Common polymorphisms in the PKP3-SIGIRR-TMEM16J gene region are associated with susceptibility to tuberculosis.
BACKGROUND
Tuberculosis has been associated with genetic variation in host immunity. We hypothesized that single-nucleotide polymorphisms (SNPs) in SIGIRR, a negative regulator of Toll-like receptor/IL-1R signaling, are associated with susceptibility to tuberculosis.


METHODS
We used a case-population study design in Vietnam with cases that had either tuberculous meningitis or pulmonary tuberculosis. We genotyped 6 SNPs in the SIGIRR gene region (including the adjacent genes PKP3 and TMEM16J) in a discovery cohort of 352 patients with tuberculosis and 382 controls. Significant associations were genotyped in a validation cohort (339 patients with tuberculosis, 376 controls).


RESULTS
Three SNPs (rs10902158, rs7105848, rs7111432) were associated with tuberculosis in discovery and validation cohorts. The polymorphisms were associated with both tuberculous meningitis and pulmonary tuberculosis and were strongest with a recessive genetic model (odds ratios, 1.5-1.6; P = .0006-.001). Coinheritance of these polymorphisms with previously identified risk alleles in Toll-like receptor 2 and TIRAP was associated with an additive risk of tuberculosis susceptibility.


CONCLUSIONS
These results demonstrate a strong association of SNPs in the PKP3-SIGIRR-TMEM16J gene region and tuberculosis in discovery and validation cohorts. To our knowledge, these are the first associations of polymorphisms in this region with any disease.
University of Washington School of Medicine, Seattle, Washington, USA.
David J
DJ
Horne
April K
AK
Randhawa
Tran T H
TT
Chau
Nguyen D
ND
Bang
Nguyen T B
NT
Yen
Jeremy J
JJ
Farrar
Sarah J
SJ
Dunstan
Thomas R
TR
Hawn
D000293:Adolescent; D000328:Adult; D000075368:Anoctamins; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D049294:Phospholipid Transfer Proteins; D051191:Plakophilins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D014390:Tuberculosis, Meningeal / Q000235:genetics*; D014397:Tuberculosis, Pulmonary / Q000235:genetics*; D014744:Vietnam; D055815:Young Adult
D000075368:Anoctamins; D008565:Membrane Proteins; D049294:Phospholipid Transfer Proteins; D051191:Plakophilins; D017472:Receptors, Interleukin-1; C570645:ANO9 protein, human; C495339:PKP3 protein, human; C546891:SIGIRR protein, human