Contributed by Jean-Laurent Casanova, March 22, 2019 (sent for review March 4, 2019; reviewed by Mary Carrington, Dinakantha Kumararatne, and Michael Levin)
Only ∼5% of individuals infected with Mycobacterium tuberculosis develop clinical TB in their lifetime. We previously reported that homozygosity for the P1104A variant of the TYK2 gene, found in ∼1/600 Europeans and ∼1/5,000 individuals from elsewhere (except East Asians and sub-Saharan Africans), was a monogenic etiology of TB in a genetically heterogeneous cohort of patients from non-European countries endemic for TB. Making use of the UK Biobank cohort, we report a strong enrichment of P1104A homozygotes in a British sample of 620 patients with TB (1%), relative to 114,473 controls (0.2%), 97% of whom were of European descent. Our findings suggest that homozygosity for the P1104A TYK2 variant may underlie TB in ∼1% of European patients.
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.
↵1N.R.-A. and Y.S. contributed equally to this work.
↵2S.B.-D., J.-L.C., and L.A. contributed equally to this work.
Author contributions: G.K., S.B.-D., J.-L.C., and L.A. designed research; G.K., N.R.-A., Y.S., R.Y., M.O., A.C., E.P., L.Q.-M., S.B.-D., and L.A. performed research; G.K., N.R.-A., Y.S., R.Y., A.C., E.P., L.Q.-M., S.B.-D., J.-L.C., and L.A. analyzed data; and G.K., N.R.-A., Y.S., L.Q.-M., S.B.-D., J.-L.C., and L.A. wrote the paper.
Reviewers: M.C., SAIC-Frederick; D.K., Cambridge University Foundation Hospitals NHS Trust; and M.L., Imperial College of Science, Technology and Medicine.
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.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1903561116/-/DCSupplemental.
Published under the PNAS license.
