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; Soumya Raychaudhuri

doi:10.1038/s41467-019-11664-1

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

Nat Commun. 2019 Aug 21;10(1):3765. doi: 10.1038/s41467-019-11664-1.

Authors

Yang Luo^{1

2

3

4

5}, Sara Suliman¹, Samira Asgari^{1

2

3

4

5}, Tiffany Amariuta^{1

2

3

4

5

6}, Yuriy Baglaenko^{1

2

3

4

5}, Marta Martínez-Bonet¹, Kazuyoshi Ishigaki^{1

2

3

4

5}, Maria Gutierrez-Arcelus^{1

2

3

4

5}, Roger Calderon⁷, Leonid Lecca⁷, Segundo R León⁷, Judith Jimenez⁷, Rosa Yataco⁷, Carmen Contreras⁷, Jerome T Galea⁸, Mercedes Becerra⁹, Sergey Nejentsev^{10

11}, Peter A Nigrovic^{1

12}, D Branch Moody¹, Megan B Murray¹³, Soumya Raychaudhuri^{14

15

16

17

18

19}

Affiliations

¹ Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁵ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Graduate School of Arts and Sciences, Harvard University, Cambridge, MA, 02138, USA.
⁷ Socios En Salud, Lima, Peru.
⁸ School of Social Work, University of South Florida, Tampa, FL, USA.
⁹ Department of Global Health and Social Medicine, and Division of Global Health Equity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Medicine, University of Cambridge, Cambridge, UK.
¹¹ Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, Amsterdam, Netherlands.
¹² Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
¹³ Department of Global Health and Social Medicine, and Division of Global Health Equity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. megan.murray.epi@gmail.com.
¹⁴ Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
¹⁵ Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA. soumya@broadinstitute.org.
¹⁷ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
¹⁸ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
¹⁹ Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. soumya@broadinstitute.org.

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 ([Formula: see text]) 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Disease Progression*
Female
Gene Expression
Genetic Loci
Genome-Wide Association Study
Genotype
Humans
Male
Monocytes
Mycobacterium tuberculosis / genetics
Mycobacterium tuberculosis / pathogenicity*
Peru
Sodium-Potassium-Exchanging ATPase / genetics
Tuberculosis / genetics*

Substances

ATP1B3 protein, human
Sodium-Potassium-Exchanging ATPase

Abstract

Publication types

MeSH terms

Substances

Grants and funding