Download Human genetics to inform drug target discovery and validation for

Human genetics to inform drug target discovery and validation for
cardiovascular disease
Supervisors: Dr A Butterworth, Dr D Freitag, Dr. E Di Angelantonio, Dr. S Burgess, Prof J
Danesh, Cardiovascular Epidemiology Unit
Project code for application: SCM033
Project description:
Late stage failure of pharmaceutical compounds to show efficacy and/or an acceptable safety
profile is a key challenge of drug development in the 21st century. Evidence from human
genetics can guide discovery of drug targets and help inform investigators of the potential
impact of intervening on a pathway prior to clinical trials.
Within the cardiovascular epidemiology unit (CEU), there is a range of projects available
focusing on areas of therapeutic relevance, e.g. inflammation (e.g. Interleukin-1 & -6),
triglycerides (e.g. ApoC3, LPL) or iron metabolism.
Approach: The projects will harness several inter-disciplinary resources:
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Large-scale epidemiological studies: ultra-fine mapping and sequencing data in several
studies of coronary heart disease (~ 100,000 individuals in total); in subsets of these
individuals: measurements of relevant circulating biomarkers
Functional genomics: use of cellular-reprogramming technology (iPSC), cellular
phenotyping and transcriptomics as well as transgenic animal models in order to
underpin genetic association signals with a biological mechanism
Systems medicine: NMR metabolomics (>200 different metabolic fractions), >50 bloodbased proteins and biomarkers and ~850,000 genetic variants, are available in the
50,000 person UK-based INTERVAL study, which has active follow-up for clinical
outcomes using electronic health record linkage.
Mendelian randomization methods: analytical frameworks have been developed at
CEU to enable testing the causality of biomarkers using Mendelian randomization or
factorial Mendelian randomization, in analogy to a randomized controlled trial (RCT)
or factorial RCT, respectively.
The project will involve close collaboration with pharmaceutical companies (e.g., Pfizer,
Merck) and other institutes (e.g. the Wellcome Trust Sanger Institute).