Elucidating causal mechanisms linking micronutrient deficiencies to life- threatening childhood infections

Micronutrient deficiencies are common in Africa and cause about 745,000 deaths annually. Some studies indicate strong associations between micronutrient deficiencies and life-threatening infections, but findings are inconsistent. Moreover, causality has not been established for most micronutrient-infection relationships and underlying biological mechanisms are poorly understood, preventing the deployment of clear data-driven interventions. My project will bring together cutting-edge human genetics with detailed phenotypic follow-up to identify causality and elucidate biological mechanisms. To infer causality, I will apply a Mendelian randomization approach. This will involve a) identifying and validating genetic variants that predict zinc, iron, folate, and vitamins A, D and B12 status in African populations; and b) testing whether these variants influence risk of severe malaria, tuberculosis, bacteraemia, pneumonia, diarrhoea, and mortality in large case control studies involving available samples and data. As proof of concept my career re-entry fellowship work has identified novel Africa-specific genetic variants, which predict iron and vitamin D status, and show that a novel genomic locus controlling cellular iron intake influences susceptibility to severe malaria. To discover the mechanisms underpinning causal micronutrient-infection relationships, I will conduct detailed phenotyping using a recall-by-genotype approach. Understanding these mechanisms will help to inform the development and targeting of effective interventions.