P21 Gene Variation and Late-Onset Alzheimer’s Disease in the Italian Population

Scacchi, R.; Gambina, Giuseppe; Moretto, Giuseppe; Corbo, Rosa Maria

doi:10.1159/000345788

Cited by 8 publications

(6 citation statements)

References 58 publications

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“…Inconsistent with our observations, the case and control groups were not significantly different [17]. The association between P21 polymorphisms and susceptibility to uterine leiomyoma [14], late-onset Alzheimer’s disease [37], and cancer [38] has been investigated in the literature; however, the effects of P21 polymorphisms on diseases are controversial. In addition, we found that level of relative placental mRNA expression in TP53 gene was 5.6 times higher in the PE group ( P < 0.0001), however, TP53 mRNA expression showed no significant difference between rs1042522 genotypes.…”

Section: Discussionsupporting

confidence: 74%

Analysis of polymorphisms, promoter methylation, and mRNA expression profile of maternal and placental P53 and P21 genes in preeclamptic and normotensive pregnant women

et al. 2019

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BackgroundPreeclampsia (PE), as a multisystem disorder, is associated with maternal hypertension and proteinuria. Apoptosis seems to be involved in the pathophysiology of PE, although its precise pathogenic mechanisms are not well established. In this study, we aimed to identify the association between maternal TP53-rs1042522, P21-rs1801270, and P21-rs1059234 polymorphisms and PE. In addition, we examined the effects of promoter methylation and TP53 and P21 polymorphisms on placental mRNA expression in PE women.MethodsThe blood of 226 PE women and 228 normotensive pregnant women was examined in this study. In addition, the placentas were genotyped in 109 PE and 112 control women. The methylation status was assessed by a methylation-specific PCR assay, while mRNA expression was examined via Quantitative Real Time PCR.ResultsThe maternal and placental P21-rs1801270 CA genotype had a significant association with the reduced risk of PE. In the dominant, recessive, and allelic models, maternal/placental P21-rs1059234 polymorphism had no statistically significant association with the risk of PE. On the other hand, the reduced risk of PE was associated with maternal, but not placental TP53-rs1042522 polymorphism in the dominant and recessive models. The maternal and placental P21-rs1801270 polymorphism was associated with PE risk. The maternal P21 Trs1059234Crs1801270 haplotype was associated with 3.4-fold increase in PE risk, However the maternal P21 Trs1059234Ars 1801270 haplotype and placental Crs1059234CA rs1801270 haplotype led to 0.5 and 0.4-fold decrease in PE risk, respectively. PE women showed 5.6 times higher levels of placental mRNA expression of TP53 gene, although it was not associated with rs1042522 polymorphism. The relative placental mRNA expression of P21 gene was 0.2 in PE women. It was also 2.4 times higher in individuals with rs1801270CA genotype than those with AA genotype. The hyper-methylation of P21 and TP53 genes in the promoter region was associated with a 3.4-fold and 3-fold increase in PE risk, respectively. However, no association was found between P21 and TP53 mRNA expression and promoter methylation.ConclusionIn conclusion, P21-rs1801270 and TP53-rs1042522 polymorphisms were involved in reduced risk of PE. P21-rs1801270 was associated with decreased P21 mRNA expression. The hyper-methylation of P21 and TP53 genes in the promoter region was associated with a higher PE risk.

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Section: Discussionsupporting

confidence: 74%

Analysis of polymorphisms, promoter methylation, and mRNA expression profile of maternal and placental P53 and P21 genes in preeclamptic and normotensive pregnant women

et al. 2019

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“…In previous studies on this AD patient sample, nine other genes (CHAT, CYP17, CYP19, ESR1, FSHR, P53, P73, P21, PPARG) were found associated with susceptibility to developing AD [Corbo et al, , , , ; Scacchi et al, , , , ]. No difference in the distribution of risk genotypes for any these genes was observed between the FH+ and the FH− AD patients [CHAT rs2177369, P = 0.95; CYP17 rs743572, P = 0.80; CYP19 rs4646, P = 0.57; ESR1 rs2234693, P = 0.17; FSHRrs6165/rs6166, P = 0.77; P53 rs1042522, P = 0.60; P73rs 3765728, P = 0.92; P21rs1059234, P = 0.71; PPARGrs1801282, P = 0.74).…”

Section: Resultsmentioning

confidence: 66%

“…In the present investigation, we asked whether FH (degree of relationship and number of relatives) increases the risk of AD development and influences disease severity (age at onset and cognitive impairment) and, in particular, among first degree relatives, we analyzed the differences between having affected parents or siblings. In addition, we investigated whether FH is a risk factor for developing AD independent of carrying the APOE e4 risk allele, or the risk genotypes of nine other AD susceptibility genes [ESR1 (estrogen receptor 1), PPARG (peroxisome proliferator‐activated receptor‐gamma), CYP19 (aromatase), CHAT (choline acetyltransferase), TP53 (tumor protein P53), TP73 (tumor protein P73), FSHR (follicle‐stimulating hormone receptor), P21 (cyclin‐dependent kinase inhibitor 1a), CYP17 (cytochrome P450c17α)] previously investigated in this AD patient sample and turned out to be involved in AD occurrence [Corbo et al, , , , ; Scacchi et al, , , , ]. The role of some relationship measures (number of affected relatives) in the AD susceptibility has been scarcely studied before, as well as the difference among first‐degree relatives (parents and siblings).…”

Section: Introductionmentioning

confidence: 99%

Influence of family history of dementia in the development and progression of late‐onset Alzheimer's disease

Scarabino

Gambina

Broggio

et al. 2015

American J of Med Genetics Pt B

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Family history of dementia (FH) is a recognized risk factor for developing late-onset Alzheimer's disease (AD). We asked whether having FH increases AD risk and influences disease severity (age at onset and cognitive impairment) in 420 AD patients and 109 controls with (FH+) or without (FH-). The relationships of APOE and other AD risk genes with FH were analyzed as well. The proportion of APOE e4 allele carriers was higher among the FH+ than the FH- AD patients (49.6% vs. 38.9%; P = 0.04). The distribution of the risk genotypes of nine AD susceptibility genes previously examined (CHAT, CYP17, CYP19, ESR1, FSHR, P53, P73, P21, PPARG) did not differ between the FH+ and the FH- AD patients, indicating that none contributed significantly to familial clustering of disease. FH was associated with an increased AD risk (odds ratio [OR] 2.71, 95% confidence interval [CI] 1.44-5.09; P = 0.002) independent of carrying the APOE e4 allele (OR 2.61, 95%CI 1.53-4.44; P = 0.0004). Having a first-degree relative or a parent with dementia was significantly associated with AD risk (OR 2.9, 95%CI 1.3-6.4; P = 0.009 and OR 2.7, 95%CI 1.1-6.2; P = 0.02) but having a sibling with dementia was not (OR 1.7, 95%CI 0.2 to 14.7; P = 0.6). Among the FH+ AD patients, having one or both parents affected seemed to raise the risk of earlier onset age (P = 0.02) and greater cognitive impairment (P = 0.02) than having only an affected sibling, whereas having two or more affected relatives did not.

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“…Recently, energy sensing pathways have been investigated in the context of both diabetic complications and cancer [ 116 – 118 ]. In addition, reentry of differentiated cells into the cell cycle as well as genetic polymorphism in the p21 gene has been implicated in Alzheimer's disease [ 119 , 120 ]. Our findings may prompt further research in these fields.…”

Section: Discussionmentioning

confidence: 99%

p21^WAF1/CIP1Expression is Differentially Regulated by Metformin and Rapamycin

Molnár

Millward

Tse

et al. 2014

International Journal of Chronic Diseases

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The mammalian target of rapamycin (mTOR) pathway plays an important role in the development of diabetic nephropathy and other age-related diseases. One of the features of DN is the elevated expression of p21WAF1/CIP1. However, the importance of the mTOR signalling pathway in p21 regulation is poorly understood. Here we investigated the effect of metformin and rapamycin on mTOR-related phenotypes in cell lines of epithelial origin. This study reports that metformin inhibits high glucose-induced p21 expression. High glucose opposed metformin in regulating cell size, proliferation, and protein synthesis. These effects were associated with reduced AMPK activation, affecting downstream mTOR signalling. However, the inhibition of the mTOR pathway by rapamycin did not have a negative effect on p21 expression, suggesting that metformin regulates p21 upstream of mTOR. These findings provide support for the hypothesis that AMPK activation may regulate p21 expression, which may have implications for diabetic nephropathy and other age-related pathologies.

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P21 Gene Variation and Late-Onset Alzheimer’s Disease in the Italian Population

Cited by 8 publications

References 58 publications

Analysis of polymorphisms, promoter methylation, and mRNA expression profile of maternal and placental P53 and P21 genes in preeclamptic and normotensive pregnant women

Analysis of polymorphisms, promoter methylation, and mRNA expression profile of maternal and placental P53 and P21 genes in preeclamptic and normotensive pregnant women

Influence of family history of dementia in the development and progression of late‐onset Alzheimer's disease

p21^WAF1/CIP1Expression is Differentially Regulated by Metformin and Rapamycin

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P21 Gene Variation and Late-Onset Alzheimer’s Disease in the Italian Population

Cited by 8 publications

References 58 publications

Analysis of polymorphisms, promoter methylation, and mRNA expression profile of maternal and placental P53 and P21 genes in preeclamptic and normotensive pregnant women

Analysis of polymorphisms, promoter methylation, and mRNA expression profile of maternal and placental P53 and P21 genes in preeclamptic and normotensive pregnant women

Influence of family history of dementia in the development and progression of late‐onset Alzheimer's disease

p21WAF1/CIP1Expression is Differentially Regulated by Metformin and Rapamycin

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p21^WAF1/CIP1Expression is Differentially Regulated by Metformin and Rapamycin