Genome-wide association study of resistance to Mycobacterium tuberculosis infection identifies a locus at 10q26.2 in three distinct populations.

The natural history of tuberculosis (TB) is characterized by a large inter-individual outcome variability after exposure to Mycobacterium tuberculosis. Specifically, some highly exposed individuals remain resistant to M. tuberculosis infection, as inferred by tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). We performed a genome-wide association study of resistance to M. tuberculosis infection in an endemic region of Southern Vietnam. We enrolled household contacts (HHC) of pulmonary TB cases and compared subjects who were negative for both TST and IGRA (n = 185) with infected individuals (n = 353) who were either positive for both TST and IGRA or had a diagnosis of TB. We found a genome-wide significant locus on chromosome 10q26.2 with a cluster of variants associated with strong protection against M. tuberculosis infection (OR = 0.42, 95%CI 0.35-0.49, P = 3.71×10-8, for the genotyped variant rs17155120). The locus was replicated in a French multi-ethnic HHC cohort and a familial admixed cohort from a hyper-endemic area of South Africa, with an overall OR for rs17155120 estimated at 0.50 (95%CI 0.45-0.55, P = 1.26×10-9). The variants are located in intronic regions and upstream of C10orf90, a tumor suppressor gene which encodes an ubiquitin ligase activating the transcription factor p53. In silico analysis showed that the protective alleles were associated with a decreased expression in monocytes of the nearby gene ADAM12 which could lead to an enhanced response of Th17 lymphocytes. Our results reveal a novel locus controlling resistance to M. tuberculosis infection across different populations.

ADDING TWO NEW CONTACT CIRCUMSTANCES TO 'MERGED PHANTOM TOOL' AND A TECHNIQUE TO CONVERT STRUCTURE INFORMATION SEGMENTED BY THE CARIMAS SOFTWARE INTO GEANT4 GEOMETRY.

Two new contact circumstances called 'stand-lie' and 'front-rear' are implemented to the merged phantom tool. To allow more flexibility for users when they calculate the dose for a volume of interest (VOI) with arbitrary geometry, an optional utility to convert segmented structure information from the CARIMAS software into parallel geometry of GEANT4 is provided. The effective dose for a person who has been in contact with a male patient being treated for thyroid cancer with 131I is calculated for four circumstances: opposite, side by side, stand-lie and front-rear. The biggest dose is the 'opposite' circumstance and the smallest one is the 'stand-lie' circumstance. Using the dose distribution in the patient's body and applying the right circumstance should be done to optimise the dose calculation for the contact person.