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Native Peruvian Genetic Ancestry Linked to Increased Risk of Tuberculosis Progression

NEW YORK — A higher proportion of native Peruvian ancestry is associated with an increased risk that infection with Mycobacterium tuberculosis will progress to active disease, a new study has found.

M. tuberculosis has had a high historical prevalence in Europe, which may have led to selective pressure affecting the frequency of host risk alleles in that population. TB, however, has become more prevalent in South America more recently, where exposure had been lower until the arrival of Europeans. Peru in particular has one of the highest disease incidence rates, leading a team led by researchers at the Broad Institute to examine how ancestry-specific factors may affect disease progression.

The researchers conducted a longitudinal household contacts-based study of M. tuberculosis infection progression and genetic ancestry. In all, they analyzed more than 3,000 Peruvians, both with active TB and controls with latent tuberculosis, to find that individuals with higher genetically determined native Peruvian ancestry were more likely to develop active disease.

"I had certainly expected for individuals living in the same household, that genetic ancestry wouldn't matter too much. So this was surprising to me," senior author Soumya Raychaudhuri from the Broad Institute said in an email.

As they were unable to home in on any one genetic locus to account for this effect, the researchers suspected that it may be polygenic, as they reported in Cell Genomics on Monday.

They enrolled 2,105 individuals with confirmed active TB in their study and also screened their household contacts for TB within 14 days and again at two, six, and 12 months. Of those household contacts, 1,320 individuals who tested positive for TB but did not develop active disease during follow-up served as controls.

For all participants, the researchers additionally quantified their global genetic ancestry, which assumed four ancestral populations based on Peru's history: native Peruvian, European, West African, and East Asian.

Through a logistic regression analysis, the researchers estimated the effect of each individual's portion of native Peruvian, European, West African, and East Asian genetic ancestry on whether that person was a case or a control. After controlling for factors like age, sex, and socioeconomic status, they noted an association between native Peruvian genetic ancestry and TB progression risk, but no such effect for any of the other genetic ancestries.

In particular, the researchers estimated that a 10 percent increase in an individual's native Peruvian genetic ancestry was associated with a 25 percent increase in TB progression risk. Further, individuals in the highest decile of native Peruvian genetic ancestry had a threefold increased risk in disease progression compared to those in the lowest decile.

This effect held when the researchers accounted for additional nongenetic factors like BMI, educational level, smoking, alcohol use, and more.

They cautioned, though, that the effect of native Peruvian genetic ancestry on TB progression risk is relative to the other genetic ancestries.

When the researchers conducted a combined local ancestry interference and admixture mapping analysis, they were unable to identify any particular genetic locus that could explain this association between native Peruvian genetic ancestry and TB progression risk. This suggested to them that the effect is likely polygenic. They added that this idea is supported by previous work that found a high SNP heritability of TB progression among Peruvians but only uncovered one locus with genome-wide significance for progression risk.

"We are now trying to understand how genetic ancestry might relate to differences in important immune responses that are required to prevent TB progression," Raychaudhuri said.