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

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.