Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians

Yang Luo, Sara Suliman, Samira Asgari, Tiffany Amariuta, Yuriy Baglaenko, Marta Martínez-Bonet, Kazuyoshi Ishigaki, Maria Gutierrez-Arcelus, Roger Calderon, Leonid Lecca, Segundo R. León, Judith Jimenez, Rosa Yataco, Carmen Contreras, Jerome T. Galea, Mercedes Becerra, Sergey Nejentsev, Peter A. Nigrovic, D. Branch Moody, Megan B. Murray () and Soumya Raychaudhuri ()
Additional contact information
Yang Luo: Brigham and Women’s Hospital, Harvard Medical School
Sara Suliman: Brigham and Women’s Hospital, Harvard Medical School
Samira Asgari: Brigham and Women’s Hospital, Harvard Medical School
Tiffany Amariuta: Brigham and Women’s Hospital, Harvard Medical School
Yuriy Baglaenko: Brigham and Women’s Hospital, Harvard Medical School
Marta Martínez-Bonet: Brigham and Women’s Hospital, Harvard Medical School
Kazuyoshi Ishigaki: Brigham and Women’s Hospital, Harvard Medical School
Maria Gutierrez-Arcelus: Brigham and Women’s Hospital, Harvard Medical School
Roger Calderon: Socios En Salud
Leonid Lecca: Socios En Salud
Segundo R. León: Socios En Salud
Judith Jimenez: Socios En Salud
Rosa Yataco: Socios En Salud
Carmen Contreras: Socios En Salud
Jerome T. Galea: University of South Florida
Mercedes Becerra: Harvard Medical School
Sergey Nejentsev: University of Cambridge
Peter A. Nigrovic: Brigham and Women’s Hospital, Harvard Medical School
D. Branch Moody: Brigham and Women’s Hospital, Harvard Medical School
Megan B. Murray: Harvard Medical School
Soumya Raychaudhuri: Brigham and Women’s Hospital, Harvard Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract Of the 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5–15% will develop active tuberculosis (TB). Approximately half will progress to active TB within the first 18 months after infection, presumably because they fail to mount an effective initial immune response. Here, in a genome-wide genetic study of early TB progression, we genotype 4002 active TB cases and their household contacts in Peru. We quantify genetic heritability ( $${\it{h}}_{\it{g}}^2$$ h g 2 ) of early TB progression to be 21.2% (standard error 0.08). This suggests TB progression has a strong genetic basis, and is comparable to traits with well-established genetic bases. We identify 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 × 10−8). With in silico and in vitro analyses we identify rs73226617 or rs148722713 as the likely functional variant and ATP1B3 as a potential causal target gene with monocyte specific function.

Date: 2019
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DOI: 10.1038/s41467-019-11664-1

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