Host genetics and susceptibility to infectious diseases

This is undoubtedly one of the most difficult lectures I've ever had to prepare and give, given the complexity of the subject, which requires a mastery of human genetics and the varied and evolving methods for identifying the genes responsible for susceptibility to certain diseases. In contexts of high consanguinity, mutations transmitted in a Mendelian fashion give rise to almost caricatural situations of susceptibility to infectious agents, whether bacterial, viral or fungal. They mainly affect young children, and their effect diminishes with age in those who survive. These mutations enable therapeutic approaches to be substituted, and above all, they provide a formidable window onto the functions of certain known or unknown effectors of the human immune system. The situation involving attempts to identify gene mutations/polymorphisms responsible for susceptibility to major endemic diseases is more complex, since this analysis must involve large cohorts studied on agenome-wide scale (genome-wide association studies or GWAS). Apart from historical examples such as the association of sickle cell trait or absence of the Duffy gene with resistance to malaria, susceptibility situations are complex and multigenic, with the contribution of the polymorphisms responsible generally limited (low " lodd score "). Nevertheless, this is a fast-growing field with high hopes, thanks to advances in sequencing and the availability of libraries of increasingly diverse polymorphisms in human genes (e.g. HAPMAP). Perhaps we'll finally find the Holy Grail(s).