Mendelian randomization of therapeutic targets for CVD prevention in China Kadoorie Biobank
Project Reference: NDPH/MT16/030
Although existing drugs such as statins and antihypertensives effectively reduce risk of CVD, there remains a considerable residual risk of disease. Identifying new therapeutic targets to treat residual risk is a major research priority, however progress is hampered by high late-stage attrition due to lack of efficacy.
Genetic information can be exploited to predict outcomes of clinical trials through Mendelian randomization. Two emerging targets for CVD are apoliproprotein B (apoB) and the interleukin-6 receptor (IL6R), both of which have therapeutics (mipomersen for ApoB and tocilizumab for IL6R) in clinical trials.
The China Kadoorie Biobank (CKB) study of over 0.5 million adults was set up to investigate genetic and environmental causes of chronic diseases in the Chinese population. Individuals have extensive questionnaire-based health and lifestyle data at baseline, biomarkers (including cardiovascular biomarkers such as blood pressure, adiposity, serum lipids) and prospective follow-up for incident events from hospital registries and health insurance data. The cohort is undergoing genotyping using a GWAS array (~800K SNPs) specifically designed for individuals of Asian ancestry to identify genetic determinants of disease, and facilitate causal analyses of biomarkers using genetic epidemiological techniques such as Mendelian randomization.
Research Experience, Research Methods and Training
The student will gain a broad range of classical and genetic epidemiological skills. First, the student will characterize the association of SNPs in APOB and IL6R with lipid levels and inflammatory biomarkers in CKB. Second, the student will investigate the association of APOB and IL6R SNPs with cardiovascular traits, cIMT and cardiovascular events. Third, the student will conduct a Mendelian randomization analysis of the relationship of APOB and IL6R SNPs with cardiovascular disease events to predict the expected outcome of clinical trials. Finally, the student will investigate the association of SNPs with “safety signals” such as cancer sub-types and autoimmune disease. These investigations will provide novel insights into expected downstream consequences of APOB and IL6R inhibition, and will provide invaluable for anticipating results from ongoing phase III clinical trials.
Field Work, Secondments, Industry Placements and Training
In-house training and short courses on Mendelian randomization and the use and interpretation of large-scale data and statistical analyses.
Candidates should have a 2.1 or higher degree in Medicine or medical sciences and an MSc in epidemiology, statistics, genetics or public health would be desirable. The project requires some previous statistical and programming training/experience and an interest in extending these skills. Candidates should also have a strong interest in cardiovascular epidemiology.