Association Between Gene Polymorphism Of LTA4H And Tuberculous Meningitis

Objective: Tuberculous meningitis(TBM) is a central nervous system non suppurative inflammation caused by Mycobacterium tuberculosis(Mtb), which is one of the most serious form in tuberculosis(TB). It,s estimated that one third of the world's population are potentially infected with Mtb, only 10% of that develop into TB, and TBM makes up 1% of TB patiens. Different individuals which expose to the same etiology develop into different forms in TB. Most of the patients develop pulmonary tuberculosis, while only a small part develop TBM and have different clinical manifestation and prognosis. These findings suggest that host genetics strongly influences susceptibility to TBM. The mutations of genes invole in immuning response to Mtb may partly explain the dissemination of Mtb to the central nervous system from lung more easily. Leukotriene A4 hydrolase(LTA4H)gene play an important role in controlling the balance of proinfl-ammatory and anti-inflammatory eicosanoid to influence immune response to Mtb. Our research try to study the possible association between LTA4 H gene single nucleotide polymorphisms and TBM in han population of northern China and evaluate the effect of corticosteroids therapy on TBM patients with different genotypes.Methods:1 110 TBM patients and 105 healthy individuals were enrolled in this study. All subjects came from Han nationality of northern China. All patients fulfilled the criteria of the definite and probable TBM according to the consensus case definition for TBM developed by the International Organization in 2010. The patient's condition in admission and outcome in discharge were evaluated based on MRC TBM grade and modified Rakin scores(MRS) respectively.2 Venous blood samples from all subjects were collected and DNA was extracted. The gene polymorphisms of LTA4 H rs17525495 were detected via gene sequencing.3 CSF specimen from a part of TBM patients before antituberculosis treatment and patients with non infectious neurological diseases as control group were collected. Levels of TNF? in TBM and control group were determined by means of sandwich enzyme-linked immunosorbent assay(ELISA), using TNF? immunoassay kits.4 The clinical datum of TBM patients were anlysed retrospectively. According to whether to use corticosteroids, these cases were divided into 2 groups, corticosteroids treatment group(33 patients) and non-corticosteroids treatment group(42 patients). The treatment effect was evaluated as MRS scores(Modified Rakin Scale,MRS) in discharge.5 Statistical was analyzed by SPSS 21.0 statistical analysis software. The Hardy-Weinberg equilibrium test was assessed in control group. The allele and genotype frequency were calculated by direct counting. The comparison of allele and genotype distribution were examined with Chi-squared tests. TNF levels were reported as median±SD, and the differences between different groups were tested by Student t test or non-parameter test when appropriate. The differences of the effect of corticosteroids treatment on patients with different genotypes were test with the ?2 test. A p-value of <0.05 was accepted as significant difference.Results:1 Cases and controls:The case group included 110 subjects, of which 77 were male while 33 were female. The median age for case group was 38.6±16.8 years. The control group included 105 subjects, of which 65 were male while 40 were female. The median age for control group was 37.5±13.7 years. There was significant difference between control and case group in age and gender comparison.2 The detection of Hardy-Weinberg equilibrium(HWE):The genotypes of control were in Hardy-Weinberg equilibrium(HWE)(P>0.05).3 LTA4 H gene polymorphisms in TBM patients :There were no signify- cant difference of allele frequency of LTA4 H gene rs17525495 between cases and controls. LTA4 H gene rs17525495 TT genotype distribution in TBM group was higher than that in control group in recessive inheritance model(OR=3.092, 95 %CI: 0.964-9.914, P=0.047)4 LTA4 H gene polymorphisms in TBM patients in different grade :The frequency of CT+TT genotype distribution in TBM patients in grade III increased significantly in comparison to that in control group in dominant inheritance model(OR=2.321,95%CI: 1.055-5.107, P=0.034). This study also showed that the frequecy of TT genotype in TBM patients in grade III was higher than that in control group in recessive inheritance model(OR=6.546,95%CI: 1.784-24.015, P=0.005).5 LTA4 H gene polymorphisms in TBM patients with different clinical outcomes in discharge:LTA4H gene rs17525495 TT genotype distribution in TBM patients with poor outcome increased significantly than control group in recessive inheritance model(OR=6.012, 95%CI: 1.488-24.289. P=0.015)6(1)The CSF concentration of TNF? were higher compared with the control group(12.15±1.76 pg/ml vs 7.35±0.98 pg/ml,P<0.05;(2) The level of TNF?(22.99±6.23pg/ml)of serious TBM patients in grade III increased than patients in grade I and grade II;(3) TBM patients with poor clinical outcome have more higher TNF? concentration(23.28±6.80 pg/ml) than patients with good clinical outcome.(4)The CSF levels of TNF? were found to be highest in patients with TT genotype, followed by CT genotype, and TT genotype were lowest.7 The effect of corticosteroids therapy on TBM patients with different genotypes :(1)TT genotype: The effective rate of corticosteroids treatment group and non-corticosteroids treatment group were 83.3% and 0 respectively, the corticosteroids treatment group was significantly higher than that of the non-corticosteroids treatment group in effective rate(P<0.05);(2)CT genotype: The effective rate of treatment group and non-corticosteroids treatment group were 58.3% and 64.3% respectively. There were no significantly difference between the two groups in effective rate;(3)CC genotype: The effective rate of corticosteroids treatment group and non-corticosteroids treatment group were 60% and 91.7% respectively, the non-corticosteroids treatment group was significantly higher than that of the treatment group in effective rate.(P<0.05)Conclusions:1 LTA4 H gene rs17525495 genetype of TT may increase the risk of TBM and patients with TT genotype likely have more severe pathogenesis and poor outcomes.2 There were diference of the CSF concentration of TNF? between TBM patients with different genotype. The CSF levels of TNF? were highest in patients with TT genotype, followed by CT genotype, and TT genotype were lowest. Patients in serious clinical stage and with poor clinical outcome have higher TNF-? concentration.3 The genotype of LTA4 H gene rs17525495 may influence the effect of corticosteroids treatment on patients. The patients with TT genotype may benefit from corticosteroids treatment and patients with CC genotype may have poor response to corticosteroids treatment.