Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, No.37, Guo Xue Alley, Chengdu, 610041, Sichuan Province, People's Republic of China; Intensive Care Unit, Deyang People's Hospital, No 173, North Taishan Road, Deyang, 618000, Sichuan Province, People's Republic of China.
Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, No.37, Guo Xue Alley, Chengdu, 610041, Sichuan Province, People's Republic of China.
Microb Pathog. 2023 Oct;183:106289. doi: 10.1016/j.micpath.2023.106289. Epub 2023 Aug 9.
Host genetic single nucleotide polymorphisms can exert an influence susceptibility to tuberculosis infection. Previous investigations have demonstrated an association between the polymorphism in the ALOX5 gene and a range of diseases, encompassing not only noninfectious conditions like asthma, acute myocardial infarction, and cerebral infarction but also infections caused by various pathogens. However, the relationship between ALOX5 gene polymorphism and susceptibility to tuberculosis has received limited research attention. The ALOX5 gene encodes arachidonic acid 5-lipoxygenase(5-LO), which serves as the initiating catalyst in the generation of the inflammatory mediator leukotriene. Leukotrienes, products derived from the 5-LO pathway, are potent proinflammatory lipid mediators that assume a pivotal role in tuberculosis infections.Consequently, ALOX5 gene variants may be intricately associated with the pathogenesis of tuberculosis. In instances where the host exhibits immunocompromisation, infection with Mycobacterium tuberculosis can impact multiple systems. The involvement of multiple systems significantly augments the complexity of treatment and escalates patient mortality rates. Regrettably, the underlying mechanisms driving multisystem tuberculosis pathogenesis remain enigmatic, with clinicians paying scant attention to this aspect. Although the protein encoded by the ALOX5 gene represents a pivotal enzyme that catalyzes the metabolism of arachidonic acid into LXA4, and thereby plays a significant role in the inflammatory response during tuberculosis infection, studies investigating ALOX5 gene polymorphism and its association with susceptibility to multisystem tuberculosis in the Chinese Han population are exceptionally scarce. Therefore, the primary objective of this study is to comprehensively examine the correlation between ALOX5 gene polymorphisms and susceptibility to tuberculosis within the Chinese Han population, with particular emphasis on multisystemic tuberculosis.
A case‒control study design was employed, encompassing 382 individuals with pulmonary tuberculosis and 367 individuals with multisystemic tuberculosis as the case groups, along with 577 healthy controls.Whole blood DNA was extracted from all patients and healthy controls. Subsequently, three tag polymorphisms (rs2029253, rs7896431, rs2115819) within the ALOX5 gene were selectively identified and genotyped.
After adjusting for age and sex, the presence of allele A at rs2029253 exhibited a pronounced association with an elevated risk of TB susceptibility when compared to the tuberculosis group and healthy control group. (OR: 2.174, 95% CI: 1.827-2.587; P<0.001, respectively). Notably, the rs2029253 AG genotype and AA genotype displayed a significantly increased susceptibility to tuberculosis (OR: 2.236, 95% CI: 1.769-2.825; P <0.001 and OR: 4.577, 95% CI: 2.950-7.100; P <0.001, respectively) compared to the GG genotype. Moreover, in the analysis utilizing genetic models, rs2029253 also exhibited a markedly heightened susceptibility to tuberculosis in additive models, dominant models, and recessive models (P <0.001). Conversely, no significant association was observed between rs7896431, rs2115819, and tuberculosis. In the subgroup analysis, when comparing the pulmonary tuberculosis group with the healthy control group, we observed no significant disparities in the distribution frequencies of alleles, genotypes, and gene models (additive model, dominant model, and recessive model) for the three tag SNPs, with P-values were >0.05 after adjusting for age and sex. Additionally, we noted that the presence of allele A at rs2029253 was linked to an increased susceptibility to tuberculosis in the multisystemic tuberculosis group relative to the healthy control group (OR: 2.292, 95% CI: 1.870-2.810; P<0.001). Similarly, the rs2029253 AG genotype, AA genotype, and gene models, including the additive model, dominant model, and recessive model, demonstrated a significantly elevated risk of tuberculosis susceptibility.
The polymorphism in the ALOX5 gene is associated with susceptibility to multisystemic tuberculosis in the Chinese Han population.
宿主遗传单核苷酸多态性可能对结核感染易感性产生影响。先前的研究表明，ALOX5 基因的多态性与一系列疾病有关，不仅包括哮喘、急性心肌梗死和脑梗死等非传染性疾病，还包括各种病原体引起的感染。然而，ALOX5 基因多态性与结核易感性的关系受到的关注有限。ALOX5 基因编码花生四烯酸 5-脂氧合酶（5-LO），它是炎症介质白三烯生成的起始催化剂。白三烯是 5-LO 途径的产物，是强有力的促炎脂质介质，在结核感染中起着至关重要的作用。因此，ALOX5 基因变异可能与结核的发病机制密切相关。在宿主免疫功能低下的情况下，结核分枝杆菌感染可能会影响多个系统。多个系统的受累显著增加了治疗的复杂性，并使患者的死亡率升高。遗憾的是，驱动多系统结核发病机制的潜在机制仍然是一个谜，临床医生对此关注甚少。虽然 ALOX5 基因编码的蛋白质代表一种关键酶，可催化花生四烯酸转化为 LXA4，从而在结核感染的炎症反应中发挥重要作用，但研究 ALOX5 基因多态性及其与中国汉族人群多系统结核易感性的相关性非常罕见。因此，本研究的主要目的是全面研究 ALOX5 基因多态性与中国汉族人群结核易感性之间的相关性，特别是多系统结核。
采用病例对照研究设计，纳入 382 例肺结核患者和 367 例多系统结核患者作为病例组，同时纳入 577 例健康对照。从所有患者和健康对照中提取全血 DNA。随后，选择并鉴定了 ALOX5 基因内的三个标签多态性（rs2029253、rs7896431、rs2115819）。
在调整年龄和性别后，与肺结核组和健康对照组相比，rs2029253 中的等位基因 A 与结核易感性显著相关。（OR：2.174，95%CI：1.827-2.587；P<0.001）。值得注意的是，rs2029253AG 基因型和 AA 基因型显著增加了对结核的易感性（OR：2.236，95%CI：1.769-2.825；P <0.001 和 OR：4.577，95%CI：2.950-7.100；P <0.001）与 GG 基因型相比。此外，在利用遗传模型进行分析时，rs2029253 在加性模型、显性模型和隐性模型中也表现出对结核的显著易感性（P <0.001）。相反，rs7896431 和 rs2115819 与结核之间没有显著相关性。在亚组分析中，与健康对照组相比，在肺结核组中，三个标签 SNP 的等位基因、基因型和基因模型（加性模型、显性模型和隐性模型）的分布频率没有显著差异，在调整年龄和性别后 P 值均>0.05。此外，我们注意到 rs2029253 中的等位基因 A 与多系统结核组相对于健康对照组的结核易感性增加有关（OR：2.292，95%CI：1.870-2.810；P<0.001）。同样，rs2029253AG 基因型、AA 基因型和包括加性模型、显性模型和隐性模型在内的基因模型也显示出对结核易感性的显著增加。
ALOX5 基因的多态性与中国汉族人群多系统结核的易感性有关。
