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Chorionic Gonadotropin β-Gene Variants Are Associated with Recurrent Miscarriage in Two European Populations

Departments of Biotechnology (K.R., L.N., P.K., M.L.) and Bioinformatics (T.M.), Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010 Tartu, Estonia; Department of Obstetrics and Gynecology (K.R.), University of Tartu, Lossi 36, 51003 Tartu, Estonia; Departments of Obstetrics and Gynecology (V.-M.U.) and Clinical Genetics (K.A.), Helsinki University Central Hospital, Helsinki FI-00029 HUS, Finland; and Folkhälsan Institute of Genetics (M.K., K.A.), University of Helsinki, FI-00014 Helsinki, Finland

Address all correspondence and requests for reprints to: Maris Laan, Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu; Riia Street 23, 51010 Tartu, Estonia. E-mail: maris.laan{at}ut.ee.

Context: The incidence of recurrent miscarriage (RM) (3 consecutive pregnancy losses) is estimated as 1–2% in fertile couples. Familial clustering of RM has suggested the contribution of a genetic component.

Objective: 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 β-subunit genes (CGBs) expressed in placenta may contribute to the risk of RM.

Design: Resequencing of CGB5 and CGB8, the two most actively transcribed loci of the four HCG β-duplicate genes, was performed.

Setting: A case-control study involving two sample sets, from Estonia (n = 194) and Finland (n = 185), was performed.

Patients: RM patients (n = 184) and fertile controls (n = 195) participated in the study.

Results: 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.

Conclusion: 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.