Fine-mapping analysis of a chromosome 2 region linked to resistance to Mycobacterium tuberculosis infection in Uganda reveals potential regulatory variants

Abstract

Tuberculosis (TB) is a major public health burden worldwide, and more effective treatment is sorely needed. Consequently, uncovering causes of resistance to Mycobacterium tuberculosis (Mtb) infection is of special importance for vaccine design. Resistance to Mtb infection can be defined by a persistently negative tuberculin skin test (PTST–) despite living in close and sustained exposure to an active TB case. While susceptibility to Mtb is, in part, genetically determined, relatively little work has been done to uncover genetic factors underlying resistance to Mtb infection. We examined a region on chromosome 2q previously implicated in our genomewide linkage scan by a targeted, high-density association scan for genetic variants enhancing PTST– in two independent Ugandan TB household cohorts (n = 747 and 471). We found association with SNPs in neighboring genes ZEB2 and GTDC1 (peak meta p = 1.9 × 10–5) supported by both samples. Bioinformatic analysis suggests these variants may affect PTST– by regulating the histone deacetylase (HDAC) pathway, supporting previous results from transcriptomic analyses. An apparent protective effect of PTST– against body-mass wasting suggests a link between resistance to Mtb infection and healthy body composition. Our results provide insight into how humans may escape latent Mtb infection despite heavy exposure.

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Acknowledgements

The authors wish to acknowledge the contributions made by senior physicians, medical officers, health visitors, laboratory and data personnel: Dr. Lorna Nshuti, Dr. Roy Mugerwa, Dr. Alphonse Okwera, Dr. Deo Mulindwa, Dr. Christopher Whalen, Denise Johnson, Allan Chiunda, Mark Breda, Dennis Dobbs, Mary Rutaro, Albert Muganda, Richard Bamuhimbisa, Yusuf Mulumba, Deborah Nsamba, Barbara Kyeyune, Faith Kintu, Gladys Mpalanyi, Janet Mukose, Grace Tumusiime, Pierre Peters, Annet Kawuma, Saidah Menya, Joan Nassuna, Keith Chervenak, Karen Morgan, Alfred Etwom, Micheal Angel Mugerwa, and Lisa Kucharski. We would like to acknowledge Dr. Francis Adatu Engwau, former Head of the Uganda National Tuberculosis and Leprosy Program, for supporting this project. We would like to acknowledge the medical officers, nurses, and counselors at the National Tuberculosis Treatment Centre, Mulago Hospital, the Ugandan National Tuberculosis and Leprosy Program, and the Uganda Tuberculosis Investigation Bacteriological Unit, Wandegeya, for their contributions to this study. Clinical study implementation and data management were supported by the National Institutes of Health, grants N01-AI95383, HHSN266200700022C/N01-AI70022. Genotyping and data analysis was supported by R01HL096811 and analyses were also supported by T32HL007567. This study would not be possible without the generous participation of the Ugandan patients and families.

Author contributions

E.M., M.J., W.H.B., and C.M.S. conceived and designed the study. E.M. and M.J. recruited families and collected the study sample. L.L.M. maintained the database of clinical study data. R.P.I., N.H.B., B.T., F.Q., L.T., and A.S. processed the raw genotype data and conducted quality control. T.R.H., W.H.B., and C.M.S. developed the conceptual biologic model. R.P.I., N.H.B., J.B.H., and W.S.B. performed statistical analyses. R.P.I. and C.M.S. drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Catherine M. Stein.

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