Vascular Endothelial Growth Factor 936 C/T Gene Polymorphism in Indonesian Subjects with Diabetic Polyneuropathy
DOI:
https://doi.org/10.3889/oamjms.2018.399Keywords:
VEGF 936 C/T polymorphism, VEGF-A level, Diabetic polyneuropathyAbstract
AIM: This study aimed to confirm the role of f VEGF gene 936 C/T polymorphism and Diabetic Polyneuropathy (DPN) in the Indonesian population as well as to investigate its relationship with VEGF-A level and the role of vascular risk factors.
MATERIAL AND METHODS: This was a cross-sectional study involving 152 subjects. Clinical symptoms and signs of DPN were examined using DNE and DNS scoring followed by nerve conduction study. All subjects underwent anthropometric, clinical examination and laboratory procedures to obtain body mass index, HbA1C level, lipid profile, Polymorphism of +936 C/T VEGF gene (PCR-RFLP technique), and VEGF-A plasma level (ELISA). Statistical analysis using a t-test or Mann-Whitney was performed to assess continuous data and Chi-square for categorical data. Multivariate logistic regressions were also performed to determine the relationship between independent variables and DPN.
RESULTS: Sixty-nine (45.4%) fulfilled the diagnostic criteria of DPN. There was a significant association between CT + TT genotype and DPN (OR 0.35 95%CI 0.16-0.79 p = 0.01). Multivariate logistic regression showed that plasma VEGF-A level (OR = 1.003; 95% CI = 1.000-1.007; p = 0.03), diabetes duration (OR = 1.108; 95% CI = 1.045-1.175; p = 0.001), and CT+TT genotype (OR = 0.347; 95%CI = 0.148-0.817; p = 0.013) were associated with DPN. Sub-group analysis on subjects with HbA1C level ≥7% showed that VEGF-A (OR = 1.011; 95%CI = (1.004-1.017; p = 0.03), diabetes duration (OR = 1.245; 95% CI = 1.117-1.388; p < 0.001), CT + TT genotype (OR = 0.259; 95%CI = 0.074-0.911p = 0.035), with an adition of HDL (OR = 0.916; 95% CI = 0.857-0.978; p = 0.009) were significant predictors of DPN while LDL (OR = 1.017; 95% CI = 1.000-1.035; p = 0.053) acted as modifying factor.
CONCLUSION: It appeared that CT + TT genotype of VEGF +936 gene might act as a protecting factor for DPN while VEGF-A, diabetes duration, HDL, and LDL acted as risk factors especially on subjects with HbA1C level ≥ 7.
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Sugimoto K, Murakawa Y, Sima AAF. Diabetic neuropathy–a continuing enigma. Diabetes/metabolism research and reviews. 2000; 16(6):408–433. https://doi.org/10.1002/1520-7560(200011/12)16:6<408::AID-DMRR158>3.0.CO;2-R
Bhutani J, Bhutani S. Worldwide burden of diabetes. Indian journal of endocrinology and metabolism. 2014; 18(6):868. https://doi.org/10.4103/2230-8210.141388 PMid:25364686 PMCid:PMC4192997
Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacology & Therapeutics. 2008; 120(1):1–34. https://doi.org/10.1016/j.pharmthera.2008.05.005 PMid:18616962 PMCid:PMC4007052
Soewondo P, Soegondo S, Suastika K, Pranoto A, Soeatmadji DW, Tjokroprawiro A. The DiabCare Asia 2008 study–Outcomes on control and complications of type 2 diabetic patients in Indonesia. Medical Journal of Indonesia. 2010; 19(4):235–44. https://doi.org/10.13181/mji.v19i4.412
Deguchi T, Hashiguchi T, Horinouchi S, Uto T, Oku H, Kimura K, et al. Serum VEGF increases in diabetic polyneuropathy, particularly in the neurologically active symptomatic stage. Diabetic Medicine. 2009; 26(3):247–252. https://doi.org/10.1111/j.1464-5491.2009.02680.x PMid:19317819
Zhang X, Sun Z, Jiang H, Song X. Relationship between single nucleotide polymorphisms in the 3'-untranslated region of the vascular endothelial growth factor gene and susceptibility to diabetic peripheral neuropathy in China. Archives of medical science. 2014; 10(5):1028–1034. https://doi.org/10.5114/aoms.2013.39381 PMid:25395956 PMCid:PMC4223128
Kim HW, Ko GJ, Kang YS, Lee MH, Song HK, Kim HK, et al. Role of the VEGF 936 C/T polymorphism in diabetic microvascular complications in type 2 diabetic patients. Nephrology. 2009; 14(7):681–688. https://doi.org/10.1111/j.1440-1797.2009.01085.x PMid:19796028
Yang C-P, Lin C-C, Li C-I, Liu C-S, Lin W-Y, Hwang K-L, et al. Cardiovascular risk factors increase the risks of diabetic peripheral neuropathy in patients with type 2 diabetes mellitus: the Taiwan Diabetes Study. Medicine. 2015; 94(42). https://doi.org/10.1097/MD.0000000000001783
Meijer JW, van Sonderen E, Blaauwwiekel EE, Smit AJ, Groothoff JW, Eisma WH, et al. Diabetic neuropathy examination: a hierarchical scoring system to diagnose distal polyneuropathy in diabetes. Diabetes Care. 2000; 23(6):750–753. https://doi.org/10.2337/diacare.23.6.750 PMid:10840990
Meijer J-WG, Bosma E, Lefrandt JD, Links TP, Smit AJ, Stewart RE, et al. Clinical diagnosis of diabetic polyneuropathy with the diabetic neuropathy symptom and diabetic neuropathy examination scores. Diabetes care. 2003; 26(3):697–701. https://doi.org/10.2337/diacare.26.3.697
Dyck PJ, Albers JW, Andersen H, Arezzo JC, Biessels G-J, Bril V, et al. Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. Diabetes/metabolism research and reviews. 2011; 27(7):620–628. https://doi.org/10.1002/dmrr.1226 PMid:21695763
Krippl P, Langsenlehner U, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, et al. A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk. International journal of cancer. 2003; 106(4):468–471. https://doi.org/10.1002/ijc.11238 PMid:12845639
rs3025039 (SNP) - Population genetics - Homo sapiens - Ensembl genome browser 92 [Internet]. [cited 2018 Jul 10]. Available from: http://asia.ensembl.org/Homo_sapiens/Variation/Population?db=core;r=6:43784299-43785299;v=rs3025039;vdb=variation;vf=2313204
Tavakkoly-Bazzaz J, Amoli MM, Pravica V, Chandrasecaran R, Boulton AJ, Larijani B, et al. VEGF gene polymorphism association with diabetic neuropathy. Molecular biology reports. 2010; 37(7):3625–3630. https://doi.org/10.1007/s11033-010-0013-6 PMid:20352346
Cao C, Ding Q, Lv D, Dong Z, Sun S, Chen Z, et al. Vascular endothelial growth factor genotypes and haplotypes contribute to the susceptibility of obstructive sleep apnea syndrome. PloS one. 2014; 9(12):e114582. https://doi.org/10.1371/journal.pone.0114582 PMid:25541696 PMCid:PMC4277275
Elias I, Franckhauser S, Bosch F. New insights into adipose tissue VEGF-A actions in the control of obesity and insulin resistance. Adipocyte. 2013; 2(2):109–112. https://doi.org/10.4161/adip.22880 PMid:23805408 PMCid:PMC3661112
Zacchigna S, Lambrechts D, Carmeliet P. Neurovascular signalling defects in neurodegeneration. Nature Reviews Neuroscience. 2008; 9(3):169. https://doi.org/10.1038/nrn2336 PMid:18253131
Grisold A, Callaghan BC, Feldman EL. Mediators of diabetic neuropathy-is hyperglycemia the only culprit? Current opinion in endocrinology, diabetes, and obesity. 2017; 24(2):103. https://doi.org/10.1097/MED.0000000000000320 PMid:28098594 PMCid:PMC5831542
Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nature Reviews Neurology. 2011; 7(10):573. https://doi.org/10.1038/nrneurol.2011.137 PMid:21912405
Perez-Matos MC, Morales-Alvarez MC, Mendivil CO. Lipids: a suitable therapeutic target in diabetic neuropathy? Journal of diabetes research. 2017; 2017.
Cho YN, Lee KO, Jeong J, Park HJ, Kim S-M, Shin HY, et al. The role of insulin resistance in diabetic neuropathy in Koreans with type 2 diabetes mellitus: a 6-year follow-up study. Yonsei medical journal. 2014; 55(3):700–708. https://doi.org/10.3349/ymj.2014.55.3.700 PMid:24719137 PMCid:PMC3990070
Ghisleni MM, Biolchi V, Jordon BC, Rempel C, Genro JP, Pozzobon A. Association study of C936T polymorphism of the VEGF gene and the C242T polymorphism of the p22phox gene with diabetes mellitus type 2 and distal diabetic polyneuropathy. Molecular medicine reports. 2015; 12(3):4626–4633. https://doi.org/10.3892/mmr.2015.3988 PMid:26130419
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Copyright (c) 2018 Jimmy Barus, Ismail Setyopranoto, Ahmad Hamim Sadewa, Samekto Wibowo
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