Exonic sequencing identifies TLR1 genetic variation associated with mortality in Thais with melioidosis

Abstract

Melioidosis, an infectious disease caused by the bacterium Burkholderia pseudomallei , is a common cause of sepsis in Southeast Asia. We investigated whether novel TLR1 coding variants are associated with outcome in Thai patients with melioidosis. We performed exonic sequencing on a discovery set of patients with extreme phenotypes (mild vs. severe) of bacteremic melioidosis. We analysed the association of missense variants in TLR1 with severe melioidosis in a by-gene analysis. We then genotyped key variants and tested the association with death in two additional sets of melioidosis patients. Using a by-gene analysis, TLR1 was associated with severe bacteremic melioidosis ( P = 0.016). One of the eight TLR1 variants identified, rs76600635, a common variant in East Asians, was associated with in-hospital mortality in a replication set of melioidosis patients (adjusted odds ratio 1.71, 95% CI 1.01–2.88, P = 0.04.) In a validation set of patients, the point estimate of effect of the association of rs76600635 with 28-day mortality was similar but not statistically significant (adjusted odds ratio 1.81, 95% CI 0.96–3.44, P = 0.07). Restricting the validation set analysis to patients recruited in a comparable fashion to the discovery and replication sets, rs76600635 was significantly associated with 28-day mortality (adjusted odds ratio 3.88, 95% CI 1.43–10.56, P = 0.01). Exonic sequencing identifies TLR1 as a gene associated with a severe phenotype of bacteremic melioidosis. The TLR1 variant rs76600635, common in East Asian populations, may be associated with poor outcomes from melioidosis. This variant has not been previously associated with outcomes in sepsis and requires further study.

Human Melioidosis

“…In a study of melioidosis patients in northeast Thailand, HLA-B*46 and HLA-C*01 were associated with an increased risk of death (OR, 2.8 and 3.1, respectively) (505). A recent evaluation of the TLR1 variants common in East Asian populations demonstrated an association with a severe bacteremic phenotype and potentially worse outcome (580). Conversely, genetic polymorphisms for two flagellin-sensing receptors, TLR5 and NLRC4, have demonstrated survival benefit in patients with melioidosis (581)(582)(583)(584).…”

The Assessment of TLR1 Gene Polymorphism Association with the Risk of Allergic Rhinitis in the Chinese Han Population from Northern China

“…19 Furthermore, it has been reported that TLR1-rs76600635 is correlated with poor outcomes of melioidosis in Thais populations. 20 A targeted sequencing study has identified TLR1-rs72493538 as a novel genetic variant associated with asthma risk in the Chinese Han population. 21 TLR1-rs76600635 has been reported to be significantly associated with the occurrence, presentation and adverse drug reactions of tuberculosis in adults in western China.…”

Lack of Association of TLR1 and TLR5 Coding Variants with Mortality in a Large Multicenter Cohort of Melioidosis Patients

“…Power and statistical analysis. Power was estimated using the "genpwr" package in R based on minor allele frequencies (MAFs) and odds ratios (ORs) of effect observed in our prior studies 19,23,24 and on the size and frequency of outcomes in the present patient cohort. For TLR5 rs5744168, with an expected MAF of 0.05 to 0.10, the power to detect ORs of 0.2 to 0.5 for mortality and bacteremia (at rates of 25% and 82%, respectively, in the present cohort) was 0.83 to 1.00, with alpha set at 0.05 and assuming a dominant model.…”

“…The covariates included were age, sex, comorbidities, site, referral status, and time from admission to study enrollment. 19,23,24 Results were expressed as ORs, with corresponding 95% CI. A P-value of ,0.05 was defined as statistically significant.…”

“…18 However, we have reported that a novel coding variant in TLR1 (rs76600635) is associated with a severe phenotype of bacteremic melioidosis in a discovery set and with mortality in a replication set of patients; this association with mortality persisted in a validation set of patients when differences in study design influencing timing of subject recruitment were taken into account. 19 These observations implicate TLR1 in the host response to melioidosis.…”