Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, Natal, Brazil.
BMC Med Genet. 2011 Apr 7;12:51. doi: 10.1186/1471-2350-12-51.
The kynurenine (KYN) pathway has been shown to be altered in several diseases which compromise the central nervous system (CNS) including infectious diseases such as bacterial meningitis (BM). The aim of this study was to assess single nucleotide polymorphisms (SNPs) in four genes of KYN pathway in patients with meningitis and their correlation with markers of immune response in BM.
One hundred and one individuals were enrolled in this study to investigate SNPs in the following genes: indoleamine-2,3-dioxygenase (IDO1 gene), kynureninase (KYNU gene), kynurenine aminotransferase I (CCBL1 gene), and kynurenine aminotransferase II (AADAT gene). SNP analyses were performed by primer-introduced restriction analysis-PCR (PIRA-PCR) followed by RFLP. Cytokines were measured using multiplex bead assay while immunoglobulins (IG) by immunodiffusion plates and NF-kappaB and c-Jun by dot blot assay.
The variant allele of SNP AADAT+401C/T showed prevalent frequency in patients with BM. A significant decrease (p < 0.05) in TNF-α, IL-1β, IL-6, MIP-1αCCL3 and MIP-1β/CCL4 levels was observed in BM patients homozygous (TT) to the SNP AADAT+401C/T. Furthermore, a significant (p < 0.05) decrease in cell count was observed in cerebrospinal fluid (CSF) from patients with TT genotype. In addition, an increase in the IgG level in adults (p < 0.05) was observed. The variant allele for KYNU+715G/A was found with low frequency in the groups, and the SNPs in IDO1+434T/G, KYNU+693G/A, CCBL1+164T/C, and AADAT+650C/T had no frequency in this population.
This study is the first report of an association of SNP AADAT+401C/T with the host immune response to BM, suggesting that this SNP may affect the host ability in recruitment of leukocytes to the infection site. This finding may contribute to identifying potential targets for pharmacological intervention as adjuvant therapy for BM.
色氨酸（KYN）途径已被证明在几种影响中枢神经系统（CNS）的疾病中发生改变，包括细菌性脑膜炎（BM）等传染病。本研究的目的是评估 KYN 途径中四个基因的单核苷酸多态性（SNP）在脑膜炎患者中的存在，并分析其与 BM 中免疫反应标志物的相关性。
本研究共纳入 101 例个体，以研究以下基因中的 SNP：吲哚胺 2,3-双加氧酶（IDO1 基因）、犬尿氨酸酶（KYNU 基因）、色氨酸氨基转移酶 I（CCBL1 基因）和色氨酸氨基转移酶 II（AADAT 基因）。通过引物引入的限制性分析-PCR（PIRA-PCR）和 RFLP 进行 SNP 分析。使用多重珠粒分析测定细胞因子，使用免疫扩散板测定免疫球蛋白（IG），使用斑点印迹测定 NF-kappaB 和 c-Jun。
在 BM 患者中，AADAT+401C/T SNP 的变体等位基因表现出较高的频率。在 AADAT+401C/T SNP 纯合子（TT）的 BM 患者中，观察到 TNF-α、IL-1β、IL-6、MIP-1αCCL3 和 MIP-1β/CCL4 水平显著降低（p<0.05）。此外，在 TT 基因型患者的脑脊液（CSF）中观察到细胞计数显著降低（p<0.05）。此外，在成人中观察到 IgG 水平升高（p<0.05）。KYNU+715G/A 的变体等位基因在各组中频率较低，IDO1+434T/G、KYNU+693G/A、CCBL1+164T/C 和 AADAT+650C/T 的 SNP 在该人群中无频率。
本研究首次报道了 SNP AADAT+401C/T 与 BM 宿主免疫反应之间的关联，表明该 SNP 可能影响宿主将白细胞募集到感染部位的能力。这一发现可能有助于确定潜在的药物干预靶点，作为 BM 的辅助治疗。
