Genetic variants in microRNA machinery genes are associated [corrected] with idiopathic recurrent pregnancy loss risk.
OBJECTIVE
Key molecules involved in microRNA (miRNA) biogenesis, such as DROSHA, XPO5, and DICER, have been identified in trophoblast cells, confirming that the miRNA biogenesis pathway is active in human placenta. In addition, miRNAs regulate uterine gene expression associated with inflammatory responses during the peri-implantation period and participate in maternal-fetal immune tolerance. The purpose of this study was to demonstrate whether genetic polymorphisms in miRNA machinery genes show an association with idiopathic recurrent pregnancy loss (RPL) in Korean women.


METHODS
We performed a case-control study with 238 controls and 338 women who had experienced at least two consecutive pregnancy losses between 1999 and 2010. Genotypes of miRNA machinery genes, including DICER rs3742330, DROSHA rs10719, RAN GTPase (RAN) rs14035, and exportin-5 (XPO5) rs11077 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The logistic odds ratios (ORs) of RPL were estimated with a 95% confidence interval (CI) in multivariate analysis after maternal age adjustment. Gene-gene interactions among the loci of the four gene polymorphisms were evaluated using the multifactor dimensionality reduction (MDR) method.


RESULTS
The RAN rs14035 CC genotype and DICER rs3742330/DROSHA rs10719 GG/TC+CC, rs3742330/RAN rs14035 GG/CC, and DICER rs3742330/XPO5 rs11077 GG/AC+CC combinations were significantly associated with increased RPL risk, whereas the RAN rs14035 CT, DICER rs3742330/RAN rs14035 AA+AG/CT+TT, DROSHA rs10719/RAN rs14035 TC+CC/CT+TT, and RAN rs14035/XPO5 rs11077 CT+TT/AA combinations reduced RPL risk. The A-T-T-C and G-C-T-A allele combinations (DICER/DROSHA/RAN/XPO5) were 20 times more frequent in the RPL group than in the control group.


CONCLUSIONS
Our study demonstrates the relationship between RPL development and the polymorphism of the miRNA machinery gene RAN and combined genotype of DROSHA/DICER.
Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, South Korea.
Yong Wook
YW
Jung
Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
Young Joo
YJ
Jeon
Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
HyungChul
H
Rah
Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
Ji Hyang
JH
Kim
Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
Ji Eun
JE
Shin
Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
Dong Hee
DH
Choi
Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
Sun Hee
SH
Cha
Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam-si, South Korea.
Nam Keun
NK
Kim
D000026:Abortion, Habitual / Q000235:genetics*; D000328:Adult; D016022:Case-Control Studies; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D028884:Karyopherins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D043244:Ribonuclease III / Q000235:genetics*; D012306:Risk; D017422:Sequence Analysis, DNA; D055815:Young Adult; D020931:ran GTP-Binding Protein / Q000235:genetics*
D028884:Karyopherins; C120587:RAN protein, human; C446511:XPO5 protein, human; C408087:DICER1 protein, human; C517918:DROSHA protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; D020931:ran GTP-Binding Protein