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Tuberculosis GWAS Uncovers Pathogen Lineage Ties to Genetics of Host Susceptibility

NEW YORK (GenomeWeb) – The genetic factors that govern an individual's response to tuberculosis appear to depend, in part, on age and on the genetic background of Mycobacterium tuberculosis pathogens behind the infection, according to a new genome-wide association study performed in Thailand.

Investigators from Japan and Thailand considered host genotypes, age at diagnosis, and M. tuberculosis genetics for a GWAS involving almost 700 Thai individuals with TB and more than 700 without. As they reported in the Journal of Human Genetics, their search led to chromosome 1 variants neighboring the leukocyte surface glycoprotein gene CD53 that was associated with TB responses in older individuals infected with M. tuberculosis pathogens from non-Beijing lineages.

The findings hinted that a pathogen's genetic background influence the host genetic factors marshaled during the response to TB, corresponding author Surakameth Mahasirimongkol, a medical genetics researcher with Thailand Ministry of Public Health's Medical Life Sciences Institute, and his co-authors explained.

The results "demonstrate the importance of analyzing the interaction between host and pathogen genomes in TB," the team added. "[F]uture analyses considering the heterogeneity of the pathogen genome can provide a clue to identify the consistent genetic risk factors for TB among different populations and contribute to the effective control of TB."

For their study, the researchers genotyped 686 TB-infected individuals in Thailand using Illumina Human610-Quad BeadChip or HumanOmniExpressExome arrays. Almost half of the cases involved M. tuberculosis pathogens from the East-African Indian (EAI) lineage, while 39 percent of individuals were infected with Beijing lineage M. tuberculosis pathogens and 10 percent had Euro-American M. tuberculosis lineage infections.

The team compared genotyping patterns in these cases to those in 711 uninfected control individuals. Among the infected individuals, the researchers also searched for genetic differences coinciding with infection by Beijing or non-Beijing M. tuberculosis lineages.

One locus jumped out of the analysis, the researchers reported: a chromosome 1 region housing CD53 that was significantly linked to non-Beijing lineage infections in individuals diagnosed with TB at older ages.

Though more studies are needed to explore the functional basis of this association and to identify still other host response factors that depend on the TB-causing pathogen lineage in question, they noted that at least one of associated variants appears to act as an expression quantitative trait locus that dials up CD53 expression — a situation that has been implicated in active TB infections in the past.

"As CD53 is a modulator of inflammatory responses, and the ability of non-Beijing lineages to induce inflammatory responses differs from that of the Beijing lineage … specific interaction between CD53 function and non-Beijing lineages seems a promising possibility," the authors wrote. "More detailed subgroup analysis based on the pathogen genome variations will also help facilitate the identification of host genetic factors that are significantly associated with TB from the loci that are suggested to be associated in this study."