Polymorphism of<i>MDM2</i>promoter 309 (rs 2279744) and the risk of PCOS

Chan, Ying; Jiang, Hongguo; Yang, Xiaoling; Li, Dongya; Ma, Lan; Luo, Ying; Tang, Wenru

doi:10.3109/09513590.2015.1092515

Cited by 5 publications

(5 citation statements)

References 19 publications

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“…In male mice, Sertoli cell-specific Mdm2 deficiency disturbs testicular development through induction of p53 and apoptosis in this cell lineage (43), and an MDM2 inhibitor Nutlin-3a reduces sperm motility (44). In humans, MDM2 and p53 polymorphisms are associated with the incidence of infertility and polycystic ovary syndrome (45,46). A previous mouse study demonstrated Figure 8.…”

Section: Discussionmentioning

confidence: 94%

Mdm2‐p53‐SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality

Haraguchi¹,

Hirota

Saito‐Fujita³

et al. 2018

FASEB j.

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Functions of tumor suppressor p53 and its negative regulator mouse double minute 2 homolog (Mdm2) in ovarian granulosa cells remain to be elucidated, and the current study aims at clarifying this issue. Mice with Mdm2 deficiency in ovarian granulosa cells [Mdm2‐loxP/progesterone receptor (Pgr)‐Cre mice] were infertile as a result of impairment of oocyte maturation, ovulation, and fertilization, and those with Mdm2/p53 double deletion in granulosa cells (Mdm2‐loxP/p53‐loxP/Pgr‐Cre mice) showed normal fertility, suggesting that p53 induction in the ovarian granulosa cells is detrimental to ovarian function by disturbing oocyte quality. Another model of Mdm2 deletion in ovarian granulosa cells (Mdm2‐loxP/anti‐Mullerian hormone type 2 receptor‐Cre mice) also showed subfertility as a result of the failure of ovulation and fertilization, indicating critical roles of ovarian Mdm2 in ovulation and fertilization. Mdm2‐p53 pathway in cumulus granulosa cells transcriptionally controlled an orphan nuclear receptor steroidogenic factor 1 (SF1), a key regulator of ovarian function. Importantly, MDM2 and SF1 levels in human cumulus granulosa cells were positively associated with the outcome of oocyte maturation and fertilization in patients undergoing infertility treatment. These findings suggest that the Mdm2‐p53‐SF1 axis in ovarian cumulus granulosa cells directs ovarian function by affecting their neighboring oocyte quality.—Haraguchi, H., Hirota, Y., Saito‐Fujita, T., Tanaka, T., Shimizu‐Hirota, R., Harada, M., Akaeda, S., Hiraoka, T., Matsuo, M., Matsumoto, L., Hirata, T., Koga, K., Wada‐Hiraike, O., Fujii, T., Osuga, Y. Mdm2‐p53‐SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality. FASEB J. 33, 2610–2620 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 94%

Mdm2‐p53‐SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality

Haraguchi¹,

Hirota

Saito‐Fujita³

et al. 2018

FASEB j.

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“…To date, seldom study has analyzed the MDM2 rs2279744 T > G polymorphism and fetal aneuploidy. Previous studies have shown a close association of MDM2 rs2279744 T > G with the human polycystic ovarian syndrome and human reproduction [ 5 , 23 ]. Strikingly, MDM2 rs2279744 T > G polymorphism is the key element in maintaining the genomic stability of somatic cells [ 4 , 22 ], which was not revealed in female gametes and embryos.…”

Section: Discussionmentioning

confidence: 99%

Association of TP53 rs1042522 G > C, MDM2 rs2279744 T > G, and miR-34b/c rs4938723 T > C polymorphisms with aneuploidy pregnancy susceptibility

Chan,

Xu,

Feng

et al. 2023

BMC Pregnancy Childbirth

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Background Aneuploidy pregnancy is a severe major birth defect and causes about 50% spontaneous miscarriages with unknown etiology. To date, only a few epidemiological studies with small sample sizes have investigated the risk factors for aneuploidy pregnancy. TP53, MDM2, and miR-34b/c genes are implicated in tumorigenesis with aneuploidy, yet the function of their polymorphisms in aneuploidy pregnancy susceptibility needs to be clarified. Objective To elucidate the association of TP53 rs1042522 G > C, MDM2 rs2279744 309 T > G, and miR-34b/c rs4938723 T > C specific polymorphisms with aneuploidy pregnancy. Methods In the retrospective case-control study, 330 aneuploidies pregnancy women and 813 normal pregnancy controls were recruited between January 2018 and April 2022 at the First People’s Hospital of Yunnan Province, Kunming, China. Three functional polymorphisms, the TP53 rs1042522 G > C (Arg72Pro), MDM2 rs2279744 309 T > G, and miR-34b/c rs4938723 T > C, were genotyped using the snapshot method. Results The frequency distribution of three genotypic variants was not different between case and control pregnant women and was similar to with Hardy-Weinberg Equilibrium (HWE). However, in the younger subgroup (less than 35 years old), a significant difference was detected in allele and recessive model (p = 0.01). In the advanced age subgroup (more than or equal to 35 years old), G of MDM2 rs2279744 T > G revealed a significantly higher frequency in cases than controls (p = 0.045), and miR-34b/c rs4938723 T > C revealed a significant difference under the dominant model (p = 0.03), but no significant differences were observed in other models and in both younger and older subgroup (p > 0.05, respectively). These results suggest that individual polymorphisms were not associated with aneuploidy pregnancy, combined with age, they may serve as a risk factor for aneuploidy pregnancy. Conclusion Combination of TP53 rs1042522 G > C, MDM2 rs2279744 T > G, and miR-34b/c rs4938723 T > C polymorphisms with maternal age may be related to aneuploidy pregnancy susceptibility. These findings might elaborate on the genetic etiology of aneuploidy pregnancy.

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“…The variant (G) allele of the MDM2 SNP309 polymorphism (rs2279744) is known to be associated with higher levels of MDM2, resulting, in turn, in lower levels of p53 and, respectively, decreased p53-dependent suppression of cell proliferation [75], which may explain its association with increased risk for endometrial cancer [76]. The association with increased risk for PCOS was identified for the wildtype (T) MDM2 allele [74]. PCOS is characterised by follicular growth arrest at early antral stage and low levels of proliferation of granulosa cell proliferation, therefore, a genetically determined propensity for increased cell proliferation may decrease the risk for PCOS.…”

Section: Role Of Individual Repair Capacity In the Constitution Of Thmentioning

confidence: 94%

“…A recent study showed that a polymorphism in the gene coding for the major negative regulator of the stability and activity of p53 -the E3 ubiquitin ligase MDM2 -was associated with modulation of the risk for polycystic ovary syndrome (PCOS) [74]. PCOS is one Reproductive outcomes and individual repair capacity of the most common endocrine abnormalities in women of reproductive age and may be a serious risk factor for infertility, as it may interfere with ovulation patterns or altogether preclude ovulation.…”

Section: Role Of Individual Repair Capacity In the Constitution Of Thmentioning

confidence: 99%

Reproductive outcomes in pregnant women aged 35 or older: the role of individual repair capacity

Petkova¹,

Dimitrova²,

Zhelev³

et al. 2015

Biodiscovery

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Abbreviations: 8-OH-dG -8-hydroxydeoxyguanosine, AMA -advanced maternal age, AR -assisted reproduction, BER -base excision repair, CDC -US Centre for disease prevention and control, DIC -disseminated intravascular coagulation, DS -Down syndrome, HELLP -haemolysis/elevated liver enzymes/low platelets, ICSI -intracytoplasmic sperm injection, IRC -individual repair capacity, IUGR -intrauterine growth restriction, IUI -intrauterine insemination, IVF -in vitro fertilisation, LIF -leukaemia inhibitory factor, NER -nucleotide excision repair, PCOS -polycystic ovary syndrome, PIH -pregnancy-induced hypertension, ROS -reactive oxygen species, TTD -trichothiodystrophy, w.g. -weeks of gestation, WHO -World Health Organisation, XP -xeroderma pigmentosum. AbstractAt present, childbirth is being progressively postponed until later age. Women aged 35 or older may have to wait longer to conceive than younger women and are more likely to be referred to fertility evaluations, but in a significant proportion a spontaneous conception would be achieved in the timeframe typical of younger women. Pregnancies where mothers are ≥ 35 are associated with more risks for pregnancy loss, chromosomal disease, pregnancy-associated complications, prematurity and low birthweight. These concerns, however, are not uncommon in younger women as well. This puts forward the question whether advanced age per se is the underlying cause for the increased risk for adverse outcomes in older pregnant women, or whether there might be other factors that account for it but do not radically worsen the prospects for favourable outcomes. The individual risks associated with childbirth late in life may stem from maternal genetic background rather than being a simple function of age. There is plenty of preliminary evidence that individual capacity for identification and repair of DNA damage may constitute a major factor in female fertility and fecundity. Subtle deficiencies in the repair capacity may have little to no importance in younger pregnant women but may make a significant difference in older women. The outcomes of pregnancies in women >35 are largely dependent on the prepregnancy health status and the quality of antenatal care, and may not be dramatically different from outcomes in younger women.

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Polymorphism ofMDM2promoter 309 (rs 2279744) and the risk of PCOS

Cited by 5 publications

References 19 publications

Mdm2‐p53‐SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality

Mdm2‐p53‐SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality

Association of TP53 rs1042522 G > C, MDM2 rs2279744 T > G, and miR-34b/c rs4938723 T > C polymorphisms with aneuploidy pregnancy susceptibility

Reproductive outcomes in pregnant women aged 35 or older: the role of individual repair capacity

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