Genetic Variants Influence the Development of Diabetic Neuropathy
Abstract
:1. Introduction
2. Pathways Relevant to the Pathomechanism of Neuropathy
3. Genetic Variants Potentially Playing a Role in the Development of Diabetic Neuropathy
3.1. Angiotensin-Converting Enzyme (ACE)
3.2. Metylenetetrahydrofolate Reductase (MTHFR)
3.3. Glutathione S-Tansferase (GST)
3.4. Methylglyoxal
3.5. Glioxalase (GLO)
3.6. Apoliporotein E (APOE)
3.7. Vascular Endothelial Growth Factor (VEGF)
3.8. Interleukin-4 (IL-4)
3.9. Endothelial Nitric Oxide Synthase (eNOS)
3.10. Adrenoceptor Alpha 2B (ADRA2B)
3.11. MicroRNA (MIR146A, MIR128A, MIR499A)
3.12. Thiamine Transporters (THTR1/THTR2)
3.13. Transketolase (TKT)
3.14. Ion Channels
3.15. Glia Cell Line-Derived Neurotrophic Factor Family Receptor Alpha-2 (GFRA2)
3.16. Aldose Reductase (ALR)
3.17. Glutathione Peroxidase 1 (GPx-1)
3.18. Results of the First Whole-Exome Sequencing Study
3.19. Others
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gene | Variant Type | Role | Publication |
---|---|---|---|
Angiotensin-converting enzyme (ACE) | homozygous DD genotype of the I/D polymorphism | Determines ACE activity and serum levels of ACE | [15] |
MTHFR gene | C677T polymorphism | Elevates homocysteine levels | [16] |
GSTM1 and GSTT1 genes | homozygous deletion (null genotype) | Reduces enzyme activity (GST protects against endogenous oxidative stress and exogenous potential toxins) and leads to cytogenetic damage | [17] |
GLO1 gene | CC genotype | Glo-11 reduces the formation of advanced glycemic end-products (AGEs) | [18] |
APOE gene | Ɛ4 allele | Plays a role in the cholesterol and triglyceride metabolism | [19] |
TCF7L2 gene | rs7903146, rs7901695, rs12255372 | Affects the lipid metabolism and glucose homeostasis | [20] |
VEGF gene | C and T alleles | Determines the level of VEGF, which facilitates the proliferation of vascular endothelial cells | [21] |
IL-4 gene | VNTR | IL-4 is a cytokine that impacts immune cell chemotaxis and anti-inflammation | [22] |
GPX1 | rs1050450, C > T | Reduced antioxidant activity | [55] |
eNOS gene | rs2070744 (786 T/C) rs1799983 (894 G/T) | Leads to endothelial dysfunction through the change in the synthesis of nitric oxide | [23] |
ADRA2B gene | I/D polymorphism | Associated with autonomic dysfunction and increased sympathetic nervous system activity | [24] |
MIR146A, MIR128A MIR499A | rs2910164 (G > C) rs11888095 (C > T) rs3746444 (GG genotype) | Associated with the level of mitochondrial DNA | [25] |
SLC19A2, SLC19A3 encoding THTR1 and THTR2 | Intracellular transport of thiamine | [26] | |
Transketolase gene | rs7648309 rs63355988 | Loss of protective action in the prevention of diabetic neuropathy | [27] |
Glo1 gene | rs1130534 rs1049346 | Loss of defense against AGE formation | [28] |
Voltage-dependent Na channel beta-2 subunit of Nav1.7 | aspartic acid–aspartic acid mutation (D109N) | Hyperexcitability of posterior ganglion neurons | [29] |
ANO3 gene | mis-sense heterozygous variants | Increased pain sensitivity | [30] |
HCN1 gene | mis-sense heterozygous variant | Increased pain sensitivity | [30] |
TRPA1 | loss-of-function mutation | Increased pain sensitivity | [30] |
TRPV1 and TRPV4 genes | Painless diabetic neuropathy | [30] | |
SCN9A, SCN10A, and SCN11A | gain-of- function mutations | Neuron hyperexcitability | [31] |
Polymorphisms in the GFRA2 gene | rs4872521 rs4872522 rs10098807 rs11774105 rs17428041 rs17615364 rs11776842 rs12545534 rs11780601 | Role in the differentiation and survival of neurons | [56] |
ALR2 gene | 106C/T polymorphism in the promoter region | Role in nerve conduction velocities | [32] |
ALR2 gene | 50-(CA)n microsatellite polymorphism (Z + 2, Z − 2) | Susceptibility or defense against diabetic neuropathy | [57] |
GPx-1 | (rs1050450) 599C/T | Susceptibility to diabetic neuropathy | [33] |
CAT | 262C/T | Susceptibility to diabetic neuropathy | [33] |
Chromosomal loci 1p35.1 and 8p21.3. | Neuropathic pain | [58] | |
Gene polymorphisms of ACE, MTHFR, APOE, ALR2, GPx-1, NOS3, CAT, and VEGF | Susceptibility to diabetic neuropathy | [59] | |
GLP-1, PTEN, insulin, RAGE, HSP27, CW22, and DUSP1 in the phosphatidylinositol 3-kinase/phosphorylated protein kinase B [PI3/pAkt] signaling pathway | Possible therapeutic targets | [34] | |
RMI2 gene MYBPHL gene MVB12B gene RXRA gene | rs2032930, rs2032931 rs604349 rs917778 rs2234753 | Alters the risk of developing diabetic neuropathy | [35] |
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Hajdú, N.; Rácz, R.; Tordai, D.Z.; Békeffy, M.; Vági, O.E.; Istenes, I.; Körei, A.E.; Kempler, P.; Putz, Z. Genetic Variants Influence the Development of Diabetic Neuropathy. Int. J. Mol. Sci. 2024, 25, 6429. https://doi.org/10.3390/ijms25126429
Hajdú N, Rácz R, Tordai DZ, Békeffy M, Vági OE, Istenes I, Körei AE, Kempler P, Putz Z. Genetic Variants Influence the Development of Diabetic Neuropathy. International Journal of Molecular Sciences. 2024; 25(12):6429. https://doi.org/10.3390/ijms25126429
Chicago/Turabian StyleHajdú, Noémi, Ramóna Rácz, Dóra Zsuzsanna Tordai, Magdolna Békeffy, Orsolya Erzsébet Vági, Ildikó Istenes, Anna Erzsébet Körei, Peter Kempler, and Zsuzsanna Putz. 2024. "Genetic Variants Influence the Development of Diabetic Neuropathy" International Journal of Molecular Sciences 25, no. 12: 6429. https://doi.org/10.3390/ijms25126429