Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Copenhagen, Denmark.
PLoS One. 2011;6(12):e29465. doi: 10.1371/journal.pone.0029465. Epub 2011 Dec 27.
Cerebral malaria (CM) is the most severe outcome of Plasmodium falciparum infection and a major cause of death in children from 2 to 4 years of age. A hospital based study in Ghana showed that P. falciparum induces eosinophilia and found a significantly higher serum level of eosinophil cationic protein (ECP) in CM patients than in uncomplicated malaria (UM) and severe malaria anemia (SA) patients. Single nucleotide polymorphisms (SNPs) have been described in the ECP encoding-gene (RNASE3) of which the c.371G>C polymorphism (rs2073342) results in an arginine to threonine amino acid substitution p.R124T in the polypeptide and abolishes the cytotoxicity of ECP. The present study aimed to investigate the potential association between polymorphisms in RNASE3 and CM.
METHODOLOGY/PRINCIPAL FINDINGS: The RNASE3 gene and flanking regions were sequenced in 206 Ghanaian children enrolled in a hospital based malaria study. An association study was carried out to assess the significance of five SNPs in CM (n=45) and SA (n=56) cases, respectively. The two severe case groups (CM and SA) were compared with the non-severe control group comprising children suffering from UM (n=105). The 371G allele was significantly associated with CM (p=0.00945, OR=2.29, 95% CI=1.22-4.32) but not with SA. Linkage disequilibrium analysis demonstrated significant linkage between three SNPs and the haplotype combination 371G/*16G/*94A was strongly associated with susceptibility to CM (p=0.000913, OR=4.14, 95% CI=1.79-9.56), thus, defining a risk haplotype. The RNASE3 371GG genotype was found to be under frequency-dependent selection.
CONCLUSIONS/SIGNIFICANCE: The 371G allele of RNASE3 is associated with susceptibility to CM and forms part of a risk associated haplotype GGA defined by the markers: rs2073342 (G-allele), rs2233860 (G-allele) and rs8019343 (A-allele) respectively. Collectively, these results suggest a hitherto unrecognized role for eosinophils in CM pathogenesis.
脑型疟疾（CM）是恶性疟原虫感染的最严重后果，也是 2 至 4 岁儿童死亡的主要原因。加纳的一项基于医院的研究表明，恶性疟原虫诱导嗜酸性粒细胞增多症，并发现 CM 患者的血清嗜酸性粒细胞阳离子蛋白（ECP）水平明显高于无并发症疟疾（UM）和严重疟疾贫血（SA）患者。ECP 编码基因（RNASE3）中已描述了单核苷酸多态性（SNP），其中 c.371G>C 多态性（rs2073342）导致多肽中精氨酸到苏氨酸的氨基酸取代 p.R124T，并使 ECP 的细胞毒性丧失。本研究旨在探讨 RNASE3 多态性与 CM 之间的潜在关联。
方法/主要发现：在加纳一项基于医院的疟疾研究中，对 206 名儿童的 RNASE3 基因及其侧翼区进行了测序。进行了一项关联研究，以评估 5 个 SNP 在 CM（n=45）和 SA（n=56）病例中的意义。将这两个严重病例组（CM 和 SA）与非严重对照组（n=105）进行比较，非严重对照组包括患有 UM 的儿童。371G 等位基因与 CM 显著相关（p=0.00945，OR=2.29，95%CI=1.22-4.32），但与 SA 无关。连锁不平衡分析表明，三个 SNP 之间存在显著连锁，并且 371G/*16G/*94A 单体型组合与 CM 的易感性强烈相关（p=0.000913，OR=4.14，95%CI=1.79-9.56），因此定义了一个风险单体型。发现 RNASE3 371GG 基因型处于频率依赖性选择之下。
结论/意义：RNASE3 的 371G 等位基因与 CM 的易感性相关，并构成由标记 rs2073342（G-等位基因）、rs2233860（G-等位基因）和 rs8019343（A-等位基因）定义的风险相关单体型 GGA 的一部分。这些结果共同表明，嗜酸性粒细胞在 CM 发病机制中发挥了以前未被认识到的作用。
