人类叉头框蛋白 3 基因变异与特发性复发性妊娠丢失易感性改变相关：一项回顾性病例对照研究。
Human forkhead box protein 3 gene variants associated with altered susceptibility to idiopathic recurrent pregnancy loss: A retrospective case-control study.
机构信息
Research Unit of Clinical and Molecular Biology, Faculty of Pharmacy of Monastir, Department of Biochemistry, University of Monastir, Monastir, Tunisia.
Laboratory of Human Genome and Multifactorial Diseases, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia.
出版信息
Am J Reprod Immunol. 2022 Aug;88(2):e13551. doi: 10.1111/aji.13551. Epub 2022 May 16.
BACKGROUND
The pathogenesis of recurrent pregnancy loss (RPL) is multifactorial and not completely elucidated. Dysregulated immunity was implicated with RPL, in which regulatory T cells (Tregs) are key. As Tregs development and function are regulated by forkhead box P3 (FOXP3) transcription factor, and as FOXP3 expression is genetically determined, a role for FOXP3 polymorphisms in RPL pathogenesis was suggested.
AIM
To investigate the association of rs2294021, rs2232365, rs3761548, and rs141704699 FOXP3 variants with idiopathic RPL in Lebanese women.
METHODS
This retrospective case-control study included 386 RPL cases and 398 age-matched control women. Logistic odds ratios (OR) were estimated with 95% confidence interval after adjustment; a significance value of P<.05 was set.
RESULTS
Significantly lower rs22944021 and rs2232365 minor allele frequency (MAF) was found in patients with idiopathic RPL in comparison with the control group. Furthermore, statistically significantly lower frequency of heterozygous and homozygous rs2294021 and rs2232365 genotypes was seen in controls, while significantly lower rs3761548 heterozygous genotype frequencies were found in the patient group. Obesity, antihypertension treatment, smoking, positive RPL family history, abortion state, and infertility treatment correlated negatively with rs2294021, while rs2232365 negatively correlated with obesity, and rs3761548 negatively correlated with infertility treatment. Marked linkage disequilibrium (LD) was noted among FOXP3 SNPs, with TGCC and CGAC haplotypes being positive, while CAAC, CACC, and TGAC haplotypes being negatively associated with RPL risk. Except for CGAC, the association of these haplotypes with RPL persisted after adjustment.
CONCLUSION
FOXP3 gene variants and haplotypes are associated with altered incidence of RPL, proposing the role of Treg in RPL pathogenesis.
背景
复发性流产（RPL）的发病机制是多因素的，尚未完全阐明。免疫失调与 RPL 有关，其中调节性 T 细胞（Tregs）是关键。由于 Tregs 的发育和功能受叉头框 P3（FOXP3）转录因子的调节，并且 FOXP3 的表达受遗传决定，因此 FOXP3 多态性在 RPL 发病机制中的作用被提出。
目的
研究 FOXP3 基因 rs2294021、rs2232365、rs3761548 和 rs141704699 多态性与黎巴嫩女性特发性 RPL 的关系。
方法
这项回顾性病例对照研究纳入了 386 例 RPL 病例和 398 名年龄匹配的对照女性。调整后估计了 logistic 比值比（OR）及其 95%置信区间；设显著性水平 P<.05。
结果
与对照组相比，特发性 RPL 患者的 rs22944021 和 rs2232365 次要等位基因频率（MAF）显著降低。此外，对照组 rs2294021 和 rs2232365 杂合和纯合基因型频率显著降低，而患者组 rs3761548 杂合基因型频率显著降低。肥胖、降压治疗、吸烟、阳性 RPL 家族史、流产状态和不孕治疗与 rs2294021 呈负相关，而 rs2232365 与肥胖呈负相关，rs3761548 与不孕治疗呈负相关。FOXP3 SNP 之间存在明显的连锁不平衡（LD），TGCC 和 CGAC 单倍型为阳性，而 CAAC、CACC 和 TGAC 单倍型与 RPL 风险呈负相关。除 CGAC 外，这些单倍型与 RPL 的相关性在调整后仍然存在。
结论
FOXP3 基因变异和单倍型与 RPL 发生率的改变有关，提示 Treg 在 RPL 发病机制中的作用。
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