Association study of frameshift and splice variant polymorphisms with risk of idiopathic recurrent pregnancy loss

Recurrent pregnancy loss (RPL) is defined as ≥2 consecutive pregnancy losses, and can be caused by various factors, including genetics, chromosomal abnormalities, thrombophilia, immune disorders, nutritional factors, environmental factors, psychological stress or maternal infections; however, as many as 50% of RPL cases are idiopathic. In the present study, the role of genetic polymorphisms in RPL was investigated. Four gene polymorphisms were selected by whole exome sequencing, including membrane spanning 4‑domains A14 (MS4A14)D>I (rs3217518), solute carrier family 2 member 7 (SLC2A7)D>I (rs60746313), pregnancy specific β‑1‑glycoprotein 9 (PSG9)C>T (rs3746297) and ATP binding cassette subfamily B member 5 (ABCB5)C>G (rs17143187), and the aim was to investigate their association with RPL in Korean women. Genotyping was performed using polymerase chain reaction‑restriction fragment length polymorphism assay. Allele combination analysis revealed that the four‑allele combination I‑D‑T‑G, (MS4A14/SLC2A7/PSG9/ABCB5) was associated with a decreased risk for RPL. Interaction analysis demonstrated that the following genotypes: MS4A14 DI+II, SLC2A DI+II and ABCB 5 CG+GG, were associated with a prothrombin time ≥12 sec and with RPL risk. It may be concluded that the four gene polymorphisms do not affect RPL individually, but are associated with RPL when in combination with other genes or blood coagulation factors. Notably, the MS4A14 I allele, with a prothrombin time ≥12 sec, may be a potential biomarker for diagnosis, prevention and prognosis of RPL.