Interaction between host genes and Mycobacterium tuberculosis lineage can affect tuberculosis severity: Evidence for...

Area of Science:

• Genetics
• Immunology
• Infectious Diseases

Background:

• Host and Mycobacterium tuberculosis (MTB) genetic factors independently influence tuberculosis (TB) risk.
• Neither host nor pathogen genetics alone fully explains TB risk or severity.
• Previous research suggests gene-gene interactions in other infectious diseases and TB animal models.

Purpose of the Study:

• To investigate the hypothesis that host and MTB genomes interact to modulate TB risk and severity.
• To examine the combined effect of host single nucleotide polymorphisms (SNPs), MTB lineages, and their interactions on TB severity.

Main Methods:

• Analysis of a TB household contact study in Kampala, Uganda.
• Modeling TB severity (Bandim TBscore) as a function of host SNP genotype, MTB lineage (including L4-Ugandan), and their interaction.
• Utilizing two independent cohorts of TB cases (N=113 and N=121).

Main Results:

• Replication of the association between IL12B polymorphisms and TBscore in two independent cohorts (rs3212227, p=0.0006).
• Significant interaction between SLC11A1 SNP (rs17235409) and the L4-Ugandan MTB lineage (meta p=0.0002).
• The L4-Ugandan lineage with the ancestral human allele was associated with more severe disease.

Conclusions:

• IL12B is associated with TB severity, in addition to susceptibility.
• Host-pathogen genetic interactions play a role in TB severity, supporting coevolution.
• Specific host genetic variants and MTB lineages interact to determine TB disease progression.