背景:复发性自然流产(RSA)是由多种因素引起的严重且常见的妊娠并发症。病因仍未完全了解,但免疫因素起着重要作用。这里,我们旨在评估循环免疫细胞是否会对RSA造成因果关系.
方法:在本研究中,我们进行了一项全面的孟德尔随机双样本(MR)研究,以确定人类外周血淋巴细胞的731种免疫表型与自然流产和复发性流产数量之间的因果关系.进行敏感性分析以评估和最小化异质性和水平多效性。反向MR分析用于评估反向因果关系。
结果:Bonferroni校正后,八种免疫表型与自然流产的数量显着相关:CD4T细胞上的FSC-A(β=-0.051,95%CI=[-0.085,-0.017],P值=0.004),HLADR+CD8+T细胞上的CD8(β=-0.040,95%CI=[-0.067,-0.014],P值=0.003),CD33dimHLADR+CD11b-(β=-0.021,95%CI=[-0.036,-0.005],P值=0.010),HLADR+T细胞绝对计数(β=0.022,95%CI=[0.006,0.037],P值=0.008),HLADR+T细胞%淋巴细胞(β=0.026,95%CI=[0.010,0.041],P值=0.001),HLADR+T细胞%T细胞(β=0.023,95%CI=[0.007,0.039],P值=0.004),HLADR+CD4+T细胞%淋巴细胞(β=0.034,95%CI=[0.007,0.060],P值=0.012),和B细胞上的HLADR(β=0.012,95%CI=[0.003,0.021],P值=0.010)。此外,我们确定了两种与复发性流产相关的免疫表型:B细胞上的HLADR(OR=0.854,95%CI=[0.757,0.964],P值=0.011),和CD19在幼稚成熟B细胞上(OR=4.595,95%CI=[1.674,12.617],P值=0.003)。没有异质性的证据,水平多效性和反向因果关系。
结论:我们的研究证明了适应性免疫细胞和RSA之间通过遗传手段的紧密联系,从而提供潜在的治疗靶点或新的诊断生物标志物。
BACKGROUND: Recurrent spontaneous
abortion (RSA) is a serious and common complication of pregnancy caused by multiple factors. The etiology remains incompletely understood, but immunologic factors play important roles. Here, we aimed to evaluate whether circulating immune cells causally impacted RSA.
METHODS: In this study, we conducted a comprehensive two-sample Mendelian randomization (MR) study to determine the causal association between the 731 immunophenotypes of human peripheral blood lymphocytes and the number of spontaneous abortions as well as recurrent miscarriage. Sensitivity analyses were performed to assess and minimize heterogeneity and horizontal pleiotropy. Reverse MR analysis was used to assess reverse causality.
RESULTS: After Bonferroni-correction, eight immunophenotypes were significantly associated with the number of spontaneous abortions: FSC-A on CD4+ T cell (beta = -0.051, 95% CI = [-0.085, -0.017], P-value = 0.004), CD8 on HLA DR+ CD8+ T cell (beta = -0.040, 95% CI = [-0.067, -0.014], P-value = 0.003), HLA DR on CD33dim HLA DR+ CD11b- (beta = -0.021, 95% CI = [-0.036, -0.005], P-value = 0.010), HLA DR+ T cell Absolute Count (beta = 0.022, 95% CI = [0.006, 0.037], P-value = 0.008), HLA DR+ T cell % lymphocyte (beta = 0.026, 95% CI = [0.010, 0.041], P-value = 0.001), HLA DR+ T cell % T cell (beta = 0.023, 95% CI = [0.007, 0.039], P-value = 0.004), HLA DR+ CD4+ T cell % lymphocyte (beta = 0.034, 95% CI = [0.007, 0.060], P-value = 0.012), and HLA DR on B cell (beta = 0.012, 95% CI = [0.003, 0.021], P-value = 0.010). In addition, we identified two immunophenotypes associated with recurrent miscarriage: HLA DR on B cell (OR = 0.854, 95% CI = [0.757, 0.964], P-value = 0.011), and CD19 on naive-mature B cell (OR = 4.595, 95% CI = [1.674, 12.617], P-value = 0.003). There was no evidence of heterogeneity, horizontal pleiotropy and reverse causality.
CONCLUSIONS: Our study demonstrated a tight link between adaptive immune cells and RSA through genetic means, thus providing potential therapeutic targets or novel diagnostic biomarkers.