Ferwerda Bart, Valls Serón Mercedes, Jongejan Aldo, Zwinderman Aeilko H, Geldhoff Madelijn, van der Ende Arie, Baas Frank, Brouwer Matthijs C, van de Beek Diederik
Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, P.O. Box 22660, Amsterdam, The Netherlands.
Bioinformatics Laboratory, Academic Medical Center, P.O. Box 22660, Amsterdam, The Netherlands.
EBioMedicine. 2016 Aug;10:77-84. doi: 10.1016/j.ebiom.2016.07.011. Epub 2016 Jul 12.
Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Early recognition of the pathogen and subsequent innate immune response play a vital role in disease susceptibility and outcome. Genetic variations in innate immune genes can alter the immune response and influence susceptibility and outcome of meningitis disease. Here we conducted a sequencing study of coding regions from 46 innate immune genes in 435 pneumococcal meningitis patients and 416 controls, to determine the role of genetic variation on pneumococcal meningitis susceptibility and disease outcome. Strongest signals for susceptibility were rs56078309 CXCL1 (p=4.8e-04) and rs2008521 in CARD8 (p=6.1e-04). For meningitis outcome the rs2067085 in NOD2 (p=5.1e-04) and rs4251552 of IRAK4 were the strongest associations with unfavorable outcome (p=6.7e-04). Haplotype analysis showed a haplotype block, determined by IRAK4 rs4251552, significantly associated with unfavorable outcome (p=0.004). Cytokine measurements from cerebrospinal fluid showed that with the IRAK4 rs4251552 G risk allele had higher levels of IL-6 compared to individuals with A/A genotype (p=0.04). We show that genetic variation within exons and flanking regions of 46 innate immunity genes does not yield significant association with pneumococcal meningitis. The strongest identified signal IRAK4 does imply a potential role of genetic variation in pneumococcal meningitis.
肺炎球菌性脑膜炎是细菌性脑膜炎最常见且最严重的形式。病原体的早期识别及随后的先天免疫反应在疾病易感性和预后中起着至关重要的作用。先天免疫基因的遗传变异可改变免疫反应，并影响脑膜炎疾病的易感性和预后。在此，我们对435例肺炎球菌性脑膜炎患者和416例对照者的46个先天免疫基因的编码区进行了测序研究，以确定遗传变异对肺炎球菌性脑膜炎易感性和疾病预后的作用。易感性最强的信号是CXCL1基因的rs5,607,8309（p = 4.8×10⁻⁴）和CARD8基因的rs2008521（p = 6.1×10⁻⁴）。对于脑膜炎预后，NOD2基因的rs2067085（p = 5.1×10⁻⁴）和IRAK4基因的rs4251552与不良预后的关联最强（p = 6.7×10⁻⁴）。单倍型分析显示，由IRAK4基因的rs4251552确定的一个单倍型块与不良预后显著相关（p = 0.004）。脑脊液细胞因子测量显示，与A/A基因型个体相比，携带IRAK4基因rs4251552 G风险等位基因的个体IL-6水平更高（p = 0.04）。我们发现，46个先天免疫基因的外显子和侧翼区域内的遗传变异与肺炎球菌性脑膜炎无显著关联。所确定的最强信号IRAK4确实暗示了遗传变异在肺炎球菌性脑膜炎中的潜在作用。
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