Association of Estrogen Receptor 1 PvuII and XbaI Polymorphisms and Peripheral Estrogen Receptor 1 mRNA Levels with Alzheimer’s Disease in Turkish Patients
Gamze Güven1
, Pınar Köseoğlu Büyükkaya1, Melisa Kılıç1, Damla Uzun1, Betül Cavuş1, Filiz Güçlü Geyik1, Ebba Lohmann2, Bedia Samancı3, Hakan Gürvit3, Hasmet Hanağası3, Başar Bilgiç3
1Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Genetics, Istanbul, Türkiye
2University of Tübingen, Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, Tübingen, Germany;German Center for Neurodegenerative Diseases, Tübingen, Germany
3Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioural Neurology and Movement Disorders Unit, Istanbul, Türkiye
Keywords: Alzheimer hastalığı, östrojen reseptörü 1, PvuII, XbaI, gen polimorfizmi, mRNA ekspresyonu
Abstract
Objective: Estrogen receptor 1 (ESR1) polymorphisms are associated with Alzheimer’s disease (AD) and polymorphisms in the first intronic region of the gene are known to affect ESR1 mRNA transcription. The first intronic region of the ESR1 contains two polymorphisms that have received the most attention: PvuII rs2234693 (NM 000125.3: c.453-397T>C) and XbaI rs9340799 (NM 000125.3: c.453-351A>G). Both polymorphisms have been shown to be associated with AD, but consistent findings across populations have not been established. This study aimed to determine whether ESR1 PvuII and XbaI polymorphisms are associated with the disease in a cohort of Turkish AD patients. Whether PvuII and XbaI polymorphisms affect disease susceptibility by influencing ESR1 mRNA expression was also examined.
Materials and Methods: Genotyping was performed in 424 patients with AD (mean age: 64.5 ± 11.1 yrs) and 302 controls (mean age: 56.4 ± 13.0 yrs). The polymerase chain reaction (PCR) and restriction enzyme digestion methods were used to determine the prevalence of the ESR1 PvuII and XbaI polymorphisms. The ESR1 mRNA expression was analyzed in the peripheral blood cells of 85 patients and 53 age-matched controls using quantitative real-time PCR.
Results: No significant difference in genotype and allele frequencies of ESR1 PvuII and XbaI polymorphisms between the patients and controls was found. However, the frequencies of the PvuII C and XbaI G alleles were significantly higher in the patients with the apolipoprotein-E (APOE) ε4 allele. The ESR1 mRNA levels were significantly lower in the patients with AD compared with the controls (P = 0.001). The XbaI A allele was significantly associated with lower ESR1 mRNA levels (P = 0.044) and this association remained significant even after adjusting for confounders such as age, gender and APOE ε4 carrier status (P = 0.035).
Conclusion: This study demonstrated that the distribution of PvuII and XbaI alleles is associated with the APOE ε4 allele. The XbaI polymorphism may be associated with a higher risk of AD by altering ESR1 mRNA levels.
The study was approved by the Ethics Committee of the Istanbul University, Istanbul Faculty of Medicine, while the procedures used adhered to the tenets of the Declaration of Helsinki (date: 10/09/21/no: 16).
Informed consent was obtained from the participants or from legal guardians for those unable to consent.
Externally and internally peer-reviewed.
Surgical and Medical Practices: E.L., B.S., H.G., H.H., B.B., Concept: G.G., E.L., B.S., H.G., H.H., B.B., Design: G.G., F.G., Data Collection or Processing: G.G., P.K-B., M.K., D.U., B.Ç., F.G-G., Analysis or Interpretation: G.G., P.K-B., M.K., D.U., B.Ç., E.L., B.S., H.G., H.H., B.B., Literature Search: G.G., P.K-B., Writing: G.G.
No conflict of interest was declared by the authors.
This work was supported by the Research Fund of Istanbul University (Project no: TLO-2021- 38074).
The authors would like to thank all the patients and their families.