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mTOR gene variant rs2295080 might be a risk factor for atherosclerosis in Iranian women with type 2 diabetes mellitus

BMC Endocrine Disorders volume 24, Article number: 162 (2024) Cite this article

Abstract

Background

Type 2 diabetes mellitus, one of the most prevalent metabolic disorders worldwide, is closely linked with an enhanced risk of atherosclerosis. However, the molecular mechanism of this linkage is not still clear. Genetic variations in the mTOR gene may increase the susceptibility of individuals to these diseases.

Methods

One hundred nine diabetic patients and 375 healthy subjects participated in this study. mTOR Single Nucleotide Polymorphism (SNP) rs2295080 was determined using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP).

Results

Comparison of genotypic, allelic, and genotypic combination frequencies between cases and controls revealed no significant result. Nevertheless, the frequency of rs2295080 GT + TT genotype was significantly more in diabetic women with atherosclerosis compared with those without atherosclerosis (p = 0.047). Besides, the rs2295080 G allele was more frequently detected in diabetic women without atherosclerosis compared to those with atherosclerosis (p = 0.046).

Conclusion

The rs2295080 GT + TT genotype predisposes Iranian diabetic women to atherosclerosis, while the rs2295080 G allele protects them against atherosclerosis. However, additional experiments using larger sample sizes are needed to verify this result.

Peer Review reports

Background

Type 2 Diabetes Mellitus (T2DM) is a challenging public health burden and may result in macro- and microvascular complications [1]. Atherosclerosis, as the major macrovascular complication of T2DM, is the leading cause of morbidity and mortality, especially in low- and middle-income countries [2,3,4]. The exact molecular mechanisms of these chronic diseases are not yet well understood [2, 5, 6]. The PI3K/AKT/mTOR signaling pathway is required for the normal metabolism of the cells. This pathway has been studied in a variety of human diseases such as cancer [7, 8], diabetes [9], atherosclerosis [10], cardiovascular disease [11] and obesity [12]. Mammalian Target of Rapamycin (mTOR) is an intracellular molecule that acts as a hub within this pathway [13]. mTOR senses the cellular and environmental cues, such as growth factors, nutrients, and energy then regulates the phosphorylation of intracellular proteins which are crucial for cellular metabolism, survival, homeostasis, growth, and differentiation [14, 15]. Although mTOR pathway critically is implicated in the progression of several metabolic and inflammatory disorders including aging, tumorigenesis, and diabetes, its exact molecular mechanisms are still controversial [2, 6, 16, 17]. Dysfunction of the mTOR might play an important role in the development of T2DM and atherosclerosis [18, 19]. Impairment of mTOR can lead to insulin resistance and obesity which in turn exacerbates and creates a vicious cycle in disease development [20]. Numerous research have used Single Nucleotide Polymorphisms (SNPs) to assess their possible effects on susceptibility to various diseases [21,22,23]. Indeed, these single-base pair substitutions are the most common type of genetic variation among individuals that may influence the binding of transcription factors, the splicing, conformation, and stability of mRNA, and the expression of genes and thereby may affect disease susceptibility [24]. The 156 kb mTOR gene is located on chromosome 1p36.2 and contains 60 exons [25]. Numerous studies have investigated the role of rs2295080, a functional polymorphism in the mTOR promoter region, in the development and progression of several diseases [26, 27]. This SNP might affect mTOR gene expression, as well as, protein function and stability [28]. In this study the possible association between rs2295080 and susceptibility to T2DM and atherosclerosis was evaluated in an Iranian population.

Methods

Subjects

The study recruited 109 diabetic patients from Fars province, Iran, including 57 males and 52 females with a mean age of 58. 9 ± 24.2 years. Patients were selected from hospitals affiliated with Shiraz University of Medical Sciences. The criteria for the diagnosis of T2DM were: HbA1C ≥ 6.5% according to the National Glycohemoglobin Standardization, fasting plasma glucose ≥ 126 mg/dl (7.0 mmol/l), 2-hour plasma glucose ≥ 200 mg/dl (11.1 mmol/l) during an oral glucose tolerance test, and in patients with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose of ≥ 200 mg/dl (11.1 mmol/l) [29]. The diagnostic criteria for clinical atherosclerosis were established based on the degree of stenosis observed in the main coronary arteries during diagnostic angiography by a cardiologist. Specifically, stenosis equal to 50 or more in at least one of the main coronary arteries was considered positive while lower than 50 was negative for atherosclerosis [30, 31]. A control group of 375 healthy volunteers from the Fars Blood Transfusion Center with a mean age of 47.32 ± 9.75 years including 213 males and 162 females was recruited for this study. The control group was age and sex-matched with the case group and had neither diabetes nor atherosclerosis confirmed through clinical examinations and self-reported forms.

The study was done in keeping with the Declaration of Helsinki (https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/) and was evaluated and approved by the Ethics Committee of Shiraz University of Medical Sciences Shiraz, Iran (the code of ethical approval was IR.SUMS.REC.1401.382). All participants provided informed consent for blood donation and data publication. Detailed information about the patients, including their age, body mass index (BMI), hypertension status, and smoking status was collected (Table 1).

Table 1 Demographic and clinical findings of participants
Full size table

DNA extraction and genotyping analysis

A total of 4 ml of whole blood sample was collected from each participant into EDTA tubes. Genomic DNA was extracted using the salting out method, and all DNA samples were stored at -20 °C until testing. The mTOR rs2295080 was genotyped using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Table 2 shows details of the used primers and the required restriction enzyme. The amplification process involved an initial denaturation at 95 °C for 5 min, followed by 30 cycles of denaturation at 95 °C for 30 s, annealing at 56 °C for 30 s, and extension at 72 °C for 30 s, with a final extension step at 72 °C for 5 min. The PCR products were then digested with the BseGI restriction enzyme. Finally, the PCR products were analyzed using a 2.5% agarose gel stained with DNA safe stain and visualized under ultraviolet light (Fig. 1).

Table 2 The primer sequence, restriction enzymes, and fragment length of the mTORgene SNP rs2295080
Full size table
Fig. 1
figure 1

PCR-RFLP image of the mTOR gene polymorphism rs2295080 shows TT (lanes 1 and 2), GT (lanes 3 and 4), and GG (lanes 5 and 6) genotypes

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Statistical analysis

The Statistical Package for Social Sciences (SPSS) software (version 26) and EPI INFO 7.2.2.6 software were used to conduct statistical analyses. The OSSE online tool available at http://osse.bii.a-star.edu.sg/calculation1.php was used to estimate the sample size. Deviation from Hardy-Weinberg equilibrium was analyzed using the website https://wpcalc.com/en/equilibrium-hardy-weinberg. To remove the confounding effects of variables, binary logistic regression analysis was performed. All tests were two-sided with a significant level of P-value < 0.05.

Results

Genotype and allele frequencies of rs2295080 in diabetic patients and healthy controls

The studied SNP followed the Hardy-Weinberg Equilibrium (patient group: p = 0.090, control group: p = 0.068). As shown in Table 3, the most frequent genotype and allele in diabetic patients and healthy controls were TT and T, respectively. However, comparing genotypes and allele frequency between cases and controls did not show a statistically significant difference.

Table 3 Genotype and allele frequencies of rs2295080 polymorphism in type 2 diabetic patients and healthy controls
Full size table

Comparison of rs2295080 between diabetic patients with and without atherosclerosis

According to the angiographic data, diabetic patients were divided into those with atherosclerosis and those without. As shown in Table 4, comparing genotypes and alleles of rs2295080 revealed a significantly higher frequency of the GT + TT genotype among diabetic women with atherosclerosis compared to those without atherosclerosis (p = 0.047). Moreover, G allele frequency was significantly more in diabetic women without atherosclerosis (p = 0.046).

Table 4 The association between rs2295080 and atherosclerotic complication of type 2 diabetes
Full size table

The association between rs2295080 and clinical characteristics of diabetes

Evaluation of the genotypes and alleles of rs2295080 with body mass index (BMI), smoking, and blood pressure status of diabetic patients revealed no significant differences (data not shown).

Discussion

In this study, the possible association between mTOR gene polymorphism rs2295080 and susceptibility to type 2 diabetes and its major complication, atherosclerosis was evaluated. The PI3K/AKT/mTOR signaling pathway plays a vital role in glucose homeostasis and regulates the response of cells to extracellular stimuli such as insulin [32]. In this manner, it regulates the translocation of glucose transporter type 4 to the cell surface, the uptake of glucose, the synthesis of glycogen, the suppression of glucose production, triglyceride synthesis, and insulin-induced mitogenesis [33]. If any of these functions are impaired, hyperglycemia and diabetes can occur [34]. On the other hand, T2DM can trigger the development of atherosclerosis or further accelerate its progression [1]. Elevated blood glucose levels, dyslipidemia, and other metabolic changes associated with disease development are involved in the pathogenesis of atherosclerosis at almost every stage of the atherogenic process [5]. More evidence has indicated that the mTOR signaling pathway is activated by atherosclerotic ox-LDL via PI3K/Akt which is required for vascular smooth muscle cell proliferation [35]. Genetic variations in this signaling pathway might influence the development of T2DM and atherosclerosis. These variants may alter the expression of mTOR, thereby deregulating the signaling pathway involved in disease initiation. A recent study by Hu Li et al. evaluated the possible association between some polymorphisms in the mTOR gene, including rs2295080 (G > T), rs2536 (T > C), rs1034528 (G > C), and rs11121704 (C > T) with atherosclerosis and the risk of coronary heart disease (CHD) and its prognosis among a Chinese population [36]. They proved that rs2295080 TT genotype and T allele; rs2536 CC + CT and CC genotypes, and C allele; rs1034528 CC + GC genotypes, and C allele are associated with significantly increased risk of CHD onset. Furthermore, they demonstrated that rs2295080 TT, TT + GT genotypes, and T allele were associated with poor atherosclerosis and CHD prognosis. Similar results were seen for the rs2536 CC + CT genotype and the C allele. However, they found no significant association between rs11121704 and atherosclerosis and the risk of CHD. Few studies have investigated the effect of mTOR polymorphisms on the risk of T2DM. A study reported that the intron variant rs4845856 is not associated with the development of T2DM [33]. As far as we know, our study is the first to evaluate the possible role of mTOR rs2295080 in the pathogenesis of atherosclerosis among diabetic patients. In line with the study by Hu Li et al. mentioned above, our results revealed a significantly higher frequency of the rs2295080 GT + TT genotype in diabetic women with atherosclerosis compared with those without atherosclerosis. Interestingly, a higher frequency of the rs2295080 G allele was also indicated among diabetic women without atherosclerosis. These findings indicate the GT + TT genotype increases the susceptibility of Iranian diabetic women to atherosclerosis while the G allele is a protective factor against it. In support, another study has shown that the rs2295080 G allele decreases the susceptibility of Han Chinese females to Microscopic Polyangiitis (MPA) [37]. Several other studies have demonstrated the importance of this polymorphism in different disease states. The significance of rs2295080 has been shown in various malignancies, such as urinary tract cancer [38, 39], colorectal adenocarcinoma [40], leukemia [41], gastric cancer [42], breast cancer [43], prostate and liver malignancies. These studies have found that the TT genotype and the T allele increase the risk of cancer, while the GG genotype and the G allele are protective. Functional assays for the mTOR gene have revealed that the rs2295080 G allele significantly decreases its transcriptional activity [38] while the T allele increases its expression and at the same time, affects the binding of other transcription factors that dysregulate its expression [40, 42]. On the contrary, a study in Finland showed that the TT genotype and the T allele of rs2295080 reduce the risk of age-related macular degeneration (AMD) [44]. In addition, a German study on liver transplant recipients suggested that the rs2295080 GG genotype is associated with the development of new-onset diabetes mellitus following Everolimus treatment [45]. Such discrepancy might be due to the different ethnicity, the synergic/suppressing effects of other genes inside the mTOR signaling pathway, epigenetics, and exposure to different environmental factors. Understanding the relationship between gene variants and susceptibility to diseases and their complications can pave the way for a better understanding of the mechanism of disease initiation and progression, and might contribute in the development of new therapeutic modalities. Targeting mTOR is now an effective therapeutic approach in many diseases, including Alzheimer’s, RA, and cancer therapy [46,47,48,49]. mTOR polymorphisms might resist some therapeutic procedures and be a possible explanation for why some mTOR inhibitory drugs are not beneficial [45, 50]. For instance, new-onset diabetes mellitus was reported following the mTOR inhibitor Everolimus administration in some liver transplant recipients who had rs2295080 CC genotype [45]. So, the existence of mTOR variants requires further analyses and consideration when making treatment choices. It seems desirable to design studies investigating the effect of genetic variation on the quality of resistance to mTOR inhibitors. Accordingly, Prospective randomized clinical trials that include mTOR genotype testing would be promising. Our study had some limitations such as the limited sample size, not considering other functional mTOR SNPs, and thereby not evaluating the effect of linkage between adjacent SNPs, and not confirming PCR-RFLP results with sequencing.

Conclusion

Our study suggested that the GT + TT genotype increases the susceptibility of Iranian diabetic females to atherosclerosis while the G allele could be a protective factor against it. However, more research with a larger sample size is needed to confirm these results. Moreover, functional and linkage analyses would elucidate the precise role of rs2295080 in the pathogenesis of T2DM and atherosclerosis.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Data Availability

Data is provided within the manuscript or supplementary information files

Abbreviations

T2DM:

Type 2 Diabetes Mellitus

mTOR:

mammalian Target of Rapamycin

SNP:

Single Nucleotide Polymorphism

BMI:

body mass index

PCR-RFLP:

Polymerase Chain Reaction-Restriction Fragment Length Polymorphism

SPSS:

Statistical Package for Social Sciences

ORs:

Odds ratios

CIs:

Confidence intervals

MPA:

Microscopic Polyangiitis

AMD:

Age-related Macular Degeneration

References

  1. Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The effects of type 2 diabetes mellitus on organ metabolism and the immune system. Front Immunol. 2020;11:e1582.

  2. Ye J, Li L, Wang M, Ma Q, Tian Y, Zhang Q, et al. Diabetes mellitus promotes the development of atherosclerosis: the role of NLRP3. Front Immunol. 2022;13:e900254.

  3. Maric-Bilkan C. Sex differences in micro-and macro-vascular complications of diabetes mellitus. Clin Sci. 2017;131(9):833–46.

    Article  CAS  Google Scholar 

  4. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 study. J Am Coll Cardiol. 2020;76(25):2982–3021.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Poznyak A, Grechko AV, Poggio P, Myasoedova VA, Alfieri V, Orekhov AN. The diabetes mellitus–atherosclerosis connection: the role of lipid and glucose metabolism and chronic inflammation. Int J Mol Sci. 2020;21(5):e1835.

  6. Tapia-Vieyra JV, Delgado-Coello B, Mas-Oliva J. Atherosclerosis and cancer; a resemblance with far-reaching implications. Arch Med Res. 2017;48(1):12–26.

    Article  CAS  PubMed  Google Scholar 

  7. Peng Y, Wang Y, Zhou C, Mei W, Zeng C. PI3K/Akt/mTOR pathway and its role in cancer therapeutics: are we making headway? Front Oncol. 2022;12:e819128.

  8. Mafi S, Mansoori B, Taeb S, Sadeghi H, Abbasi R, Cho WC, et al. mTOR-mediated regulation of immune responses in cancer and tumor microenvironment. Front Immunol. 2022;12:e774103.

  9. Camaya I, Donnelly S, O’Brien B. Targeting the PI3K/Akt signaling pathway in pancreatic β-cells to enhance their survival and function: an emerging therapeutic strategy for type 1 diabetes. J Diabetes. 2022;14(4):247–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ji W, Sun J, Hu Z, Sun B. Resveratrol protects against atherosclerosis by downregulating the PI3K/AKT/mTOR signaling pathway in atherosclerosis model mice. Experimental Therapeutic Med. 2022;23(6):1–9.

    Article  CAS  Google Scholar 

  11. Walkowski B, Kleibert M, Majka M, Wojciechowska M. Insight into the role of the PI3K/Akt pathway in ischemic injury and post-infarct left ventricular remodeling in normal and diabetic heart. Cells. 2022;11(9):e1553.

  12. Savova MS, Mihaylova LV, Tews D, Wabitsch M, Georgiev MI. Targeting PI3K/AKT signaling pathway in obesity. Biomed Pharmacother. 2023;159:e114244.

  13. Oh WJ, Jacinto E. mTOR complex 2 signaling and functions. Cell Cycle. 2011;10(14):2305–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhong Chong Z. mTOR: a novel therapeutic target for diseases of multiple systems. Curr Drug Targets. 2015;16(10):1107–32.

    Article  Google Scholar 

  15. Ben-Sahra I, Manning BD. mTORC1 signaling and the metabolic control of cell growth. Curr Opin Cell Biol. 2017;45:72–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Qi G-H, Wang C-H, Zhang H-G, Yu J-G, Ding F, Song Z-C, et al. Comprehensive analysis of the effect of rs2295080 and rs2536 polymorphisms within the mTOR gene on cancer risk. Biosci Rep. 2020;40(7):BSR20191825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell. 2010;40(2):310–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xu J, Ji J, Yan X-H. Cross-talk between AMPK and mTOR in regulating energy balance. Crit Rev Food Sci Nutr. 2012;52(5):373–81.

    Article  CAS  PubMed  Google Scholar 

  19. Maya-Monteiro C, Bozza P. Leptin and mTOR: partners in metabolism and inflammation. Cell Cycle. 2008;7(12):1713–7.

    Article  CAS  PubMed  Google Scholar 

  20. Daryabor G, Kabelitz D, Kalantar K. An update on immune dysregulation in obesity-related insulin resistance. Scand J Immunol. 2019;89(4):e12747.

    Article  PubMed  Google Scholar 

  21. Tadayon Z, Shahzadeh Fazeli SA, Gholijani N, Daryabor G. Toll-like receptor 9 (TLR9) genetic variants rs187084 and rs352140 confer protection from Behcet’s disease among iranians. BMC Rheumatol. 2024;8(1):e13.

  22. Kahmini FR, Gholijani N, Amirghofran Z, Daryabor G. Single nucleotide polymorphisms rs7799039 and rs2167270 in leptin gene and elevated serum levels of adiponectin predispose iranians to Behçet’s disease. Cytokine. 2023;162:e156100.

  23. Daryabor G, Mahmoudi M, Jamshidi A, Nourijelyani K, Amirzargar A, Ahmadzadeh N, et al. Determination of IL-23 receptor gene polymorphism in Iranian patients with ankylosing spondylitis. Eur Cytokine Netw. 2014;25(1):24–9.

    Article  PubMed  Google Scholar 

  24. Schork NJ, Fallin D, Lanchbury JS. Single nucleotide polymorphisms and the future of genetic epidemiology. Clin Genet. 2000;58(4):250–64.

    Article  CAS  PubMed  Google Scholar 

  25. Wang K, Xiao J, Jiang L, Guo J, Zhang Y, Jiang H, et al. The associations of single nucleotide polymorphism rs2295080 in mTOR with cancer risk: an updated meta-analysis. Int J Clin Exp Med. 2019;12(7):8004–13.

    CAS  Google Scholar 

  26. Saravani M, Shahraki-Ghadimi H, Maruei-Milan R, Mehrabani M, Mirzamohammadi S, Nematollahi MH. Effects of the mTOR and AKT genes polymorphisms on systemic lupus erythematosus risk. Mol Biol Rep. 2020;47:3551–6.

    Article  CAS  PubMed  Google Scholar 

  27. Zhu A, Yang X, Sun M, Zhang Z, Li M. Associations between INSR and MTOR polymorphisms in type 2 diabetes mellitus and diabetic nephropathy in a Northeast Chinese Han population. Genet Mol Res. 2015;14(1):1808–18.

    Article  CAS  PubMed  Google Scholar 

  28. Yasmin T. In silico comprehensive analysis of coding and non-coding SNPs in human mTOR protein. PLoS One. 2022;17(7):e0270919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Committee ADAPP, Committee. ADAPP. 2. Classification and diagnosis of diabetes: standards of Medical Care in Diabetes—2022. Diabetes Care. 2022;45(Supplement1):S17–38.

    Google Scholar 

  30. Ye H, Zhao Q, Huang Y, Wang L, Liu H, Wang C, et al. Meta-analysis of low density lipoprotein receptor (LDLR) rs2228671 polymorphism and coronary heart disease. Biomed Res Int. 2014;2014:e564940.

  31. Monjezi MR, Fouladseresht H, Farjadian S, Gharesi-Fard B, Khosropanah S, Doroudchi M. T cell proliferative responses and IgG antibodies to β2GPI in patients with diabetes and atherosclerosis. Endocr Metab Immune Disord Drug Targets. 2021;21(3):495–503.

  32. Ramasubbu K, Devi Rajeswari V. Impairment of insulin signaling pathway PI3K/Akt/mTOR and insulin resistance induced AGEs on diabetes mellitus and neurodegenerative diseases: a perspective review. Mol Cell Biochem. 2023;478(6):1307–24.

    Article  CAS  PubMed  Google Scholar 

  33. Yin X, Xu Z, Zhang Z, Li L, Pan Q, Zheng F, et al. Association of PI3K/AKT/mTOR pathway genetic variants with type 2 diabetes mellitus in Chinese. Diabetes Res Clin Pract. 2017;128:127–35.

    Article  CAS  PubMed  Google Scholar 

  34. Khan KH, Wong M, Rihawi K, Bodla S, Morganstein D, Banerji U, et al. Hyperglycemia and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) inhibitors in phase I trials: incidence, predictive factors, and management. Oncologist. 2016;21(7):855–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yao X, Yan C, Zhang L, Li Y, Wan Q. LncRNA ENST00113 promotes proliferation, survival, and migration by activating PI3K/Akt/mTOR signaling pathway in atherosclerosis. Medicine. 2018;97(16):e0473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li H, Liu Y, Huang J, Liu Y, Zhu Y. Association of genetic variants in lncRNA GAS5/miR-21/mTOR axis with risk and prognosis of coronary artery disease among a Chinese population. J Clin Lab Anal. 2020;34(10):e23430.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lan J, Zhu Y, Rao J, Liu L, Gong A, Feng F, et al. MTOR gene polymorphism may be associated with microscopic polyangiitis susceptibility in a Guangxi population of China. Gene. 2023;854:e147101.

  38. Cao Q, Ju X, Li P, Meng X, Shao P, Cai H, et al. A functional variant in the MTOR promoter modulates its expression and is associated with renal cell cancer risk. PLoS One. 2012;7(11):e50302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Min Z, Mi Y, Lv Z, Sun Y, Tang B, Wu H, et al. Associations of genetic polymorphisms of mTOR rs2295080 T/G and rs1883965 G/a with susceptibility of urinary system cancers. Dis Markers. 2022;2022:1–16.

    Google Scholar 

  40. Xu M, Gao Y, Yu T, Wang J, Cheng L, Cheng L, et al. Functional promoter rs2295080 T > G variant in MTOR gene is associated with risk of colorectal cancer in a Chinese population. Biomed Pharmacother. 2015;70:28–32.

    Article  CAS  PubMed  Google Scholar 

  41. Huang L, Huang J, Wu P, Li Q, Rong L, Xue Y, et al. Association of genetic variations in mTOR with risk of childhood acute lymphoblastic leukemia in a Chinese population. Leuk Lymphoma. 2012;53(5):947–51.

    Article  CAS  PubMed  Google Scholar 

  42. Xu M, Tao G, Kang M, Gao Y, Zhu H, Gong W, et al. A polymorphism (rs2295080) in mTOR promoter region and its association with gastric cancer in a Chinese population. PLoS One. 2013;8(3):e60080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhao Y, Diao Y, Wang X, Lin S, Wang M, Kang H, et al. Impacts of the mTOR gene polymorphisms rs2536 and rs2295080 on breast cancer risk in the Chinese population. Oncotarget. 2016;7(36):e58174.

  44. Paterno JJ, Koskela A, Hyttinen JM, Vattulainen E, Synowiec E, Tuuminen R, et al. Autophagy genes for wet age-related macular degeneration in a Finnish case-control study. Genes. 2020;11(11):e1318.

  45. Husen P, Straub K, Willuweit K, Hagemann A, Wedemeyer H, Bachmann HS, et al. editors. SNPs within the MTOR gene are associated with an increased risk of developing de novo diabetes mellitus following the administration of everolimus in liver transplant recipients. Transplant Proc. 2019;51(6):1962–71.

  46. Wang C, Yu J-T, Miao D, Wu Z-C, Tan M-S, Tan L. Targeting the mTOR signaling network for Alzheimer’s disease therapy. Mol Neurobiol. 2014;49:120–35.

    Article  CAS  PubMed  Google Scholar 

  47. Zhang F, Cheng T, Zhang S-X. Mechanistic target of rapamycin (mTOR): a potential new therapeutic target for rheumatoid arthritis. Arthritis Res Therapy. 2023;25(1):e187.

  48. Magaway C, Kim E, Jacinto E. Targeting mTOR and metabolism in cancer: lessons and innovations. Cells. 2019;8(12):e1584.

  49. Hua H, Kong Q, Zhang H, Wang J, Luo T, Jiang Y. Targeting mTOR for cancer therapy. J Hematol Oncol. 2019;12:1–19.

    Article  CAS  Google Scholar 

  50. Birdwell KA, Decker B, Barbarino JM, Peterson JF, Stein CM, Sadee W, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clin Pharmacol Ther. 2015;98(1):19–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors express their gratitude to Mr. Mohammad-Reza Malekmakan for his assistance in conducting the experiments.

Funding

Shiraz University of Medical Sciences, Iran provided the financial support for this study (Grant Numbers: 25611).

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Authors and Affiliations

  1. Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Afsaneh Zare & Mehrnoosh Doroudchi

  2. Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Shahdad khosropanah

  3. Department of Cardiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Shahdad khosropanah

  4. Autoimmune Diseases Research Center, School of Medicine, Shiraz University of Medical Sciences, PO Box: 71345-1583, Shiraz, Iran

    Gholamreza Daryabor

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  1. Afsaneh Zare
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Contributions

AZ performed the experiments and analysis and prepared a preliminary manuscript draft. SK helped in designing the study. GD and MD conceived and designed the study, wrote the paper, and critically revised the manuscript.

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Correspondence to Gholamreza Daryabor or Mehrnoosh Doroudchi.

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Our study was approved by the Ethics Committee of the Shiraz University of Medical Science (SUMS) and was conducted following the ethical principles outlined in the Declaration of Helsinki (https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/). Before participation, all the individuals provided written informed consent.

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Zare, A., khosropanah, S., Daryabor, G. et al. mTOR gene variant rs2295080 might be a risk factor for atherosclerosis in Iranian women with type 2 diabetes mellitus. BMC Endocr Disord 24, 162 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12902-024-01703-4

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BMC Endocrine Disorders

ISSN: 1472-6823

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