomyocyte-protective properties in animal models. However, the systemic effects of adiponectin in humans are unknown.\n\nObjectivesOur aims were to define the metabolic profile associated with higher blood adiponectin concentration and investigate whether variation in adiponectin concentration affects the systemic metabolic profile.\n\nMethodsWe applied multivariable regression in up to 5,906 adults and Mendelian randomization (using cis-acting genetic variants in the vicinity of the adiponectin gene as instrumental variables) for analysing the causal effect of adiponectin in the metabolic profile of up to 38,058 adults. Participants were largely European from six longitudinal studies and one genome-wide association consortium.\n\nResultsIn the multivariable regression analyses, higher circulating adiponectin was associated with higher HDL lipids and lower VLDL lipids, glucose levels, branched-chain amino acids, and inflammatory markers. However, these findings were not supported by Mendelian randomization analyses for most metabolites. Findings were consistent between sexes and after excluding high risk groups (defined by age and occurrence of previous cardiovascular event) and one study with admixed population.\n\nConclusionOur findings indicate that blood adiponectin concentration is more likely to be an epiphenomenon in the context of metabolic disease than a key determinant.

epidemiology↗