IL6-174 G/C promoter polymorphism influences susceptibility to mucosal but not localized cutaneous leishmaniasis in Brazil
IL6-174 G/C promoter polymorphism influences susceptibility to mucosal but not localized cutaneous leishmaniasis in Brazil
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DOI：
10.1086/505504
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发表时间：
2006-08-15
影响因子：
6.4
通讯作者：
Carvalho, Edgar M.
中科院分区：
文献类型：
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作者：
Castellucci, Lea;Menezes, Eliane;Carvalho, Edgar M.
背景。粘膜利什曼病（ML）与肿瘤坏死因子- α和干扰素- γ反应和组织破坏有关。ML继发于巴西利什曼原虫感染引起的局部皮肤利什曼病。白细胞介素(IL)-6下调辅助性T细胞（Th） 1型分化并驱动Th2细胞分化。il -174 G/C多态性与促炎疾病及IL-6调控有关。对巴西CL和ML人群样本和家族进行了-174 G/C多态性基因分型。通过logistic回归和家庭关联检验（FBAT）分析比较ML患者、CL患者和2个对照组的基因型频率。检测巨噬细胞中IL-6水平。C等位基因在ML患者中比在CL患者中更常见（比值比[OR]， 2.55[95%可信区间{CI}， 1.32-4.91]; P = 0.005），比在leishmanin皮肤试验阳性患者中更常见（OR, 2.23 [95% CI, 1.23-4.05]; P = 0.009），比在邻居对照组中更常见（OR, 2.47 [95% CI, 1.24-4.90]; P = 0.01）。FBAT分析证实，在加性模型（P = 0.000017）和显性模型（z = 4.325; P = 0.000015）下，等位基因C和ML之间存在关联。CC患者巨噬细胞中IL-6水平明显低于GG患者（P = 0.003）和可溶性利什曼原虫抗原刺激后（P = 0.009）。IL-6可能调节1型促炎反应，使巨噬细胞IL-6水平低的个体患ML的风险增加。
Background. Mucosal leishmaniasis (ML) is associated with exaggerated tumor necrosis factor-alpha and interferon-gamma responses and tissue destruction. ML follows localized cutaneous leishmaniasis (CL) caused by Leishmania braziliensis infection. Interleukin (IL)-6 down-regulates T helper (Th) cell type 1 differentiation and drives Th2 cell differentiation. The IL6 -174 G/C polymorphism is associated with proinflammatory diseases and IL-6 regulation.Methods. The -174 G/C polymorphism was genotyped in population samples and families with CL and ML from Brazil. Genotype frequencies were compared among patients with ML, patients with CL, and 2 control groups by logistic regression and family-based association test (FBAT) analysis. IL-6 levels were measured in macrophages.Results. The C allele was more common in patients with ML than in patients with CL (odds ratio [OR], 2.55 [95% confidence interval {CI}, 1.32-4.91]; P = .005), than in patients who were leishmanin skin-test positive (OR, 2.23 [95% CI, 1.23-4.05]; P = .009), and than in neighborhood control subjects (OR, 2.47 [95% CI, 1.24-4.90]; P = .01). FBAT analysis confirmed an association between allele C and ML under both additive (P = .000017) and dominant (z = 4.325; P = .000015) models. Significantly lower levels of IL-6 were measured in unstimulated macrophages from CC individuals than from GG individuals (P = .003) as well as after stimulation with soluble leishmania antigen (P = .009).Conclusions. IL-6 may regulate type 1 proinflammatory responses, putting individuals with low macrophage IL-6 levels at increased risk for ML.