Factor H, a regulator of complement activity, is a major determinant of meningococcal disease susceptibility in UK Caucasian patients
Factor H, a regulator of complement activity, is a major determinant of meningococcal disease susceptibility in UK Caucasian patients
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DOI：
10.1080/00365540600643203
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发表时间：
2006-09-01
影响因子：
--
通讯作者：
Levin, Michael
中科院分区：
文献类型：
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作者：
Haralambous, Elene;Dolly, Saoirse O.;Levin, Michael
对脑膜炎奈瑟菌的防御涉及补体介导的杀菌活性。因子H(Fh)下调补体激活。在Fh基因(C-496T)的核因子-kappaB反应元件(NFkB)中存在一个可能具有功能性的单核苷酸多态(SNP)。进行了遗传和功能研究，以确定C-496T是否在脑膜炎双球菌病(MD)易感性中起作用。遗传易感性是在两项独立的研究中进行的，这两项研究是病例对照和基于家族的传递不平衡检验(TDT)，使用了两个独立的英国高加索患者队列。MD的易感性与C/C纯合子(OR=2.0，95%CI1.3~3.2，p=0.001)和C等位基因相关(P=0.0 4)，在C组感染患者中关联最为显著(OR=2.9，95%CI1.6~5.5，p=0.0002)。FH血清浓度也与C-496T基因型相关，在C/C纯合子个体中Fh浓度最高(p=0.01)。功能研究表明，NF-kappa-B与C-496T区结合，FH与脑膜炎球菌预先孵育降低了杀菌活性，并增加了脑膜炎球菌B和C在血液中的存活率。这项研究表明，C-496T与MD有关联和联系，具有FH C-496T C/C基因型的人更有可能血清FH蛋白水平升高，对脑膜炎球菌的杀菌活性降低，感染MD的风险增加。
Defence against Neisseria meningitidis involves complement-mediated bactericidal activity. Factor H (fH) down-regulates complement activation. A putatively functional single-nucleotide-polymorphism ( SNP) exists within a presumed nuclear-factor-kappa-B B responsive element (NF-kB) in the fH gene (C-496T). Genetic and functional investigations were carried out to determine whether C-496T has a role in meningococcal disease ( MD) susceptibility. Genetic susceptibility was investigated in 2 independent studies, a case-control and family-based transmission-disequilibrium-test (TDT), using 2 separate cohorts of UK Caucasian patients. MD susceptibility was both genetically associated with the C/C homozygous genotype (OR = 2.0, 95% CI 1.3 - 3.2, p = 0.001) and linked to the C allele ( p = 0.04), the association being most significant in serogroup C infected patients ( OR = 2.9, 95% CI 1.6 - 5.5, p = 0.0002). FH serum concentrations were also associated with C-496T genotype, with highest fH concentrations in C/C homozygous individuals (p = 0.01). Functional studies showed NF-kappa-B binding to the C-496T-containing region and that pre-incubation of fH with meningococci reduced bactericidal activity and increased meningococci B and C survival in blood. This study shows that C-496T is both associated and linked with MD and that individuals possessing the fH C-496T C/C genotype are more likely to have increased serum fH protein levels, have reduced bactericidal activity against meningococci and be at an increased risk of contracting MD.