Rull Kristiina, Nagirnaja Liina, Ulander Veli-Matti, Kelgo Piret, Margus Tõnu, Kaare Milja, Aittomäki Kristiina, Laan Maris
Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia.
J Clin Endocrinol Metab. 2008 Dec;93(12):4697-706. doi: 10.1210/jc.2008-1101. Epub 2008 Sep 9.
The incidence of recurrent miscarriage (RM) (>or=3 consecutive pregnancy losses) is estimated as 1-2% in fertile couples. Familial clustering of RM has suggested the contribution of a genetic component.
A low level of human chorionic gonadotropin (HCG) in maternal serum during the first trimester of the pregnancy is a clinically accepted risk factor for miscarriage. We sought to study whether variation in chorionic gonadotropin beta-subunit genes (CGBs) expressed in placenta may contribute to the risk of RM.
Resequencing of CGB5 and CGB8, the two most actively transcribed loci of the four HCG beta-duplicate genes, was performed.
A case-control study involving two sample sets, from Estonia (n = 194) and Finland (n = 185), was performed.
RM patients (n = 184) and fertile controls (n = 195) participated in the study.
From 71 identified variants in CGB5 and CGB8, 48 polymorphisms were novel. Significant protective effect was associated with two single nucleotide polymorphisms located at identical positions in intron 2 in both CGB5 [P = 0.007; odds ratio (OR) = 0.53] and CGB8 (P = 0.042; OR = 0.15), and with four CGB5 promoter variants (P < 0.03; OR = 0.54-0.58). The carriers of minor alleles had a reduced risk of RM. The haplotype structure of the CGB8 promoter was consistent with balancing selection; a rare mutation in CGB8 initiator element was detected only among patients (n = 3). In addition, three rare nonsynonymous substitutions were identified among RM cases as possible variants increasing the risk of recurrent pregnancy loss.
The findings encourage studying the functional effect of the identified variants on CGB expression and HCG hormone activity to elucidate further the role of CGB variation in RM.
复发性流产（RM，即连续≥3次妊娠丢失）在育龄夫妇中的发生率估计为1%-2%。RM的家族聚集现象提示了遗传因素的作用。
妊娠早期母血清中人绒毛膜促性腺激素（HCG）水平低是临床上公认的流产危险因素。我们试图研究胎盘表达的绒毛膜促性腺激素β亚基基因（CGBs）的变异是否会增加RM的风险。
对4个HCGβ重复基因中两个转录最活跃的位点CGB5和CGB8进行重测序。
进行了一项病例对照研究，涉及来自爱沙尼亚（n = 194）和芬兰（n = 185）的两个样本组。
RM患者（n = 184）和生育对照者（n = 195）参与了该研究。
在CGB5和CGB8中鉴定出的71个变异中，48个多态性是新发现的。位于CGB5内含子2相同位置的两个单核苷酸多态性[P = 0.007；优势比（OR）= 0.53]和CGB8（P = 0.042；OR = 0.15），以及4个CGB5启动子变异（P < 0.03；OR = 0.54 - 0.58）具有显著的保护作用。次要等位基因携带者的RM风险降低。CGB8启动子的单倍型结构与平衡选择一致；仅在患者中检测到CGB8起始元件中的一个罕见突变（n = 3）。此外，在RM病例中鉴定出3个罕见的非同义替换，可能是增加复发性妊娠丢失风险的变异。
这些发现鼓励研究已鉴定变异对CGB表达和HCG激素活性的功能影响，以进一步阐明CGB变异在RM中的作用。
