Polo-like kinase 4 and Stromal antigen 3 are not associated with recurrent pregnancy loss caused by embryonic aneuploidy

Hiroyuki Yoshihara,Takeshi Nishiyama,Katsushi Tokunaga,Yosuke Omae,Yasuhiko Ozaki,Fumiko Ozawa,Yasuhiro Shibata,Tamao Kitaori,Mayumi Sugiura-Ogasawara,Shinya Ugawa,Koji Aoki

doi:10.1038/s41439-020-0106-2

Hiroyuki Yoshihara, Takeshi Nishiyama + Show 9 more

Open Access

https://doi.org/10.1038/s41439-020-0106-2

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Abstract

No genetic association with recurrent pregnancy loss (RPL) caused by embryonic aneuploidy has been found. Recent studies have indicated that the common genetic variant rs2305957, surrounding the PLK4 gene, contributes to mitotic-origin aneuploidy risk during human early embryo development. The decrease in meiosis-specific cohesin causes predivision of sister chromatids in the centromere and chromosome segregation errors. STAG3 is a component of cohesin and is a meiosis-specific gene. Our case-control study included 184 patients with RPL whose previous products of conception (POC) exhibited aneuploidy and 190 fertile control women without a history of miscarriage. We performed a genetic association study to examine the genotype distribution at PLK4 (rs2305957) and STAG3 in patients with RPL caused by aneuploidy compared with controls. Regarding STAG3, SNPs with a minor allele frequency (MAF) threshold > 0.05 that were predicted to be binding sites of transcription factors and that showed significant associations in expression quantitative trait locus (e-QTL) analysis were selected. No significant differences in the MAF or distribution in any model of PLK4 (rs2305957) and 5 selected tag SNPs in STAG3 were found between the patients and controls. A further genome-wide association study is needed since a combination of genetic risk alleles might be useful in predicting future age-dependent RPL caused by aneuploidy.

Highlights

Recurrent pregnancy loss (RPL) is defined as two or more losses at any time during pregnancy[1,2]
We examined the respective association between RPL and Stromal antigen 3 (STAG3) or Polo-like kinase 4 (PLK4) rs2305957 polymorphism in RPL patients whose previous products of conception (POC) showed aneuploidy
Single-nucleotide polymorphism selection of the genes We focused on STAG3 as a meiosis-related gene and

Summary

Materials and methods

Study population We analyzed the data of 184 Japanese patients with a history of two or more unexplained pregnancy losses and at least one miscarriage whose POC showed aneuploidy. SNPs were chosen by applying the following selection criteria: (i) a minor allele frequency (MAF) threshold of >0.05 in the 1000 Genomes JPT population, (ii) an r2 threshold of ≥0.8. From the 115 SNPs, those that were predicted to be binding sites of transcription factors and those that showed significant associations in e-QTL analysis were selected using the Regulome DB database Our study has 60–80% power to detect a genotype risk ratio of 1.5 under the multiplicative model when the allele frequency is within the range observed in the sample (20–50%) (Supplementary Fig.).

Results

Discussion

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