Faculté des Sciences et Techniques, Département de Biologie animale, Unité postulante de Biologie Génétique, Génomique et Bioinformatique (G2B), Université Cheikh Anta DIOP de Dakar, UCAD, Avenue Cheikh Anta DIOP, BP: 5005, Dakar, Sénégal.
Unité d'Immunogénétique, Institut Pasteur de Dakar, 36, avenue Pasteur, BP: 220, Dakar, Senegal.
Malar J. 2018 Feb 5;17(1):61. doi: 10.1186/s12936-018-2205-9.
Severe forms of malaria (SM) are an outcome of Plasmodium falciparum infection and can cause death especially in children under 4 years of age. RNASE3 (ECP) has been identified as an inhibitor of Plasmodium parasites growth in vitro, and genetic analysis in hospitalized Ghanaian subjects has revealed the RNASE3 +371G/C (rs2073342) polymorphism as a susceptibility factor for cerebral malaria. The +371 C allele results in an Arg/Thr mutation that abolishes the cytotoxic activity of the ECP protein. The present study aims to investigate RNASE3 gene polymorphisms and their putative link to severe malaria in a malaria cohort from Senegal.
METHODS/RESULTS: Patients enrolled from hospitals were classified as having either uncomplicated (UM) or severe malaria (SM). The analysis of the RNASE3 gene polymorphisms was performed in 241 subjects: 178 falciparum infected (96 SM, 82 UM) and 63 non-infected subjects as population control group (CTR). Six frequent SNPs (MAF > 3%) were identified, and one SNP was associated with malaria severity by performing a logistic regression analysis SM vs.UM: RNASE3 +499G/C (rs2233860) under age, sex as covariates and HbS/HbC polymorphisms adjustment (p = 0.003, OR 0.43, CI 95% 0.20-0.92). The polymorphisms: +371G/C (rs2073342), +499G/C (rs2233860) and +577A/T (rs8019343) defined a haplotype risk (G-G-T) for malaria severity (Fisher exact test, p = 0.03) (OR 4.1, IC 95% (1.1-14.9).
In addition to the previously described association of +371G/C polymorphism in Ghanaians cohort, the RNASE3 +499G/C polymorphism was associated with susceptibility to SM in a Senegalese population. The haplotype +371G/+499G/+577T defined by RNASE3 polymorphisms was associated with severity. The genetic association identified independently in the Senegalese population provide additional evidence of a role of RNASE3 (ECP) in malaria severity.
恶性疟疾（SM）是由恶性疟原虫感染引起的严重疾病，尤其是在 4 岁以下儿童中，可导致死亡。RNASE3（ECP）已被鉴定为抑制疟原虫在体外生长的抑制剂，对加纳住院患者的遗传分析表明，RNASE3+371G/C（rs2073342）多态性是脑型疟疾的易感因素。+371C 等位基因导致精氨酸/苏氨酸突变，从而消除 ECP 蛋白的细胞毒性活性。本研究旨在调查 RNASE3 基因多态性及其与塞内加尔疟疾队列中严重疟疾的潜在联系。
方法/结果：从医院招募的患者被分为无并发症疟疾（UM）或严重疟疾（SM）。对 241 例患者进行了 RNASE3 基因多态性分析：178 例疟原虫感染（96 例 SM，82 例 UM）和 63 例未感染患者作为人群对照组（CTR）。鉴定了 6 个常见 SNP（MAF>3%），并通过逻辑回归分析 SM vs.UM 发现一个 SNP 与疟疾严重程度相关：年龄、性别作为协变量，镰状细胞病/血红蛋白 C 多态性调整后，RNASE3+499G/C（rs2233860）（p=0.003，OR 0.43，95%CI 0.20-0.92）。多态性：+371G/C（rs2073342）、+499G/C（rs2233860）和+577A/T（rs8019343）定义了疟疾严重程度的风险单倍型（G-G-T）（Fisher 精确检验，p=0.03）（OR 4.1，95%CI（1.1-14.9）。
除了先前在加纳队列中描述的+371G/C 多态性与 SM 易感性相关外，在塞内加尔人群中，RNASE3+499G/C 多态性也与 SM 易感性相关。由 RNASE3 多态性定义的单倍型+371G/+499G/+577T 与严重程度相关。在塞内加尔人群中独立鉴定的遗传关联提供了 RNASE3（ECP）在疟疾严重程度中的作用的额外证据。
