Novel genes and mutations in patients affected by recurrent pregnancy loss

Quintero-Ronderos, Paula; Mercier, É.; Fukuda, Michiko; González, Ronald; Suárez, Carlos F.; Patarroyo, Manuel A.; Vaiman, Daniel; Gris, Jean‐Christophe; Laissue, Paul

doi:10.1371/journal.pone.0186149

Cited by 62 publications

(35 citation statements)

References 45 publications

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“…In a somewhat similar study, transcriptome analysis compared endometrial tissues from women experiencing recurrent implantation failure to controls (either spontaneously fertile women or women with at least 1 successful implantation via in vitro fertilization) and identified 82 consistently differentially expressed genes (79). Of the 82 genes identified by this study, 13 (or 15.8%) were identified as modulators of decidualization in our screen (80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96). These findings are in Dataset S7.…”

Section: Discussionmentioning

confidence: 57%

Development and utilization of human decidualization reporter cell line uncovers new modulators of female fertility

Haller

Yin

2019

Proc. Natl. Acad. Sci. U.S.A.

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Failure of embryo implantation accounts for a significant percentage of female infertility. Exquisitely coordinated molecular programs govern the interaction between the competent blastocyst and the receptive uterus. Decidualization, the rapid proliferation and differentiation of endometrial stromal cells into decidual cells, is required for implantation. Decidualization defects can cause poor placentation, intrauterine growth restriction, and early parturition leading to preterm birth. Decidualization has not yet been systematically studied at the genetic level due to the lack of a suitable high-throughput screening tool. Herein we describe the generation of an immortalized human endometrial stromal cell line that uses yellow fluorescent protein under the control of the prolactin promoter as a quantifiable visual readout of the decidualization response (hESC-PRLY cells). Using this cell line, we performed a genome-wide siRNA library screen, as well as a screen of 910 small molecules, to identify more than 4,000 previously unrecognized genetic and chemical modulators of decidualization. Ontology analysis revealed several groups of decidualization modulators, including many previously unappreciated transcription factors, sensory receptors, growth factors, and kinases. Expression studies of hits revealed that the majority of decidualization modulators are acutely sensitive to ovarian hormone exposure. Gradient treatment of exogenous factors was used to identify EC50 values of small-molecule hits, as well as verify several growth factor hits identified by the siRNA screen. The high-throughput decidualization reporter cell line and the findings described herein will aid in the development of patient-specific treatments for decidualization-based recurrent pregnancy loss, subfertility, and infertility.

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Section: Discussionmentioning

confidence: 57%

Development and utilization of human decidualization reporter cell line uncovers new modulators of female fertility

Haller

Yin

2019

Proc. Natl. Acad. Sci. U.S.A.

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“…[ 10 ] A study based on whole genomic sequencing and bioinformatics analysis demonstrated that mutations in MMP9 showed close association with RSA. [ 11 ] MMP2 and MMP9 belong to gelatinases, a subgroup of MMPs, which are involved in various physiological and pathological progresses. [ 12 ] MMP2 is usually secreted by endothelial cells, interstitial cells, macrophages, T cells, eosnophils, and neutrophils, and MMP9 is mainly synthesized and secreted by inflammatory cells.…”

Section: Introductionmentioning

confidence: 99%

The association of polymorphisms in promoter region of MMP2 and MMP9 with recurrent spontaneous abortion risk in Chinese population

Liu

Qin

et al. 2018

Medicine

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This study aimed to reveal the genetic association between polymorphisms in promoter region of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) and the risk of recurrent spontaneous abortion (RSA) in Chinese population.A total of 129 RSA patients and 116 relative controls were selected and the genotyping of polymorphism was conducted by polymerase chain reaction with sequencing. Genotype distribution of polymorphism in the control group was tested the status of Hardy–Weinberg equilibrium and then, genotype frequencies were compared between the case and control groups by chi-squared test. Odds ratio (OR) with the corresponding 95% confidence interval (95% CI) was computed to express the risk of RSA caused by polymorphism. Moreover, the linkage disequilibrium of polymorphisms in MMP2 was analyzed by Haploview software.CT genotype and T allele of rs243865 in MMP2 were significantly associated with the increased susceptibility to RSA in Chinese population (CT vs. CC: OR = 1.926, 95% CI = 1.101–3.368; T vs. C: OR = 1.751, 95% CI = 1.146–2.676). Similarly, CT genotype carriers of rs3918242 in MMP9 were obviously more in RSA patients than that of the controls (P = .037), which indicated it was associated with the risk of RSA occurrence (OR = 1.760, 95% CI = 1.034–2.995). So was T allele in RSA development (OR = 1.595, 95% CI = 1.061–2.398). Haplotypes C-T and T-C were also the risk factors of RSA (OR = 1.673, 95% CI = 1.103–2.536; OR = 2.171, 95% CI = 1.372–2.436).MMP2 rs243865 and MMP9 rs3918242 polymorphisms are significantly associated with the risk of RSA in Chinese population.

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“…Successful studies have been made by our research group using WES to identified candidate genes of complex diseases and now in pharmacogenetics. [9][10][11][12][13] According to the Naranjo scale, it was estimated for the patient analyzed that the rhabdomyolysis was induced by rosuvastatin (8 points "probable"). 14,15 Considering the timeline of our patient's medication use (Rosuvastatinezetimibe treatment had been established two years prior the reaction), we estimate that exposure to ticagrelor triggered the rhabdomyolysis.…”

Section: Discussionmentioning

confidence: 99%

<p>A Pharmacogenomic Dissection of a Rosuvastatin-Induced Rhabdomyolysis Case Evokes the Polygenic Nature of Adverse Drug Reactions</p>

Calderón-Ospina¹,

Hernández-Somerson²,

Garcı́a³

et al. 2020

PGPM

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Rosuvastatin, is a widely-used statin for the treatment of hypercholesterolemia and the prevention of cardiovascular diseases. Although rosuvastatin is well tolerated, about 3/10.000 patients can suffer severe myopathy. Rhabdomyolysis is a severe medical condition that causes injury to the skeletal muscle, electrolyte imbalances, acute renal failure and extreme creatine kinase (CK) elevation. Little is known regarding the molecular involvement of rosuvastatin-induced rhabdomyolysis (RIR). It has been demonstrated that genomic variants associated with decreased enzymatic activity of proteins are important determinants in plasmatic and skeletal muscle distribution of rosuvastatin and its toxicity. Until now, no interactions of ticagrelor, ezetimibe and rosuvastatin have been described with the consideration of pharmacogenomics predisposition. The present report involves a whole-exome sequencing (WES), in a patient affected by rosuvastatin-induced rhabdomyolysis. A pharmacogenomic dissection was performed by analyzing a comprehensive subset of candidate genes (n=160) potentially related to RIR. The genes were selected according to their implication in drug metabolism or inherited myopathies. Using an innovative approach of bioinformatics analysis, considering rare and common variants, we identified 19 genomic variations potentially related to the pharmacokinetic/pharmacodynamic modifications of rosuvastatin, ezetimibe and ticagrelor. The affected genes are involved in Phase I metabolism (CYP2C19, CYP2E1, CYP1A1, CYP2D6 and CYP2C9), Phase II metabolism (UGT2B15 and UGT2B7), influx transportation (SLCO1B3 and SLCO2B1), efflux transportation (ABCG8, ABCB11, ABCC4 and ABCB1), drug targeting (NPC1L1) and inherited myopathy etiology (OBSCN). We report three rare, potentially pathogenic molecular variants in CYP2C19, NPC1L1 and OBSCN genes. Pharmacogenetic analysis indicated that the patient was a carrier of inactivating alleles in several pharmacogenes involved in drug toxicity. The whole-exome sequencing and bioinformatics analysis presented here represents an innovative way to identify genomic variants contributing with RIR´s origin and evokes the polygenic nature of adverse drug reactions.

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Novel genes and mutations in patients affected by recurrent pregnancy loss

Cited by 62 publications

References 45 publications

Development and utilization of human decidualization reporter cell line uncovers new modulators of female fertility

Development and utilization of human decidualization reporter cell line uncovers new modulators of female fertility

The association of polymorphisms in promoter region of MMP2 and MMP9 with recurrent spontaneous abortion risk in Chinese population

<p>A Pharmacogenomic Dissection of a Rosuvastatin-Induced Rhabdomyolysis Case Evokes the Polygenic Nature of Adverse Drug Reactions</p>

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