Dataset Information

Significant association of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) rs3846662 and sirtuin 1 (SIRT1) rs7895833 and apolipoprotein E (APOE) hypermethylation with mild cognitive impairment (MCI).

ABSTRACT: Our study investigated the association of five genes with MCI in the Xinjiang Uygur population in China. In addition, we also analyzed the association between APOE methylation and MCI.Forty-three MCI and 125 controls were included in the present study. Genotyping was done by Sanger sequencing. DNA methylation assay was done using quantitative methylation-specific polymerase chain reaction (qMSP).The distribution of HMGCR rs3846662 allele frequencies was significantly different between the MCI group and the control group (P?=?.04), especially in women (P?=?.032). Subgroup analysis showed that there was a statistically significant association of HMGCR rs3846662 with MCI in the non-APOE ?4 group (P?=?.024), especially in the females with non-APOE ?4. Similarly, HMGCR rs3846662 genotype and allele frequency in the ApoE E2 protein group were significantly different in the MCI group and the control group (genotype P?=?.021; allele P?=?.007). In addition, SIRT1 rs7895833 genotype frequency in the APOE ?4 group was found to be significantly different between the MCI and the control group (P?=?.005). We also observed a significant association of SIRT1 rs7895833 with MCI in the ApoE E4 protein subgroup (P?=?.005). In addition, APOE methylation levels were significantly different between the MCI group and the control group (P?=?.021), especially in men (P?=?.006). Subgroup analysis showed that APOE methylation levels were significantly associated with MCI in the non-APOE ?4 group (P?=?.009), especially in men (P?=?.015).This study found a significant association of HMGCR rs3846662 with MCI in females independent of APOE ?4. In contrast, we revealed that the association of SIRT1 rs7895833 with MCI was dependent on with APOE ?4. We also showed that hypermethylation of APOE in MCI was independent of APOE ?4.

SUBMITTER: Zou T

PROVIDER: S-EPMC6641831 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Significant association of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) rs3846662 and sirtuin 1 (SIRT1) rs7895833 and apolipoprotein E (APOE) hypermethylation with mild cognitive impairment (MCI).

Zou Ting T Duan Yali Y Zhou Xiaohui X Chen Wei W Ying Xiuru X Liu Guili G Zhao Yongjie Y Zhu Meisheng M Pari Abuliz A Alimu Kader K Miao Haijun H Kabinur Keyim K Zhang Lei L Wang Qinwen Q Duan Shiwei S

Medicine 20190701 28

Our study investigated the association of five genes with MCI in the Xinjiang Uygur population in China. In addition, we also analyzed the association between APOE methylation and MCI.Forty-three MCI and 125 controls were included in the present study. Genotyping was done by Sanger sequencing. DNA methylation assay was done using quantitative methylation-specific polymerase chain reaction (qMSP).The distribution of HMGCR rs3846662 allele frequencies was significantly different between the MCI gr ...[more]

PMID: 31305452

Similar Datasets

Project description:The mevalonate pathway has emerged as a promising target for several solid tumors. Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of this pathway, and are commonly used to treat patients with hypercholesterolemia. Pleiotropic antitumor mechanisms of statins have been demonstrated for several human cancer types. However, cancer cells differ in their individual statin sensitivity and some cell lines have shown relative resistance. In this study we demonstrate, that the human breast cancer cell lines MDA-MB-231, MDA-MB-468, MCF-7, and T47D are differentially affected by statins. Whereas the vitality of MDA-MB-231 and MDA-MB-468 cells was reduced by up to 60% using atorvastatin, simvastatin, or rosuvastatin (p < 0.001), only marginal effects were seen in T47D and MCF-7 cells following exposure to statins. Statin treatment led to an upregulation of HMGCR mRNA and protein expression by up to sixfolds in the statin-resistant cells lines (p < 0.001), but no alterations of HMGCR were observed in the statin-sensitive MDA-MB-231 and MDA-MB-468 cells. The knockdown of HMGCR prior to statin treatment sensitized the resistant cell lines, reflected by a 70% reduction in vitality, increased apoptotic DNA fragmentation (sixfold) and by accumulation of the apoptosis marker cleaved poly-ADP ribose polymerase. Statins induced a cleavage of the sterol-regulatory element-binding protein (SREBP)-2, a transcriptional activator of the HMGCR, in T47D and MCF-7 cells. The inhibition of SREBP-2 activation by co-administration of dipyridamole sensitized MCF-7 and T47D cells for statins (loss of vitality by 80%; p < 0.001). Furthermore, assessment of a statin-resistant MDA-MB-231 clone, generated by long-term sublethal statin exposure, revealed a significant induction of HMGCR expression by up to 12-folds (p < 0.001). Knockdown of HMGCR restored statin sensitivity back to levels of the parental cells. In conclusion, these results indicate a resistance of cancer cells against statins, which is in part due to the induction of HMGCR.

Dataset Information

Significant association of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) rs3846662 and sirtuin 1 (SIRT1) rs7895833 and apolipoprotein E (APOE) hypermethylation with mild cognitive impairment (MCI).

Publications

Significant association of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) rs3846662 and sirtuin 1 (SIRT1) rs7895833 and apolipoprotein E (APOE) hypermethylation with mild cognitive impairment (MCI).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets