Genetics of host susceptibility/resistance to tuberculosis in Ache and Ava of Paraguay

Tuberculosis is a significant world health problem, and mounting evidence indicates that host genetics play an important role in determining susceptibility. Research in worldwide populations indicates that susceptibility is polygenic, and that these loci differ by population. Incidence in Native American populations since European contact has been high, yet little research into genetics of tuberculosis susceptibility has been undertaken in these groups.;This project examines the role of host genetics in tuberculosis susceptibility in the Ache and Ava of Paraguay. Candidate genes associated with tuberculosis in other populations (vitamin D receptor, solute carrier family 11 member 1, and mannose binding lectin) were analyzed for association with three different measures of tuberculosis status: PPD status, diagnosed disease, and PCR of M. tuberculosis DNA from buccal swabs. Discordant results were found between the three measures of TB status, and several hypotheses are set forth in order to attempt to explain these.;Markers in all three genes showed significant, and in some cases strong, association with various measures of tuberculosis status. The vitamin D receptor Fok1 and Tag1 variants, the mannose-binding lectin codon 54 variant of exon 1, and several SLC11A1 variants all exhibited associations with TB status similar to those observed in other populations. Further, in the Ache, the frequency of the mannose-binding lectin codon 54 B allele is many times higher than is reported anywhere else in the world. Based on the evidence found in this dissertation, further research with expanded samples is warranted in these and other Native South American populations.;As Native American groups have been strongly impacted by TB in the past and continue to be so even today, it is urgent to include them in research on natural resistance to the disease. A direct benefit to communities participating in these studies is that persons and groups with increased risk of developing TB can be identified and preventive measures can be implemented. It is hoped that elucidation of immune pathways involved in susceptibility to TB can help pave the way for novel treatments, preventions, and vaccines for South American Natives.