ALOX5 variants associated with susceptibility to human pulmonary tuberculosis
ALOX5 variants associated with susceptibility to human pulmonary tuberculosis
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DOI：
10.1093/hmg/ddm378
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发表时间：
2008-04-01
影响因子：
3.5
通讯作者：
Meyer, Christian G.
中科院分区：
文献类型：
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作者：
Herb, Florian;Thye, Thorsten;Meyer, Christian G.
5-脂氧合酶（ALOX 5）衍生的脂质介质白三烯和脂氧素通过调节免疫细胞的活性和细胞因子的产生而在炎症中具有调节功能。最近，在ALOX 5（-/-）小鼠中显示结核分枝杆菌的宿主控制受5-脂氧合酶（5-LO）调节。对来自加纳的1916例结核病阳性肺结核（TB）患者和2269例暴露的明显健康对照者进行ALOX 5多态性基因分型。通过片段长度测定和荧光共振能量转移以及DNA测序分析ALOX 5启动子和外显子非同义变体g.760G > A的可变数目串联重复序列（VNTR）的多态性。对> 1400株分离物的分枝杆菌谱系进行了生化和遗传分化。携带一个变异体（n重复不等于5）和一个野生型VNTR等位基因（n = 5）或外显子等位基因g.760A的携带者具有更高的TB风险[P校正= 0.026，比值比（OR）1.19（95%CI 1.04-1.37）和P校正= 0.026，OR 1.21（95%CI 1.04-1.41）]。外显子变异的关联在分枝杆菌谱系M引起的感染中更强。非洲西部非洲2 [P校正= 0.024，OR 1.70;（95% CI 1.2-2.6）]。单倍型的确定显示与TB的关联性最强的是“非5/760 A”单倍型，而不是“非5/760 G”单倍型（P = 0.003，OR 1.50）。我们观察到ALOX 5变异体与对TB的易感性相关，这为5-LO产物在调节对结核分枝杆菌的免疫应答中的重要性提供了证据。结核
The 5-lipoxygenase (ALOX5)-derived lipid mediators leukotrienes and lipoxins have regulatory functions in inflammation by modulating activities of immune cells and cytokine production. Recently, it was shown in ALOX5(-/-) mice that host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase (5-LO). ALOX5 polymorphisms were genotyped in 1916 sputum-positive patients with pulmonary tuberculosis (TB) from Ghana and in 2269 exposed, apparently healthy controls. Polymorphisms of a variable number of tandem repeats (VNTR) of the ALOX5 promoter and of the exonic non-synonymous variant g.760G > A were analysed by fragment length determination and fluorescence resonance energy transfer, respectively, and DNA sequencing. Mycobacterial lineages of > 1400 isolates were differentiated biochemically and genetically. Carriers of one variant (n repeats not equal 5) and one wild-type VNTR allele (n = 5) or of the exonic allele g.760A had a higher risk of TB [P-corrected = 0.026, odds ratio (OR) 1.19 (95% CI 1.04-1.37) and P-corrected = 0.026, OR 1.21 (95% CI 1.04-1.41), respectively]. The association of the exonic variant was stronger in infections caused by the mycobacterial lineage M. africanum West-African 2 [P-corrected = 0.024, OR 1.70; (95% CI 1.2-2.6)]. Determination of haplotypes revealed the strongest associaton with TB for the 'non-5/760A' haplotype compared with the 'non-5/760G' haplotype (P = 0.003, OR 1.50). Our observation of an association of ALOX5 variants with susceptibility to TB contributes evidence of the importance of 5-LO products to the regulation of immune responses to M. tuberculosis.