Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2019 May 21;116(21):10430-10434. doi: 10.1073/pnas.1903561116. Epub 2019 May 8.

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry.

Author information

1
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France.
2
Imagine Institute, Paris Descartes University, 75015 Paris, France.
3
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
4
Human Evolutionary Genetics Unit, Institut Pasteur, CNRS UMR2000, 75015 Paris, France.
5
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; casanova@rockefeller.edu.
6
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
7
Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065.

Abstract

The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common TYK2 P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans and ∼1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96-10.31, P = 2 × 10-3]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with Mycobacterium tuberculosis, as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for TYK2 P1104A may account for ∼1% of TB cases in Europeans.

KEYWORDS:

IFN-γ; TYK2; immunodeficiency; monogenic; tuberculosis

PMID:
31068474
PMCID:
PMC6534977
[Available on 2019-11-08]
DOI:
10.1073/pnas.1903561116

Conflict of interest statement

Conflict of interest statement: J.-L.C. and M.L. are coauthors on a 2019 paper [Ahmad L (2019) J Allergy Clin Immunol 143:765–769] and a 2017 paper [Israel L (2017) Cell 168:789–800] in which they independently provided unpublished reagents/analytic tools. J.-L.C., L.A., and D.K. are coauthors on a 2018 paper [Bolze A (2018) Proc Natl Acad Sci USA 115:E8007–E8016] in which they independently provided unpublished reagents/analytic tools.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center