Gene gene interactions and risk of recurrent miscarriages in carriers of endocrine gland derived vascular endothelial growth factor and prokineticin receptor polymorphisms

Two nonsynonymous prokineticin receptor variants were significantly associated with idiopathic recurrent miscarriages, and endocrine gland–derived vascular endothelial growth factor variant has genetic interactions with two receptor genes that contribute to miscarriage risk.


Mei-Tsz Su, M.D., Ph.D., Sheng-Hsiang Lin, Ph.D., Yi-Chi Chen, Ph.D., Pao-Lin Kuo, M.D.

Volume 102, Issue 4, Pages 1071-1077



To study endocrine gland–derived vascular endothelial growth factor (EG-VEGF), prokineticin receptor (PROKR) 1, and PROKR2 variants in the coding regions of idiopathic recurrent miscarriage (RM) patients and further evaluate gene-gene interactions of these three genes.


Case-control study.


University-based reproductive clinics and genetics laboratory.


A total of 142 women with a history of idiopathic RM and 149 control subjects were included.



Main Outcome Measure(s):

All blood samples were nucleotide sequenced in the coding regions of EG-VEGF, PROKR1, and PROKR2. Gene-gene interaction of three gene variants was evaluated with the use of the multifactor dimensionality reduction method.


One nonsynonymous variant of each of the three genes was identified, and PROKR1 (I379V) and PROKR2 (V331M) were significantly associated with idiopathic RM. Genetic interactions were found not only between PROKR1 (I379V) and PROKR2 (V331M), but also among EG-VEGF (V67I), PROKR1 (I379V), and PROKR2 (V331M). Women carrying low-risk genotypes had a 77% reduced risk of experiencing miscarriages compared with those carrying high-risk genotypes.


The present study corroborates the clinical relevance of the EG-VEGF system in human early pregnancy, and provides evidence for the gene-gene interactions of EG-VEGF and PROKR variants.

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