Associations between PRF1 Ala91Val polymorphism and risk of hemophagocytic lymphohistiocytosis: a meta-analysis based on

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META-ANALYSIS

Associations between PRF1 Ala91Val polymorphism and risk of hemophagocytic lymphohistiocytosis: a meta‑analysis based on 1366 subjects Guang‑Hua Zhu1 · Li‑Ping Zhang1 · Zhi‑Gang Li1 · Ang Wei1 · Ying Yang1 · Yu Tian1 · Hong‑Hao Ma1 · Dong Wang1 · Xiao‑Xi Zhao1 · Yun‑Ze Zhao1 · Na Li1 · Wei Liu1 · Tian‑You Wang1 · Rui Zhang1 Received: 12 November 2019 / Accepted: 27 February 2020 © Children’s Hospital, Zhejiang University School of Medicine 2020

Abstract Background  Perforin (PRF1) gene mutation can cause the onset of hemophagocytic lymphohistiocytosis (HLH). It has reported that PRF1 Ala91Val polymorphism was related with HLH risk. In the meta-analysis, we aim to evaluate the association between PRF1 Ala91Val polymorphism and HLH risk. Methods  We accomplished a meta-analysis of six published case–control studies including 391 patients with HLH and 975 controls. We evaluated the quality of each study through Newcastle–Ottawa Scale (NOS). Data analysis was performed with Stata software. Results  In general, all studies were of high quality (NOS score higher than 7). There were statistically significant between the PRF1 Ala91Val polymorphism and HLH risk though the pooled analysis [for Ala/Val vs. Ala/Ala: pooled odds ratio (OR) = 3.22, 95% confidence interval (CI) 1.08–9.56, P = 0.035, random model; for Ala/Val + Val/Val vs. Ala/Ala: pooled OR = 2.96, 95% CI 1.14–7.69, P = 0.025, random model]. Furthermore, sensitivity analysis also revealed a relationship between PRF1 Ala91Val polymorphism and HLH risk (for Ala/Val vs. Ala/Ala: pooled OR = 5.236, 95% CI 2.72–10.08, P < 0.000, I2 = 12.1%, Pheterogeneity = 0.332; for Ala/Val + Val/Val vs. Ala/Ala, pooled OR = 4.856, 95% CI 2.66–8.85, P < 0.000, I2 = 5.9%, Pheterogeneity = 0.373). Funnel plot and Egger’s test did not indicate obvious published bias (P = 0.841 for Ala/Val vs. Ala/Ala; P = 0.284 for Ala/Val + Val/Val vs. Ala/Ala). Conclusion  This meta-analysis indicated that PRF1 Ala91Val polymorphism affects the factor for developing HLH and future studies of PRF1 Ala91Val on the onset of HLH will be guaranteed. Keywords  Ala91Val polymorphism · Hemophagocytic lymphohistiocytosis · PRF1

Introduction Hemophagocytic lymphohistiocytosis (HLH) is a lifethreatening disorder, characterized by hypercytokinemia and multiple-organ injury [1, 2]. There are two different types of HLH: primary HLH and secondary HLH. Primary

Electronic supplementary material  The online version of this article (https​://doi.org/10.1007/s1251​9-020-00351​-7) contains supplementary material, which is available to authorized users. * Rui Zhang [email protected] 1



Beijing Children’s Hospital, Nanlishi Road No. 56, Xicheng District, Beijing, China

HLH is composed of familial HLH (FHL), primary immunodeficiency associated HLH and Epstein–Barr virus-driven HLH. Homogenous or complicated heterogenous mutations in PRF1, UNC13D, STX11 and STXBP2 defects are the causes of FHL2-5, respectively. These mutations impair the granule-mediated cytotoxicity signaling pathway, leading to uncont