基质金属蛋白酶-9 基因单核苷酸多态性与肺结核病的相关性研究

目的:探讨基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)基因多态性(single nucleotide polymorphism,SNP)与肺结核的相关性。方法:对符合纳入及排除标准的肺结核病例组224例及健康对照组249例进行血样收集与临床资料采集。采用飞行时间质谱分析方法对MMP-9基因rs17576、rs2236416、rs3787268、rs3918254共4个多态性位点进行基因分型,数据统计分析采用SPSS20.0和Haplo View 4.0软件进行。结果:我们首次发现,在病例及对照组中,rs17576基因型频率分布存在统计学差异(X~2=7.822,P=0.020)。与对照组相比,病例组G等位基因频率显著高于对照组(X~2=7.335,P=0.007,OR=1.463,95%CI=1.110-1.927)。病例组rs17576基因型分布中,GG和AG基因型患者吸烟史显著高于AA基因型患者;GG和AG基因型患者卡介苗接种史显著低于AA基因型患者。连锁不平衡分析发现一个单倍型(rs17576-rs3918254)高度连锁(D'0.7;r~20.8)。在病例组及对照组中,G-C和A-C单倍型频率分布存在显著性差异,病例组中G-C单倍型频率显著高于对照组(P=0.022),对照组中A-C单倍型频率显著高于疾病组(P=0.024)。结论:MMP-9基因rs17576多态性位点可能与肺结核有关,携带有rs17576位点G等位基因的个体更易发生肺结核。携带G-C(rs17576-rs3918254)单倍型的个体更易患肺结核病,携带A-C(rs17576-rs3918254)单倍型的个体相对不易患肺结核病。

The Association of the Single Nucleotide Polymorphisms of Matrix Metalloproteinase -9 Gene with Tuberculosis

Objective:To examine its relevance for tuberculosis, we examined matrix metalloproteinase -9 (MMP-9) genotype differences in Shaanxi population.Methods:Genomic DNA was isolated fromthe venous blood leukocytes of 224 unrelated patients with tuberculosis and 249 healthy individuals. 4 single nucleotide polymorphisms (SNPs) were genotyped using MassARRAY system. Data were analyzed using SPSS 20.0 and HaploView 4.0 software.Results:There was difference in the genotype frequency of rs17576 between the case and control group (X2=7.822, P=0.020). The rs17576 G allele was significantly higher than controls (X2=7.335,P=0.007, OR=1.463, 95%CI=1.110-1.927). Further genotype and clinical phenotype correlation study of the rs17576 carriers showed that there were more individuals to smoke, less individuals inoculate BCG vaccine in patients with the GG and AG genotypes relative to AA genotype. Linkage disequilibrium (LD) was observed in one block (D'' > 0.7; r2>0.8), and less A-C haplotype frequency (P=0.022) and more G-C haplotype frequency (P=0.024) of block 1 was found in case group.Conclusion:The finding supports a role of MMP-9 rs17576 polymorphismin tuberculosis and may guides future studies to identify other genetic risk factors for tuberculosis.