Gene associated with diabetic foot ulcer severity and surgical outcomes

NewsBot · Sep 5, 2009

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Heat-shock protein 70 gene polymorphism is associated with the severity of diabetic foot ulcer and the outcome of surgical treatment.
Mir KA, Pugazhendhi S, Paul MJ, Nair A, Ramakrishna BS.
Br J Surg. 2009 Sep 3. [Epub ahead of print]

BACKGROUND:: Foot ulcer is a significant cause of morbidity in diabetics. Genetic make-up can determine inflammatory and healing responses. This study examined the hypothesis that specific polymorphisms of the heat-shock protein 70 gene could predispose to the severity of diabetic foot ulceration.

METHODS:: Some 106 consecutive diabetic patients (101 evaluable) with foot ulceration admitted to a tertiary care hospital were managed according to a standard protocol. DNA was extracted from venous blood and examined by polymerase chain reaction-restriction fragment length analysis for two specific polymorphisms: G1538A in the HSPA1B and C2437T in the HSPA1L gene.

RESULTS:: HSPA1B genotyping showed that 70 patients were AG and 30 GG (one not amplified). The AG genotype was significantly associated with the severity of foot ulceration (Wagner grade) (P = 0.008, chi(2) test), need for amputation (relative risk 2.02, 95 per cent confidence interval 1.02 to 4.01; P = 0.025) and median length of hospital stay (8 versus 5 days for GG; P = 0.043). HSPA1L genotypes (78 TT, 22 CT, one CC) did not show any significant association with these parameters.

CONCLUSION:: The HSPA1B genotype, was associated with the severity of diabetic foot ulceration, need for amputation and duration of hospitalization in these patient
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NewsBot · May 21, 2011

VEGF gene polymorphism association with diabetic foot ulcer.
Amoli MM, Hasani-Ranjbar S, Roohipour N, Sayahpour FA, Amiri P, Zahedi P, Mehrab-Mohseni M, Heshmat R, Larijani B, Tavakkoly-Bazzaz J.
Diabetes Res Clin Pract. 2011 May 17. [Epub ahead of print]

OBJECTIVE:
Functional polymorphisms within vascular endothelial growth factor (VEGF) gene have shown association with various conditions including diabetic neuropathy and retinopathy. In this study we have performed a candidate gene association study in order to examine VEGF gene polymorphism association with diabetic foot ulcer (DFU).

METHODS:
The study group comprised of type 2 diabetes patients with (N=247) and without (N=241) DFU. Healthy control subjects (N=98) were also recruited from the same area. The ARMS-PCR technique was applied for genotyping of VEGF gene SNPs at positions -7*C/T and -2578*C/A.

RESULTS:
The frequency of genotype AA was significantly decreased in patients with DFU compared with diabetic subjects without DFU (AA vs CA+CC, p=0.003, OR=0.44, CI=0.24-0.80). Also there was a significant decrease in frequency of A allele in patients with DFU compared to the controls (p=0.02, OR=0.68, CI=0.48-0.96).

CONCLUSION:
It seems that lower frequency of A allele in patients with DFU is conferring a protective effect which might be as a result of increased angiogenesis in patients carrying this allele.
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NewsBot · Aug 13, 2013

Association of Toll-Like Receptor 4 Polymorphisms with Diabetic Foot Ulcers and Application of Artificial Neural Network in DFU Risk Assessment in Type 2 Diabetes Patients.
Singh K, Singh VK, Agrawal NK, Gupta SK, Singh K.
Biomed Res Int. 2013;2013:318686

The Toll-Like receptor 4 (TLR4) plays an important role in immunity, tissue repair, and regeneration. The objective of the present work was to evaluate the association of TLR4 single nucleotide polymorphisms (SNPs) rs4986790, rs4986791, rs11536858 (merged into rs10759931), rs1927911, and rs1927914 with increased diabetic foot ulcer (DFU) risk in patients with type 2 diabetes mellitus (T2DM). PCR-RFLP was used for genotyping TLR4 SNPs in 125 T2DM patients with DFU and 130 controls. The haplotypes and linkage disequilibrium between the SNPs were determined using Haploview software. Multivariate linear regression (MLR) and artificial neural network (ANN) modeling was done to observe their predictability for the risk of DFU in T2DM patients. Risk genotypes of all SNPs except rs1927914 were significantly associated with DFU. Haplotype ACATC (P value = 9.3E - 5) showed strong association with DFU risk. Two haplotypes ATATC (P value = 0.0119) and ATGTT (P value = 0.0087) were found to be protective against DFU. In conclusion TLR4 SNPs and their haplotypes may increase the risk of impairment of wound healing in T2DM patients. ANN model (83%) is found to be better than the MLR model (76%) and can be used as a tool for the DFU risk assessment in T2DM patients.
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NewsBot · Apr 4, 2015

Genetic association of IL-6, TNF-α and SDF-1 polymorphisms with serum cytokine levels in diabetic foot ulcer
Umapathy Dhamodharan, Vijay Viswanathan, Ezhilarasi Krishnamoorthy, Rama Rajaram, Vivekanandhan Aravindhan
Gene; 31 March 2015

Highlights
•IL-6 − 174 C allele confers protection against DFU.
•SDF-1 801 A allele confers protection against DFU.
•TNF-α − 308 A allele (but not − 238 SNP) confers genetic susceptibility to DFU.
•IL-6 − 174 and TNF-α − 308 (but not SDF-1 801) control their respective serum cytokine levels.
•These SNPs also influence FPG, PPG, HbA1c, HDL, VLDL, TGL, urea, creatinine, adiponectin and leptin levels.
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The IL-6 − 174G/C (rs1800795), TNF-α − 308G/A (rs1800629) and − 238 G/A (rs361525) and SDF-1 801 G/A (rs1801157) are well characterized SNPs which have previously been linked to various diabetic complications. However, the involvement of these SNPs in DFU remains poorly studied. In the present study we looked at the association of these SNPs with DFU (disease phenotype) and correlated it with the serum levels of cytokines (intermediate phenotype) along with other clinical risk factors of DFU (adiponectin, leptin and hsCRP). Genotyping was carried out in Normal glucose tolerance ((NGT) / Control = 106), T2DM without DFU (T2DM = 139), T2DM with neuropathy (DFU–DN = 191) and T2DM with PVD (DFU–PVD = 79) subjects by PCR–RFLP and the serum cytokine levels were determined by ELISA. IL-6 − 176 “C” allele conferred significant protection against T2DM but not against DFU. TNF-α − 308 “A” allele (but not − 238 SNP) conferred significant susceptibility towards both T2DM and DFU–DN. The SDF-1 “A” allele conferred significant protection against both DM and DFU–DN but not against DFU–PVD. Further, these alleles were shown to influence the serum cytokine/chemokine levels under diabetic conditions. Thus SNPs in cytokine/chemokine genes serve as valuable biomarkers for DFU.
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NewsBot · Apr 27, 2017

The role of the ITLN1 gene rs2274907 polymorphism in diabetic foot patients.
Mrozikiewicz-Rakowska B, Sobczyk-Kopcioł A, Szymański K, Nehring P, Szatkowski P, Bartkowiak-Wieczorek J, Bogacz A, Aniszczuk A, Drygas W, Płoski R, Czupryniak L.
Pol Arch Intern Med. 2017 Apr 25. doi: 10.20452/pamw.4008.

INTRODUCTION Diabetic foot (DF) is a devastating complication of diabetes mellitus (DM) that occurs due to neuropathy and/or atherosclerosis of the lower limbs. Omentin (encoded by the ITLN1 gene) has been implicated as a protective factor in vascular complications of diabetes, likely due to its endothelial vasodilator activity and its anti-inflammatory actions. However, susceptibility to DF in terms of ITLN1 gene polymorphisms has not been studied. OBJECTIVES This study aimed to evaluate the association between ITLN1 gene polymorphism rs2274907and the occurrence of DF in patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS The study included 670 individuals: 204 with T2DM and DF (DF group), 299 with T2DM without DF (T2DM group), and 167 healthy controls. RESULTS Ischemic heart disease, retinopathy, nephropathy, neuropathy, obesity, hyperlipidemia, and active smoking were more frequent in the DF group than in the T2DM group. Allele A of the rs2274907 polymorphism was observed more frequently in the DF group compared to healthy controls in an additive model (P = 0.034, OR=0.7). This effect was also sex-specific for males in both the additive and recessive models (P=0.015, OR=0.6 and P=0.0017, OR=0.52, respectively). However, no differences in the distribution of alleles was observed between the DF and T2DM groups. CONCLUSIONS The rs2274907 polymorphism of ITLN1 gene is associated with the prevalence of DF.
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NewsBot · Jul 30, 2017

NOS1AP genetic variation is associated with impaired healing of diabetic foot ulcers and diminished response to healing of circulating stem/progenitor cells.
Margolis DJ et al
Wound Repair Regen. 2017 Jul 29. doi: 10.1111/wrr.12564

It is unclear why many with diabetes develop foot ulcers (DFU) and why some do not heal. It could be associated with genetic variation. We have previously shown that NOS1AP variation is associated with lower extremity amputation in those with diabetes and that circulating stem progenitor cell concentration (SPC) is associated with impaired foot ulcer healing in those with diabetes. The goal of this study was to determine if NOS1AP variation is associated with impaired wound healing and with SPC mobilization in those with DFU. In longitudinal cohort study we demonstrate that NOS1AP variants rs16849113 and rs19649113 are associated with impaired wound healing and with SPC mobilization in those with DFU. We believe that further study of NOS1AP is merited and that it NOS1AP might be associated with a functional impairment
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NewsBot · Sep 15, 2017

Network Analysis of MPO and Other Relevant Proteins Involved in Diabetic Foot Ulcer and Other Diabetic Complications.
Saumya M et al
Interdiscip Sci. 2017 Sep 13. doi: 10.1007/s12539-017-0258-z.

Network analysis and visualization of genes are very important to understand large complex biological data in a better manner. Large data on genes and proteins in the biological systems are analyzed on the occurrence, interactions, co-expression, and co-regulations of various genes. Here we have visualized the genes involved in type 1 diabetes (T1D), type 2 diabetes (T2D), and foot ulcer condition to put light on the corrective measures to the problem of impaired healing. The goal of this study was to identify the important genes involved in the pathogenesis of diabetes complications and foot ulcer and its association with the free radical-producing enzyme, the myeloperoxidase (MPO). In this study, we have used bioinformatics tools for the analysis of 24 genes that play a major role in diabetes mellitus and its complications, especially diabetic foot ulcer to reveal the relation between the genes and proteins involved in these disease conditions. We could conclude from the network model that MPO is related to foot ulcer and involved in pathogenesis of various co-associated diseases, such as oxidative stress, inflammation, peripheral vascular disease, and other related diabetes complications.
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NewsBot · Jan 18, 2022

Omentin-1 and diabetic foot
Tsvetan Gatev et al
Int J Low Extrem Wounds. 2022 Jan 5

Introduction: Diabetic foot disease is an advanced complication of diabetes mellitus, which is associated with severe invalidization and high mortality rate among affected people. Many factors are involved in its pathogenesis but not all of them are fully elucidated. Objectives: Adipose tissue and its hormones - adipokines, are related to diabetic complications and metabolic disorders. Until now, there are limited data on their role in diabetic foot. The aim of this cross-sectional study is to determine the levels of the adipokine omentin-1 in people with and without diabetic foot disease and to look for its potential involvement in this complication. Methods: Eighty patients with type 2 diabetes and mean age of 60.8±10.5 years were included in this study. They were divided into two groups: with (n=36) and without (n=44) diabetic foot disease. Standard antrometric, clinical and laboratory tests were made. Body composition was analyzed by bioelectrical impedance based device. Serum omentin-1 was measured using ELISA method. Results: Levels of omentin-1 were significantly higher among people with diabetic foot disease (700.2±345.1 ng/ml), compared to the other group (560.2±176.7 ng/ml). This difference remained significant even after adjusting for potential confounders. In a regression model omentin-1 proved its predictive value for development of diabetic foot. Conclusion: Adipokines, and particularly omentin-1, might be included in the pathogenesis of diabetic foot disease.
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NewsBot · Aug 9, 2023

Adiponectin as a therapeutic target for diabetic foot ulcer
Mona Mohamed Ibrahim Abdalla et al
World J Diabetes. 2023 Jun 15;14(6):758-782

The global burden of diabetic foot ulcers (DFUs) is a significant public health concern, affecting millions of people worldwide. These wounds cause considerable suffering and have a high economic cost. Therefore, there is a need for effective strategies to prevent and treat DFUs. One promising therapeutic approach is the use of adiponectin, a hormone primarily produced and secreted by adipose tissue. Adiponectin has demonstrated anti-inflammatory and anti-atherogenic properties, and researchers have suggested its potential therapeutic applications in the treatment of DFUs. Studies have indicated that adiponectin can inhibit the production of pro-inflammatory cytokines, increase the production of vascular endothelial growth factor, a key mediator of angiogenesis, and inhibit the activation of the intrinsic apoptotic pathway. Additionally, adiponectin has been found to possess antioxidant properties and impact glucose metabolism, the immune system, extracellular matrix remodeling, and nerve function. The objective of this review is to summarize the current state of research on the potential role of adiponectin in the treatment of DFUs and to identify areas where further research is needed in order to fully understand the effects of adiponectin on DFUs and to establish its safety and efficacy as a treatment for DFUs in the clinical setting. This will provide a deeper understanding of the underlying mechanisms of DFUs that can aid in the development of new and more effective treatment strategies.
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