Abstract
Genetic factors are known to play a significant role in the susceptibility of diabetic patients to severe complications such as diabetic nephropathy (DN). This study aimed to evaluate the association between polymorphism of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) variants (rs997509, K121Q, rs1799774, and rs7754561) and DN in patients with type 2 diabetes mellitus (T2DM). A total number of 492 patients with T2DM with and without DN were categorized into case and control groups. The extracted DNA samples were genotyped using TaqMan allelic discrimination assay amplified by polymerase chain reaction (PCR). The haplotype analysis among the case and control groups was performed using an expectation-maximization algorithm by the maximum-likelihood method. The analysis of laboratory findings demonstrated significant differences in fasting blood sugar (FBS) and hemoglobin A1c (HbA1c) between the case and control groups (P < 0.05). The results showed that K121Q was significantly related to DN under a recessive model of inheritance (P = 0.006); however, rs1799774 and rs7754561 both were protective for DN under a dominant model of inheritance (P = 0.034 and P = 0.010, respectively) among four studied variants. Two haplotypes, including C-C-delT-G with a frequency < 0.02 and T-A-delT-G with a frequency < 0.01, were associated with the increased risk of DN (P < 0.05). The present study demonstrated that K121Q was associated with the susceptibility of DN; however, rs1799774 and rs7754561 were protecrtive variants for DN in patients with T2DM.
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Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Alicic RZ, Rooney MT, Tuttle KR (2017) Diabetic kidney disease: Challenges, Progress, and possibilities. Clin J Am Soc Nephrol 12:2032–2045. https://doi.org/10.2215/CJN.11491116
Andrésdóttir G, Jensen ML, Carstensen B et al (2015) Improved prognosis of diabetic nephropathy in type 1 diabetes. Kidney Int 87:417–426. https://doi.org/10.1038/ki.2014.206
Bhatti GK, Kaur S, Vijayvergiya R et al (2018) ENPP1 K121Q functional variant enhances susceptibility to insulin resistance and dyslipidemia with metabolic syndrome in asian Indians. Dubai Diabetes Endocrinol J 24:8–15. https://doi.org/10.1159/000492478
Caramori ML, Kim Y, Huang C et al (2002) Cellular basis of diabetic nephropathy: 1. Study design and renal structural-functional relationships in patients with long-standing type 1 diabetes. Diabetes 51:506–513. https://doi.org/10.2337/diabetes.51.2.506
Cave EM, Prigge KL, Crowther NJ et al (2020) A polymorphism in the gene encoding the insulin receptor binding protein ENPP-1 is Associated with decreased glomerular filtration rate in an under-investigated indigenous African Population. Kidney Blood Press Res 45:1009–1017. https://doi.org/10.1159/000511213
Chandra S, Singh AK, Singh M et al (2021) Human ENPP1 gene polymorphism in DKD patients: a hospital-based case control study. Int J Diabetes Dev Ctries 41:63–70. https://doi.org/10.1007/s13410-020-00841-4
Cimpean A, Stefan C, Gijsbers R et al (2017) Correction: substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2. Biochem J 474:4273–4274
Committee IE (2009) International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 32:1327–1334
Eller P, Hochegger K, Feuchtner GM et al (2008) Impact of ENPP1 genotype on arterial calcification in patients with end-stage renal failure. Nephrol Dial Transplant 23:321–327
Evans K, Pyart R, Steenkamp R et al (2018) UK Renal Registry 20th Annual Report: introduction. Nephron 139(Suppl):1–12
Frittitta L, Ercolino T, Bozzali M et al (2001) A cluster of three single nucleotide polymorphisms in the 3’-Untranslated region of human glycoprotein PC-1 gene stabilizes PC-1 mRNA and is Associated with increased PC-1 protein content and insulin resistance-related abnormalities. Diabetes 50:1952–1955. https://doi.org/10.2337/diabetes.50.8.1952
García-Alegría AM, Anduro-Corona I, Pérez-Martínez CJ et al (2020) Quantification of DNA through the NanoDrop Spectrophotometer: Methodological Validation Using Standard Reference Material and Sprague Dawley Rat and Human DNA. Int J Anal Chem 2020:8896738. https://doi.org/10.1155/2020/8896738
Gohari-Lasaki S, Sharafshah A, Abbaspour S, Keshavarz P (2020) Single locus and haplotype association of ENPP1 gene variants with the development of retinopathy among type 2 diabetic patients. Int Ophthalmol 40:639–647. https://doi.org/10.1007/s10792-019-01224-3
Huang GM, Huang KY, Lee TY, Weng JTY (2015) An interpretable rule-based diagnostic classification of diabetic nephropathy among type 2 diabetes patients. BMC Bioinformatics 16:1–10. https://doi.org/10.1186/1471-2105-16-S1-S5
Keene KL, Mychaleckyj JC, Smith SG et al (2008) Association of the Distal Region of the Ectonucleotide. Diabetes 57:1057–1062. https://doi.org/10.2337/db07-0886.AIM
Keshavarz P, Habibipour R, Ghasemi M et al (2014) Lack of genetic susceptibility of KCNJ11 E23K polymorphism with risk of type 2 diabetes in an iranian population. Endocr Res 39:120–125. https://doi.org/10.3109/07435800.2013.860607
Lee PY, Costumbrado J, Hsu C-Y, Kim YH (2012) Agarose gel electrophoresis for the separation of DNA fragments. J Vis Exp 3923. https://doi.org/10.3791/3923
Lind M, Pivodic A, Svensson AM et al (2019) HbA 1c level as a risk factor for retinopathy and nephropathy in children and adults with type 1 diabetes: swedish population based cohort stuady. BMJ 366. https://doi.org/10.1136/bmj.l4894
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215. https://doi.org/10.1093/nar/16.3.1215
Murea M, Ma L, Freedman BI (2012) Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications. Rev Diabet Stud 9:6–22. https://doi.org/10.1900/RDS.2012.9.6
Nazir N, Siddiqui K, Al-Qasim S, Al-Naqeb D (2014) Meta-analysis of diabetic nephropathy associated genetic variants in inflammation and angiogenesis involved in different biochemical pathways. BMC Med Genet 15:1–14. https://doi.org/10.1186/s12881-014-0103-8
Neamati N, Hosseini SR, Hajiahmadi M et al (2017) The ENPP1 K121Q polymorphism modulates developing of bone disorders in type 2 diabetes: a cross sectional study. Gene 637:100–107. https://doi.org/10.1016/j.gene.2017.09.042
Omar GA, Khalid MM, Ghanem AI (2022) Ectonucleotide pyrophosphatase/phosphodiesterase 1 (K121Q rs1044498) polymorphism is associated with diabetic nephropathy but not obesity among type-2 diabetes mellitus egyptian patients. J Med Sci Res 5:72
Pelle MC, Provenzano M, Busutti M et al (2022) Up-Date on diabetic nephropathy. Life 12:1202
Priščáková P, Minárik G, Repiská V (2016) Candidate gene studies of diabetic retinopathy in human. Mol Biol Rep 43:1327–1345. https://doi.org/10.1007/s11033-016-4075-y
Rabieenia E, Jalali R, Mohammadi M (2020) Prevalence of nephropathy in patients with type 2 diabetes in Iran: a systematic review and meta-analysis based on geographic information system (GIS). Diabetes Metab Syndr 14:1543–1550. https://doi.org/10.1016/j.dsx.2020.08.007
Razi F, Khashayar P, Ghodssi-Ghassemabadi R et al (2018) Optimal HbA1c cut-off point for diagnosis of type 2 diabetes in iranian adults. Can J Diabetes 42. https://doi.org/10.1016/j.jcjd.2018.03.005
Santoro N, Cirillo G, Lepore MG et al (2009) Effect of the rs997509 polymorphism on the association between ectonucleotide pyrophosphatase phosphodiesterase 1 and metabolic syndrome and impaired glucose tolerance in childhood obesity. J Clin Endocrinol Metab 94:300–305. https://doi.org/10.1210/jc.2008-1659
Sawaf H, Thomas G, Taliercio JJ et al (2022) Therapeutic advances in diabetic nephropathy. J Clin Med 11:378
Selby NM, Taal MW (2020) An updated overview of diabetic nephropathy: diagnosis, prognosis, treatment goals and latest guidelines. Diabetes Obes Metab 22:3–15. https://doi.org/10.1111/dom.14007
Sheng X, Qiu C, Liu H et al (2020) Systematic integrated analysis of genetic and epigenetic variation in diabetic kidney disease. Proc Natl Acad Sci U S A 117:29013–29024. https://doi.org/10.1073/pnas.2005905117
Sortica DA, Crispim D, Zaffari GP et al (2011) The role of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 in diabetic nephropathy. Arq Bras Endocrinol Metabol 55:677–685. https://doi.org/10.1590/s0004-27302011000900002
Stevens PE, Levin A (2013) Evaluation and management of chronic kidney disease: Synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med 158:825–830. https://doi.org/10.7326/0003-4819-158-11-201306040-00007
Tanyolaç S, Bremer AA, Hodoglugil U et al (2009) Genetic variants of the ENPP1/PC-1 gene are associated with hypertriglyceridemia in male subjects. Metab Syndr Relat Disord 7:543–548. https://doi.org/10.1089/met.2009.0027
Thomas MC, Cooper ME, Zimmet P (2016) Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat Rev Nephrol 12:73–81. https://doi.org/10.1038/nrneph.2015.173
Tomino Y, Gohda T (2015) The Prevalence and Management of Diabetic Nephropathy in Asia. Kidney Dis 1:52–60. https://doi.org/10.1159/000381757
Tziastoudi M, Stefanidis I, Zintzaras E (2020) The genetic map of diabetic nephropathy: evidence from a systematic review and meta-analysis of genetic association studies. Clin Kidney J 13:768–781. https://doi.org/10.1093/ckj/sfaa077
Whiting DR, Guariguata L, Weil C, Shaw J (2011) IDF Diabetes Atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 94:311–321. https://doi.org/10.1016/j.diabres.2011.10.029
Wu X, Di F, Shen S et al (2022) Levels of serum ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) predicts severity of abdominal aortic calcification in end-stage renal disease patients receiving regular dialysis. Hemodial Int 26:23–29. https://doi.org/10.1111/hdi.12969
Zhang X-X, Kong J, Yun K (2020) Prevalence of diabetic nephropathy among patients with type 2 diabetes mellitus in China: a meta-analysis of observational studies. J Diabetes Res 2020:Web assotest.
Acknowledgements
We thankfully express our thanks to all those blood donors of the survey subjects for their contribution to the DNA samples.
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[Parvaneh Keshavarz] and [Niloofar Faraji] contributed to the study design, Material preparation, and performing molecular technics. Data collection and statistical analysis were performed by [Saima Abbaspour], and [Farzam Ajamian]. The whole draft was written by [Niloofar Faraji] and [Parvaneh Keshavarz] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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All procedures performed in studies involving human participants were in accordance with the ethical code of human genome/gene research at the Guilan University of Medical Science [IR.GUMS.REC.1394.341].
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Faraji, N., Abbaspour, S., Ajamian, F. et al. Role of ENPP1 Gene Variants in the Susceptibility to Diabetic Nephropathy in Patients with type 2 Diabetes Mellitus. Biochem Genet 61, 2710–2723 (2023). https://doi.org/10.1007/s10528-023-10402-z
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DOI: https://doi.org/10.1007/s10528-023-10402-z