LTA4H Genotype is Not Associated with Mortality in Zambian Patients with Tuberculous Meningitis (S33.001)

Objective: To characterize the effect of leukotriene A4 hydrolase ( LTA4H ) polymorphisms on survival of Zambian tuberculous meningitis (TBM) patients. Background: TBM is a devastating neuro-infectious disease, especially in HIV-endemic settings like Zambia. LTA4H , a gene encoding a protein that catalyzes production of inflammatory eicosanoid leukotriene B4, has a direct role in TB-mediated inflammation. In humans with TBM, a single nucleotide polymorphism at the LTA4H promotor site rs17525495 C/T has been associated with mortality depending on host genotype: C/C–low inflammation, C/T–mild inflammation, T/T–high inflammation. Prior studies have demonstrated higher mortality among homozygotes. Current treatment guidelines for TBM recommend corticosteroids, adjunctive to anti-tuberculosis therapy, to reduce inflammation and morbidity. The association of TBM with LTA4H genotype has not been studied in sub-Saharan Africa. Design/Methods: 151 patients with suspected TBM infection at the University Teaching Hospital in Lusaka, Zambia, from 4/8/14–10/17/17 were included in analyses. Genotypic evaluation of the LTA4H promotor from whole blood samples was performed for all patients. CSF culture was positive for TB in 33 patients, of whom all but two had confirmed HIV infection. Univariate analyses were performed to test for association between LTA4H polymorphisms and inpatient mortality in TBM patients with positive CSF culture. Results: The distribution of genotypes was as follows: C/C (0.79), C/T (0.19), T/T (0.01). Frequencies of the C and T alleles were 0.89 and 0.11, respectively. There was no association between LTA4H heterozygosity and one-year survival in patients with TBM ( p =0.76). Conclusions: The C allele was the most frequent LTA4H allele among all patients. We observed low frequency of the T/T homozygous genotype, which is the group of patients thought to benefit most from adjuvant corticosteroids in TBM. We found no relationship between LTA4H polymorphism and survival in TBM patients. Clinical prospective studies are needed to determine whether adjuvant steroids should potentially be avoided in Zambian patients with TBM. Disclosure: Dr. Love has nothing to disclose. Dr. Koralnik has nothing to disclose. Dr. Dang has nothing to disclose. Dr. Musukuma has nothing to disclose. Dr. Mubanga has nothing to disclose. Dr. Buback has nothing to disclose. Dr Birbeck has nothing to disclose. Dr. Atadzhanov has nothing to disclose. Dr. Siddiqi has nothing to disclose.