Genetics of Susceptibility to Mycobacterial Disease

Abstract The genus Mycobacteria contains important pathogens of humans including Mycobacterium tuberculosis and Mycobacterium leprae . The outcome of mycobacterial infection is influenced by variations in human genes. Genetic susceptibility to mycobacteria involves multiple genes that contribute to the innate immune recognition of mycobacteria (genes coding for pattern recognition receptors), recognition of mycobacteria by the adaptive immune system involving products of human leucocyte antigen/major histocompatibility complex genes and effector responses of the immune system (genes affecting cytokines, chemokines and immunomodulators). Host genetic susceptibility to pathogens is complicated by the genetics of pathogen, gene‐environment and gene–gene interactions. Moreover, ethnicity specific effects further add fuel to the complication. A series of concerted comprehensive immunogenetic studies are warranted to decipher new molecular players and delineate complex host–pathogen interactions. This might identify the genetic factors that are definitely associated with mycobacterial diseases and could lead to development of novel therapeutics and prophylaxis. Convergence of immunogenomics, pharmacogenomics and vaccinomics could yield better tools to tackle these dreadful diseases of mankind. Key Concepts: Outcome of a mycobacterial infection depends on gender, age, HIV infection status, malnutrition, BCG vaccination, host immune responses, pathogen variation and host genetics, which varies according to ethnicity. Extensive studies have implicated the role of alleles from human leucocyte antigen (HLA) genes/major histocompatibility complex (MHC) genes and single nucleotide polymorphisms (SNPs) of various non‐HLA genes/non‐MHC genes in conferring susceptibility to mycobacterial disease. Polymorphisms in the genes coding for pattern recognition receptors such as toll‐like receptors, mannose‐binding lectins, mannose receptors, surfactant proteins and DC‐SIGN affect susceptibility to mycobacterial disease. HLA‐DRB1 * 15 and HLA‐DQB1 alleles having aspartic acid at β57 have been shown to be associated with TB in many populations. SNPs in the genes coding for IFNG , IL10 , CCL2 , vitamin D receptor, NOS2A and other effector molecules influence susceptibility to mycobacterial disease. SNPs in the genes coding for immune mediators could predict response to treatment. Ethnicity specific effects, and strain variation in the pathogen, gene–gene and gene–environment interactions affect genetic susceptibility.