甘露糖结合凝集素基因多态性与隐球菌病易感性的遗传关联研究

Association of mannose binding lectin genetic polymorphisms with cryptococcosis

目的分析我国非AIDS隐球菌病患者甘露糖结合凝集素（MBL）基因多态性分布情况，并探讨其与隐球菌病易感性的关系。方法采用病例一对照遗传关联研究，病例组为非AIDS相关隐球菌病患者167例，包括隐球菌脑膜炎103例和肺隐球菌感染64例，健康对照组为体检者208例。提取受试者外周血标本基因组DNA。PCR特异性扩增MBL基因DNA片段，对扩增产物进行序列分析，以检测MBL单核苷酸多态性（SNP），进一步探讨MBL基因多态性与隐球菌病易感性的遗传关联性。病例组与对照组比较采用χ2检验或Fisher确切概率检验，MBL基因型各组血浆MBl差异比较采用单因素方差分析。结果167例隐球菌病患者MBL各等位基因、单倍型、基因型所占比例与健康对照组比较，差异均无统计学意义（P〉0．05）。但是，隐球菌脑膜炎患者MBL基因型缺陷组的构成比（16．5％）显著高于健康对照组（8．7％，χ2=4．25，P=0．0392，OR=2．09），在免疫正常隐球菌脑膜炎患者中（21．4%）差异更为显著（χ2=7．15，P=0．0075，OR=2．88）。此外，隐球菌脑膜炎患者MBL基因型缺陷组的构成比显著高于非中枢神经系统感染患者（3．1％，Fisher确切概率检验，P=0．010，OR=6．13），在免疫正常患者中（分别为21．4％和4．0%）差异更为显著（P=0．009，OR=6．55）。结论MBL基因型缺陷是隐球菌脑膜炎的遗传易感因素，MBI，缺陷的隐球菌病患者中枢神经系统更易爱累。

Objective To describe the distribution of mannose binding Iectin （MBL） genetic polymorphisms in non-acquired immunodeficiency syndrome （AIDS） patients with cryptococcosis in China and to verify the association of MBL polymorphisms with susceptibility to cryptococcosis. Methods The case-controlled genetic association study was conducted and 167 non-AIDS patients with cryptococcosis and 208 healthy controls were recruited. Genome DNA was extracted from the peripheral blood and MBL gene was amplified by polymerase chain reaction （PCR）. Six single- nucleotide polymorphisms （SNP） of MBL gene were sequenced. The association of MBL polymorphisms with susceptibility to cryptococcosis were analyzed. The comparison between patients and controls was performed by chi square test or Fisher＇s exact test. The differences of MBL plasma concentrations between groups with different MBL genotypes were compared by single factor variance analysis. Results There were no differences between patients and controls in terms of MBL genotype frequencies, haplotypes and genotypes （all P〉0.05）. Compared with healthy control, the deficient MBL-producing genotypes were strongly associated with cryptococcal meningitis （16. 5% vs 8. 7%, 252 = 4.25, P= 0. 0392, OR= 2.09）, particularly in patients without underlying immunocompromised conditions （21.4G vs8.7%, ）z=7.15, P=0.0075, OR=2.88）. Individuals with MBL deficiency genotypes showed significantly higher rates of central nervous system （CNS） cryptococcal infection rather than non-CNS cryptococcosis （16.5G vs 3.1%, Fisher＇s exact test, P=0. 010, OR=6.13）. The difference was even more significant in the immunocompetent patients （21.4G vs 4.0G, P= 0. 009, OR= 6.55）. Conclusion MBL deficiency is associated with cryptococcal meningitis and may play a role in CNS Cryptococcus infection.