Early Progression to Active Tuberculosis in Peruvians

In a genome-wide genetic study of early progression to active tuberculosis (TB), we genotyped 4,002 active TB cases and their household contacts in Lima, Peru. We first established TB progression has a strong genetic basis, and is comparable to traits with well-established genetic bases (h2g=0.212). We identified a novel association between early TB progression and variants located in a putative enhancer region on chromosome 3q23 (rs73226617, OR = 1.18; P = 3.93 x 10-8). With in silico and in vitro analyses we identified genetic variant rs73226617 or rs148722713 as the likely functional variant and ATP1B3 as a potential causal target gene with monocyte specific function.]]>
We enrolled index cases as adults (aged 15 and older) who presented with clinically suspected pulmonary TB at any of 106 participating health centers. We excluded patients who resided outside the catchment area, who had received treatment for TB before and those who were unable to give informed consent. Pulmonary TB patients have been diagnosed by the presence of acid fast bacilli in sputum smear or a positive M.tb culture at any time from enrollment to the end of treatment. All cultures of the index cases were genotyped using mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR). Within 2 weeks of enrolling an index patient, we enrolled his or her household contacts (HHCs). The M.tb status was determined using the Tuberculin Skin Test (TST). All HHCs were evaluated for signs and symptoms of pulmonary and extra-pulmonary TB disease at 2, 6, and 12 months after enrollment. All cases were HIV-negative, culture-positive and drug-sensitive who have pulmonary TB. We defined cases who were likely to have recently exposed TB, if a case satisfied at least one of the three criteria: (1) exposed HHCs who developed active TB during a 12 month follow up period; (2) index patients whose M.tb isolates shared a molecular fingerprint with isolates from other enrolled patients and (3) index patients who were 40-years old or younger at time of diagnosis. To maximize the likelihood that controls were exposed to M.tb but did not develop active disease, we chose them from among TST positive HHCs with no previous history of TB disease, and who remained disease free at the time of recruitment both by directly re-contacting individuals to inquire about their latest medical history and by checking their names against lists of notified TB patients at all of the 106 health clinics. Where possible, we chose controls who are less than second-degree related to the index cases.]]>