Dataset Information

Association of genetic variants of PD1 with recurrent pregnancy loss.

ABSTRACT: Purpose:Programmed cell death 1 (PD1) and PD ligand 1 (PDL1) are speculated to have an important role in maintaining a normal pregnancy and there are also a few reports of an association between the single-nucleotide polymorphisms (SNPs) of PD1 or PDL1 and diseases in humans. The association was examined between the polymorphisms of PD1,PDL1,CTLA4 and recurrent pregnancy loss (RPL). Methods:The study group consisted of 243 women with two or more pregnancy losses and 176 parous women. The frequency of three SNPs of PD1, two of PDL1, and four of CTLA4 were compared between the patients and controls. Next, the subsequent live birth rates in the patients with RPL with and without risk alleles were examined. Results:Two SNPs (rs36084323 and rs3481962) of PD1 were found to occur at significantly higher frequencies in the patient group than in the control group. The subsequent live birth rate of the patients with vs. without the risk alleles of rs36084323 and rs3481962 were 83.3% vs. 83.3% and 81.6% vs. 84.0%, respectively. Conclusion:Variations of the PD1 gene were identified as risk factors for RPL. However, the presence or absence of the PD1 risk alleles had no predictive effect on the subsequent pregnancy outcome.

SUBMITTER: Hayashi Y

PROVIDER: S-EPMC5902459 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Association of genetic variants of <i>PD1</i> with recurrent pregnancy loss.

Hayashi Yuko Y Nishiyama Takeshi T Nakatochi Masahiro M Suzuki Shugo S Takahashi Satoru S Sugiura-Ogasawara Mayumi M

Reproductive medicine and biology 20180323 2

<h4>Purpose</h4>Programmed cell death 1 (PD1) and PD ligand 1 (PDL1) are speculated to have an important role in maintaining a normal pregnancy and there are also a few reports of an association between the single-nucleotide polymorphisms (SNPs) of <i>PD1</i> or <i>PDL1</i> and diseases in humans. The association was examined between the polymorphisms of <i>PD1</i>,<i>PDL1</i>,<i>CTLA4</i> and recurrent pregnancy loss (RPL).<h4>Methods</h4>The study group consisted of 243 women with two or more ...[more]

PMID: 29692678

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Project description:Miscarriage is the most common complication of pregnancy. Approximately 1% of couples trying to conceive will experience recurrent miscarriages, defined as three or more consecutive pregnancy losses and many of these cases remain idiopathic. Complement is implicated both in the physiology and pathology of pregnancy. Therefore, we hypothesized that alterations in the C3 gene could potentially predispose to this disorder. We performed full Sanger sequencing of all exons of C3, in 192 childless women, with at least two miscarriages and without any known risk factors. All exons carrying non-synonymous alterations found in the patients were then sequenced in a control group of 192 women. None of the identified alterations were significantly associated with the disorder. Thirteen identified non-synonymous alterations (R102G, K155Q, L302P, P314L, Y325H, V326A, S327P, V330I, K633R, R735W, R1591G, G1606D, and S1619R) were expressed recombinantly, upon which C3 expression and secretion were determined. The L302P and S327P were not secreted from the cells, likely due to misfolding and intracellular degradation. Y325H, V326A, V3301I, R1591G, and G1606D yielded approximately half C3 concentration in the cell media compared with wild type (WT). We analyzed the hemolytic activity of the secreted C3 variants by reconstituting C3-depleted serum. In this assay, R1591G had impaired hemolytic activity while majority of remaining mutants instead had increased activity. R1591G also yielded more factor B activation in solution compared with WT. R1591G and G1606D showed impaired degradation by factor I, irrespectively if factor H, CD46, or C4b-binding protein were used as cofactors. These two C3 mutants showed impaired binding of the cofactors and/or factor I. Taken together, several alterations in C3 were identified and some of these affected the secretion and/or the function of the protein, which might contribute to the disorder but the degree of association must be evaluated in larger cohorts.

Dataset Information

Association of genetic variants of PD1 with recurrent pregnancy loss.

Publications

Association of genetic variants of <i>PD1</i> with recurrent pregnancy loss.

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