Recent advances in exploring the genetic susceptibility to diabetic neuropathy

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diabetes research and clinical practice

Contents available at ScienceDirect

Diabetes Research and Clinical Practice journa l home page: www.e lse vier.com/locate/diabres

Review

Recent advances in exploring the genetic susceptibility to diabetic neuropathy Cristina Politi a, Cinzia Ciccacci a, Cinzia D’Amato b, Giuseppe Novelli a, Paola Borgiani a,*, Vincenza Spallone b a b

Department of Biomedicine and Prevention, Genetics Section, University of Rome ‘‘Tor Vergata”, Italy Department of Systems Medicine, University of Rome Tor Vergata, via Montpellier 1, 00133 Rome, Italy

A R T I C L E I N F O

A B S T R A C T

Article history:

Diabetic polyneuropathy and cardiovascular autonomic neuropathy are common and dis-

Received 19 October 2015

abling complications of diabetes. Although glycaemic control and cardiovascular risk fac-

Received in revised form

tors are major contributory elements in its development, diabetic neuropathy recognizes

24 May 2016

a multifactorial influence and a multiplicity of pathogenetic mechanisms. Thus genetic

Accepted 19 August 2016

and environmental factors may contribute to its susceptibility, each with a modest contri-

Available online 26 August 2016

bution, by targeting various metabolic and microvascular pathways whose alterations intervene in diabetic neuropathy pathogenesis. This review is aimed at describing major data from the available literature regarding genetic susceptibility to diabetic neuropathies.

Keywords:

It provides an overview of the genes reported as associated with the development or pro-

Diabetic polyneuropathy

gression of these complications, i.e. ACE, MTHFR, GST, GLO1, APOE, TCF7L2, VEGF, IL-4,

Cardiovascular autonomic

GPX1, eNOS, ADRA2B, GFRA2, MIR146A, MIR128A.

neuropathy

The identification of genetic susceptibility can help in both expanding the comprehen-

Genetic susceptibility

sion of the pathogenetic mechanisms of diabetic nerve damage and identifying biomarkers

Polymorphisms

of risk prediction and response to therapeutic intervention. Ó 2016 Elsevier Ireland Ltd. All rights reserved.

Genomic biomarkers

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . Searching strategy ACE gene . . . . . . . MTHFR gene . . . . . GST gene . . . . . . . GLO1 gene . . . . . . APOE gene . . . . . .

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* Corresponding author at: Department of Biomedicine and Prevention, Genetics Section, University of Rome ‘‘Tor Vergata”, 00133 Rome, Italy. Fax: +39 (0)6 20427313. E-mail address: [email protected] (P. Borgiani). http://dx.doi.org/10.1016/j.diabres.2016.08.006 0168-8227/Ó 2016 Elsevier Ireland Ltd. All rights reserved.

8. TCF7L2 gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. VEGF gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. IL-4 gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. GPX1 gene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. eNOS gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13. ADRA2B gene . . . . . . . . . . . . . . . . . . . . . . . . . . . 14. MicroRNA and diabetic neuropathy . . . . . . . . . . 15. A genome-wide approach on neuropathic pain: 16. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.

........... ........... ........... ........... ........... ........... ........... GFRA2 gene . ........... ........... ........... ...........

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Introduction

Diabetic neuropathy is a common complication of diabetes. While estimates vary, depending on the methods and criteria used to diagnose diabetic neuropathy, it is generally held that at least 50% of all diabetic patients will develop neuropathy in their lifetime [1,2]. The neuropathies developing in patients with diabetes are known to be heterogeneous for their symptoms, pattern of neurological involvement, course, risk covariates, pathologic alterations, and underlying mechanisms [3,4]. The most common neuropathies are diabetic polineuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) [1,2]. Both these diabetic neuropathies can entail disabling consequences like neuropathic pain, foot ulceration and amputation, diabetic gastroparesis, postural hypotension, and cistopathy. Moreover, they are burdened with negative impact on quality of life and health related costs [5] and associated with increased morbidity and mortality [1,6,7]. DPN has recently been defined by the Toronto Expert Panel on Diabetic Neuropathy as a symmetrical, length-dependent sensorimotor polyneuropathy attributable to metabolic and microvessel alterations as a result of chronic hyperglycemia exposure (diabetes) and cardiovascular risk covariates [6]. Age, diabetes duration, glycaemic control, hypertension and smoking (these last two mainly in type 1 diabetes) are the major risk factors, while new and less strong clinical correlates or predictors are obesity, body mass index (BMI), waist circumference, hypoinsulinemia in type 2 diabetes, low levels of C peptide in type 1 diabetes, metabolic dyslipidemia, and cardiovascular disease including peripheral arterial disease [2,8,9]. CAN is the other common form among diabetic neuropathies. The prevalence of confirmed CAN (based on at least two abnormal cardiovascular heart rate test results) in unselected people with type 1 and type 2 diabetes is around 20%, but figures as high as 65% are reported with increasing age and diabetes duration [7]. Established risk factors for CAN are glycaemic control in type 1 diabetes, and a combination of hypertension, dyslipidaemia, obesity and glycaemic control in type 2 diabetes [7]. Although CAN often coexists with DPN, there is no totally parallel behavior between the two forms. In type 2 diabetes their development may diverge and their response to therapeutic interventions may differ [10].

The pathogenesis of DPN and CAN have not been completely understood. There is a common view that these complications are multifactorial diseases caused by complex interactions between a variety of genetic and environmental factors. Given the large inter-individual variability in terms of clinical manifestations and severity of DPN and CAN, it has been suggested that genetic factors may influence the natural course of the disease. The aim of this review is to focus the attention on the recent findings about the genetic component of these common complications of diabetes, DPN and CAN. Below we give an overview of the genes that have been found associated with the development or progression of these diabetic complications (Table 1).

2.

Searching strategy

The scientific publications were identified from the international web database PubMed. We selected the papers that investigated the association of genetic variants with the diabetes complications, focusing our attention in particular on diabetic neuropathy. We included articles published between September 2006 and May 2015. We performed the research using the following key words: diabetes mellitus/type 2 diabetes, polymorphism, diabetes complications, genetic susceptibility to diabetes, diabetic polineuropathy/DPN, peripheral neuropathy and cardiovascular autonomic neuropathy/CAN. We excluded the papers that investigated any kind of neuropathy not related to diabetes or other kinds of diabetes complications, as well as papers that did not identify any association. Furthermore we repeated the research focusing our attention on the identified genes. We included all observational population-based studies, which were conducted as case-control, cohort and cross sectional analysis, or as meta-analysis. In addition, we excluded animal studies, clinical trials, short communications, letters to editor, dissertations and in vitro studies. References of all selected articles were investigated.

3.

ACE gene

Angiotensin-converting enzyme (ACE) is a component of the renin–angiotensin system that converts Angiotensin I to

200

Table 1 – Major genes described associated with susceptibility to diabetic neuropathy. SNPs

ACE

I>D

Ethnicity

References

235 47 173 276 21 82 1720 1316 1430 230 47 1720 251 54 204 81 84 227 211; 63 139; 133 130 61 61 572 19 13

Inanir et al. [14] Settin et al. [15] Stephens et al. [16] Mansoor et al. [17] Ito et al. [18] Jurado et al. [19] Wu et al. [20] Li et al. [21] Xu et al. [22] Serbulent et al. [29] Settin et al. [15] Wu et al. [20] Groener et al. [41] Monastiriotis et al. [46] Zhang et al. [60] Tavakkoly-Bazzaz et al. [61] Stoian et al. [62] Basol et al. [72] Tang et al. [75] Shah et al. [80] Papanas et al. [88] Ciccacci et al. [94] Ciccacci et al. [94] Meng et al. [96] Vojtkova´ et al. [33] Ciccacci et al. [51]

281 311 399 496 63 201 1899 1617 1873 282 311 1899 273 180 240 167 90 241 558; 319 356; 342 60 69 69 2491 27 171

Risk Risk Risk Risk Protective Risk Risk Risk Risk Risk Risk Risk Risk Risk Protective Risk Risk Risk Risk Risk Risk Protective Risk Protective Risk Risk

0.032 <0.001 0.02 0.001 0.03 0.02 0.001 0.006 0.01 0.003 <0.0001 <0.001 0.03 0.0001 0.004 0.02 <0.0001 0.0002 0.01; 0.02 0.006 0.001 0.032 0.007 1.77
10–7 <0.05 0.02

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Turkish Egyptian Caucasian Asiatic Japanese North Catalonia Asiatic/Caucasian Asiatic/Caucasian Asiatic/Caucasian MTHFR rs1801133 C>T Turkish Egyptian Asiatic/Caucasian GLO1 rs2736654 A>C Caucasian APOE e4/Greek VEGF rs3025039 C>T Han rs25648 C>T British-Caucasian I>D Romanian IL-4 VNTR (P1/P2 allele) Turkish GPX1 rs1050450 C>T Caucasian eNOS 27VNTR (a/b) rs270744 T>C North and South Indian ADRA2B I>D Greek MIR146A rs2910164 G>C Italian MIR128A rs11888095 C>T Italian GFRA2 rs7428041 T>C UK GSTT1 wild/null Slovack TCF7L2 rs7903146 C>T Italian

Cases with DPN (n) Controls without DPN (n) Effect of association P value

diabetes research and clinical practice

Gene

diabetes research and clinical practice

Angiotensin II, a potent vasoconstrictor agent. ACE inhibitors have been used as therapeutic agents in DPN in an attempt to target the microvascular abnormalities believed to contribute to its pathogenesis. They showed some protective effects on neural dysfunction in experimental diabetes [11] and on neurological biomarkers of DPN in two clinical trials [12,13]. The I/D polymorphism of ACE gene is classified into three types – II, ID and DD – and is defined by an insertion (I allele) or deletion (D allele) of a 287-bp Alu repeat in intron 16. This polymorphism defines ACE activity and determines serum ACE levels. Several studies demonstrated that the homozygous DD genotype of I/D polymorphism is a susceptibility factor for DPN. For example, Inanir et al. [14], involving 235 unrelated patients with DPN and 281 unrelated healthy controls, have highlighted that the DD genotype was associated with DPN in a Turkish population with type 2 diabetes (OR: 1.47; 95% CI 1.03–2.11, p = 0.032) [14]. Another study reported the same association for an Egyptian population with type 2 diabetes (n = 202, 47 with DPN). The logistic regression analysis showed that ACE DD genotype was associated with a threefold increase in the risk of developing DPN compared to healthy controls (n = 311) (OR: 3.1; p < 0.001) [15]. Finally, Stephens et al. [16] reported the association of the D allele with an increased risk of DPN in female, but not in male, patients with type 2 diabetes [16]. A study conducted in the Asian population described a protective role of the ACE II genotype against the development of DPN: the prevalence of the II genotype was significantly greater than that of the DD genotype in type 2 diabetes patients without DPN (p < 0.05) [17]. In contrast with these findings, there are several studies that have shown a protective role of the D allele on the DPN development. For example in 2002, Ito et al. [18] had described that D allele had a protective effect against the development of DPN (OR: 0.34; 95% CI 0.13–0.88, p = 0.03) [18]. Another study, performed in a population of North Catalonia, showed that the heterozygous genotype was independently associated with a decreased risk of DPN (RR: 0.71; p = 0.02) [19]. Despite these controversial results, there are three recent meta-analyses that have confirmed the role of the ACE I/D polymorphism as a risk factor for the development of DPN. A first meta-analysis aimed at evaluating the effects of both ACE I/D and MTHFR 677 C>T polymorphisms in the development of DPN, including nine relevant studies, for a total number of 3619 subjects (1720 cases and 1899 controls), among which five were conducted on ACE [20]. All these were casecontrol studies, seven involved Asian populations and two involved Caucasian populations. With regard to I>D polymorphism in the ACE gene, this meta-analysis supported the association between DPN and ACE I>D polymorphism, with D allele resulting to be a risk allele (allele model, OR: 1.43; 95% CI 1.12–1.83, p = 0.004; dominant model, OR: 1.44; 95% CI 1.17–1.78, p = 0.001). In a second meta-analysis [21], a total of seven casecontrol studies in patients with type 2 diabetes were included for a total of 1316 cases and 1617 controls. Also this metaanalysis confirmed that the D variant allele was associated with a significantly increased risk of DPN (OR: 1.46; 95% CI 1.11–1.92, p = 0.006).

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201

The most recent meta-analysis included eight casecontrol studies with a total of 3303 subjects, and found that the DD and ID genotypes were significantly associated with DPN with a pooled OR of 1.25 (95% CI 1.05–1.48, p = 0.01) [22].

4.

MTHFR gene

Methylenetetrahydrofolate reductase (MTHFR) is the enzyme that catalyzes the transformation of homocysteine to methionine via the re-methylation pathway [23]. Variations of the MTHFR gene lead to a decreased enzymatic activity. The most common MTHFR variant is a C>T substitution at nucleotide 677 resulting in an enzyme with 50% less activity [24]. This variation is the most common genetic cause of elevated homocysteine levels. Hyperhomocysteinemia might exert adverse effects on vascular endothelium and smooth muscle cells leading to changes in arterial structure and function. Homocysteine is considered a risk factor for atherosclerotic disease or just a biomarker, given that there is no evidence of preventive efficacy on cardiovascular events of homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 [25]. However, homocysteine was found to be an independent risk marker for neuropathy in the general population [26] and for DPN in type 2 diabetes patients in a Caucasian [27] and a Chinese population [28]. Several studies demonstrated the existence of an association between the MTHFR gene C677T polymorphism and DPN. Recently, Serbulent et al. [29] investigated the role of the C677T polymorphism in the development of DPN in a Turkish population including 230 patients affected by DPN and 282 healthy controls. The distribution of the genotypes and allele frequencies of the MTHFR gene C677T variation were statistically different between the patients and the control group (OR: 3.20, 95% CI 1.47–7.46; p = 0.003 and OR: 1.59; 95% CI 1.19–2.13; p = 0.002). Significant differences between patients and controls were also observed comparing CC versus CT +TT and CC+CT versus TT genotypes (OR: 3.20; 95% CI 1.47– 7.46, p = 0.003 and OR: 1.53; 95% CI 1.07–2.19, p = 0.018, respectively) [29]. Settin et al. [15] confirmed this genetic association for the Egyptian population. The logistic regression analysis showed that MTHFR 677T allele was a risk factor for DPN with an OR of 5.2, p < 0.0001 [15]. Finally, the previously cited metaanalysis (including 4 studies on MTHFR 677 C>T) confirmed the role of the MTHFR 677 T allele as a risk factor for the development of DPN (allele model, OR: 1.43; 95% CI 1.08–1.90, p = 0.014; dominant model, OR: 1.99; 95% CI 1.36–2.91, p < 0.001) [20].

5.

GST gene

Glutathione S-transferases (GSTs) are a family of phase II xenobiotic metabolizing enzymes that protect against endogenous oxidative stress and exogenous potential toxins. GSTs actions involve reduction of organic hydroperoxides, conjugation of reduced glutathione (GSH) with substrates, and glutathione dependant biotransformation of xenobiotics, with consequent transportation from the cell [30]. As antioxidant enzymes, GSTs can protect cells from oxidative damage

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typical of many pathological conditions, including neurological conditions as neurodegenerative diseases [31] and DPN [11]. The GST family consists of eight classes of enzymes. GST-mu (GSTM1) and GST-theta, (GSTT1) and their polymorphisms are the most extensively investigated genes. The most common variant of the GSTM1 and GSTT1 genes is homozygous deletion (null genotype), which has been associated with the loss of enzyme activity and increased vulnerability to cytogenetic damage. It is known that individuals carrying the null genotype of GST have significantly reduced activity of this antioxidant enzyme [32]. A recent study investigated the role of GSTT1 and GSTM1 null alleles in the susceptibility to CAN in Slovak adolescents with type 1 diabetes. The study assessed the prevalence of GSTT1/M1 gene polymorphisms in 46 adolescents with type 1 diabetes (only 10 with CAN), and found that the GSTM1 null genotype was more frequent in those with CAN (OR: 1.89; 95% CI 0.56–6.37), but without statistical significance. Regarding GSTT1, the wild-type allele increased the risk of CAN significantly (OR: 4.95; 95% CI 1.13–21.74, p < 0.05). Lastly, a combination of genotypes (wildtype for GSTT1 and null for GSTM1) seemed to be a risk factor for CAN in adolescents with type 1 diabetes (OR: 1.99; 95% CI 1.0–3.86, p < 0.05) [33]. In another study in 446 patients with type 1 diabetes of short duration (less than 3 years), among which 216 with DPN, the +/null polymorphisms of GSTT1 and GSTM1 were assessed. Although a significant association was found between the ‘‘+” allele of GSTM1 and higher total activity of GST compared to the null allele, no significant association was found between GST polymorphism and DPN [34]. On the other hand, the study evaluated also the 262T>C polymorphism of the catalase gene (another key enzymatic antioxidant) and found that the 262TT genotype of the CAT gene was significantly associated with higher erythrocyte catalase activity compared to the 262CC genotype, and that 262C allele was associated with higher risk of DPN (OR: 1.98, P corrected = 0.002) [34]. One study investigated GSTM1, GSTT1, and GSTP1 gene polymorphisms in 84 patients with type 2 diabetes, and failed to find an association with the presence of DPN [35].

6.

GLO1 gene

Glyoxalase 1 (Glo1) catalyses the detoxification of methylglyoxal. Methylglyoxal, also called pyruvaldehyde, is the product of glycolysis and reacts non-enzymatically with arginine residues of proteins to form the advanced glycation end products (AGEs) [36]. It is associated with ageing, enhances in vitro platelet-neutrophil aggregation and it has been linked to the development of atherosclerosis and heart failure, neurodegenerative diseases and microvascular complications of diabetes [37]. The formation of AGEs is pivotal in the development and progression of diabetic complications since it increases both inflammation and oxidative stress [38]. Thus, Glo1 is an important defense system in preventing or reducing the formation of AGEs and may play a central role in the pathogenesis of microvascular complications, like diabetic neuropathy. Bierhaus et al. (2012) [39] have shown that

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methylglyoxal plasma levels were increased in 10 type 2 patients with painful DPN compared with 10 patients with painless DPN. Moreover, further experiments showed that methylglyoxal induces post-translational modification of the nociceptor-specific sodium channel Nav1.8 and in this way it facilitates nociceptive neuron firing, enhances sensory neuron excitability in animal models, and causes hyperalgesia in diabetic neuropathy, while at the same time slowing myelinated nerve conduction and driving Nav1.7 into slow inactivation. Thus, methylglyoxal-dependent modification in Nav1.8 has a role in diabetes-associated hyperalgesia that is independent of degenerative or regenerative changes in the nerve [39]. Moreover, Skapare et al.(2013) [40] showed that the activity of the Glo1 enzyme was lower in blood samples from type 1 and type 2 patients with painful DPN, supporting the hypothesis that Glo1 activity modulates the phenotype of diabetic neuropathy. A recent mono-centric cross sectional study, involving 733 Caucasian diabetic patients described an association between the CC genotype (rs2736654 or rs4746) of the GLO1 gene and DPN in type 2 diabetes (OR: 1.49; p = 0.03) [41]. This finding supports the hypothesis that the methylglyoxal might be a crucial mediator of DPN in type 2 diabetic patients [41].

7.

APOE gene

High levels of tryglicerides and metabolic dyslipidemia have been reported to be associated with DPN and its progression in both type 1 and type 2 diabetic patients, and dyslipidemia has been increasingly considered a significant contributor to the development of DPN through a number of mechanisms including oxidative stress in dorsal root ganglia sensory neurons [42] and endothelial dysfunction [43]. The Apolipoprotein E (APOE) gene encodes for three isoforms that are involved in the metabolism of plasma cholesterol and triglycerides. The three most common isoforms of APOE in humans are e2, e3, and e4 (rare variants have also been identified) [44]. Several studies have suggested an involvement of e4 isoform in the increased risk of neuromuscular diseases [45], it could therefore be argued that this isoform might participate in the susceptibility to DPN. A recent study tested the hypothesis that APOE e4 allele could be a risk for severe DPN in 234 patients with type 2 diabetes of Greek origin [46]. Based on the Neuropathy Disability Score (NDS), patients were divided into two groups: group A (NDS 6 6: mild or no neuropathy, n = 180) and group B (NDS > 6: severe neuropathy, n = 54). e4 carrier status was significantly more frequent in group B (27.8%) compared to group A (8.9%, p = 0.0003). In a multivariate analysis, a more than 5-fold increased risk of severe DPN was associated with e4 carrier status (OR: 5.26; 95% CI: 2.24– 12.31, p = 0.0001).

8.

TCF7L2 gene

Transcription factor 7-like2 (TCF7L2) gene encodes for a nuclear receptor for B-catenin, which mediates the Wnt signaling pathway [47], involved in lipid metabolism and glucose homeostasis. This gene is potentially relevant to DPN for the

diabetes research and clinical practice

already cited role of lipid disorders in the development of DPN [42]. The variants of TCF7L2 gene have been found to be strongly associated with an impaired insulin secretion and with an increased risk of type 2 diabetes [48,49], especially in Europeans [50]. In a recent study, we described that TCF7L2 variability, besides contributing to type 2 diabetes risk, could also contribute to the development of CAN in the Italian population [51]. Three TCF7L2 polymorphisms (rs7903146, rs7901695 and rs12255372) were analyzed. We observed a strong correlation between the rs7903146 polymorphism and the presence of CAN: patients carrying the variant allele had an eightfold increased risk of developing this form of neuropathy (OR: 8.28; p = 0.022). For another SNP, rs7901695, we observed a significant correlation only at allelic level (OR: 2.86; p = 0.02). However these data represent a preliminary result that certainly requires additional independent studies including a higher number of patients.

9.

VEGF gene

Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen that promotes the proliferation of vascular endothelial cells. The association of VEGF and DPN has attracted attention in recent years. For example, Deguchi et al. [52] found that serum VEGF levels were significantly increased in 113 patients with DPN compared to 107 without, particularly in patients in the symptomatic stage of DPN [52]. Currently, it is believed that VEGF affects nerve fibers by changing the structure and function of endothelial cells: VEGF can increase capillary permeability, promote the synthesis of extracellular matrix and the proliferation of endothelial cells. Finally, VEGF can impair the barrier function of the basement membrane and increase the endoneural vascular permeability, leading to nerve fiber ischemia and hypoxia, and thus contributes to the pathogenesis of neuropathy [53]. However, also neuroprotective effects on central and peripheral neurons have been documented and even intramuscular plasmid VEGF gene transfer was tested in a clinical trial in DPN [54]. Possibly, VEGF might behave differently in different tissues, i.e. neurons and endothelial cells, or different isoforms of VEGF (VEGF-A165a and VEGF-A165b) exert various degrees of favorable neuroprotective and adverse proangiogenic actions in the nerve [55]. Antithetic angiogenic and antiangiogenic effects of VEGF isoforms were recently suggested in peripheral vascular disease as a possible explanation for impaired vascular response to ischemia [56]. Despite the uncertainty of its true net effect in DPN pathogenesis, VEGF appears to be a potential target for intervention in DPN [57]. There are multiple polymorphic loci in the VEGF gene. The C936T gene polymorphism located in the 30 -untranslated region (30 -UTR) is associated with the expression level of VEGF [58,59]. A recent study has examined the relationship between VEGF C936T polymorphism and VEGF expression level in Han people from Shandong Province with type 2 DPN. The T allele frequency in the DPN group (n = 204) was significantly lower than in the control subjects (n = 240) and in diabetic people without DPN (n = 184) (p < 0.001). The incidence of DPN in the CC genotype group was higher than in the CT+TT genotype group (47.97% versus 39.29%, p = 0.001) and CT genotype group

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(47.97% versus 39.58%, p = 0.002). The logistic regression analysis confirmed this result: 936T allele was negatively related to the occurrence of DPN (OR: 0.46; p = 0.004, 95% CI: 0.19–0.74). Thus, the authors proposed that the C allele may be a genetic marker for DPN occurrence, while the T allele may be a protective genetic marker for DPN [60]. The contribution of the VEGF gene to DPN susceptibility was previously investigated by Tavakkoly-Bazzaz et al.(2010) [61] in 248 British Caucasian type 1 diabetic subjects (81 with and 167 without DPN). This study indicated that a polymorphism in the promoter region (7C/T, rs25648) could be implicated in the pathogenesis of DPN as it may harbor some functional/regulatory potential in VEGF gene expression. Indeed, the authors found that the distribution of genotypes at this SNP was significantly different between diabetic subjects with and without DPN, and the C allele conferred susceptibility to DPN (OR: 1.78; 95% CI 1.0–3.1, p = 0.02) [61]. Recently, Stoian et al. described a genetic association between the Insertion/Deletion (I/D) polymorphism, a 18 bp fragment in 2549 position of the promoter region of VEGF gene, and the risk to develop DPN in 84 Romanian patients with type 2 diabetes. VEGF D allele was observed to be significantly increased in DPN patients compared with 90 healthy control subjects (OR: 3.46; 95% CI 2.19–5.45, p < 0.0001). The significant association was also observed at genotypic level: the patients with ID genotype had more occurrence of DPN compared to patients with genotype II (OR: 4.82; 95% CI 2.34–9.93, p < 0.0001). Therefore, the authors suggested that D allele of VEGF gene might a risk factor for the development of DPN [62].

10.

IL-4 gene

Interleuchin-4 (IL-4) is an important cytokine secreted by T helper 2 cells, eosinophil, and mast cells. It plays a role in the formation of endothelial cell adhesion molecules, chemotaxis of immune cells, and anti-inflammation [63–65]. Several studies have reported that cytokines play a key role in nerve damage [66], in particular IL-4 regulates lipid and glucose metabolism by promoting insulin sensitivity, glucose tolerance, and inhibiting lipid deposits [67]. A common variable number of tandem repeat (VNTR) polymorphism in the third intron of IL-4 [68], consisting of two alleles, P1(183 bp) and P2 (253 bp) has been described [69]. Distinct numbers of VNTR copies might affect the transcriptional activity of the IL-4 gene [70]. There are controversial findings about the effect of VNTR polymorphism on expression and serum level of IL-4: a study on patients with rheumatoid arthritis revealed that P1P1 genotype was associated with low serum levels of IL-4 [71] whereas, inversely, Nakashima et al. reported that P2P2 genotype was associated with the same effect [69]. A recent study, involving 227 DPN patients and 241 healthy subjects of Turkish origin, suggested that VNTR polymorphism of the IL-4 gene plays an important role in the occurrence of DPN. The distribution of genotype and allele frequencies of VNTR polymorphism were statistically different between DPN patients and control subjects (p = 0.001 and p = 0.00009, respectively). A significant difference was also observed when the patients and controls were compared according to P2P2 versus P1P2 + P1P1 genotypes (OR: 2.28; 95% CI 1.46–3.58, p = 0.0002) [72].

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11.

diabetes research and clinical practice

GPX1 gene

Glutathione peroxidase-1 (GPX1) encodes an endogenous anti-oxidant enzyme. Oxidative stress is associated with adverse effects on the vascular system and both macrovascular and microvascular complications of diabetes [73]. The variant allele of polymorphism (rs1050450, C>T), resulting in amino acid change from proline to leucine at codon 198, is associated with a reduced enzyme activity [74]. A recent study has examined the association between this gene variant and DPN in two cross-sectional samples of Caucasian subjects with diabetes, 773 and 382 examined patients, respectively. The authors observed that in both groups the variant allele of the polymorphism was more present in patients with DPN than in those without DPN, with an odds ratio of 1.61 (95% CI 1.10–2.28; p = 0.01) in the first group and of 1.95 (95% CI 1.11–3.42; p = 0.02) in the second group. Therefore, the results of this study suggest that the T allele of rs1050450 is a genetic risk factor for DPN [75].

12.

eNOS gene

Endothelial dysfunction plays a key role in the pathogenesis of diabetic microangiopathy, including DPN. Nitric Oxide (NO) system, through dramatically changed NO production and local release, significantly contributes to endothelial dysfunction [76]. The process takes place by the modulation of the nitric oxide synthase (NOS) enzymes responsible for NO synthesis [77]. There are three distinct isoforms of NOS; endothelial constitutive NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS) [78]. Polymorphisms in the eNOS gene, that lead to decreased eNOS expression, have been found to be associated with the development and progression of DPN [79]. The most studied variants are two SNPs: rs2070744 (786 T/C); rs1799983 (894 G/T) and a 27-base pair tandem repeat polymorphism located in the intron 4, consisting of four (allele a) or five (allele b) repeats. In a recent study Shah et al. [80] a genetic association between the described polymorphisms and the increased risk of DPN was described. The study involved two independent cohort of North Indian origin: (1) 139 patients with DPN and 356 type 2 diabetes patients without neuropathy; (2) 133 patients with DPN and 342 type 2 diabetes patients without neuropathy. They have also replicated the study in a 3rd independent cohort of South Indian origin that was composed of 207 type 2 diabetes patients without neuropathy and 81 with DPN. The authors observed that, in all groups, the patients with ‘aa’ eNOS genotype of 27VNTR (a/b) had a major risk of DPN (p = 0.006). Furthermore, they showed that the haplotype carrying ‘a’ allele of 27VNTR (a/b) and C allele of T-786C was significantly higher in patients having DPN as compared to patients without DPN [80].

13.

ADRA2B gene

The Alpha2B adrenergic receptor, encoded by a2B-adrenergic gene (ADRA2B), mediates a variety of functions in humans [81]. A common non-synonymous variant (12Glu9) of ADRA2B gene, that encodes a receptor protein leading to the insertion/

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deletion (I/D) of three consecutive glutamate residues at amino acid positions 301–303, have been described to be associated with adverse metabolic and vascular effects including obesity [82], impaired insulin secretion [83] and earlier onset of diabetes [84]. The potential involvement of this polymorphism in the development of DPN is supported by the evidence that, in the nervous system, the I/D polymorphism has been shown to be linked with autonomic dysfunction and increased sympathetic nervous system activity [85–88]. A recent study has investigated the potential association between ADRA2B gene I/D polymorphism and DPN in a group of 190 type 2 diabetes Greek patients, 130 with and 60 without DPN. The authors, apart from showing a higher frequency of the D allele in DPN patients (p = 0.001), found a correlation between the D allele and the Diabetic Neuropathy Index (DNI) score. They observed that it was significantly higher (p = 0.04) in patients with I/D (3.7 ± 1) than in those with I/I (2.5 ± 0.9) and significantly higher (p = 0.001) in patients with D/D (5.6 ± 1.3) than in those with I/D (3.7 ± 1), suggesting that the D allele is also implicated in the severity of DPN [88].

14.

MicroRNA and diabetic neuropathy

MicroRNAs (miRs or miRNAs) are small RNA molecules (20–22 nucleotide length) that are implicated as regulators in various biological processes. It is estimated that at least 20–30% of all human genes are regulated by miRNAs through targeting sequences in their 30 untranslated region. The DNA regulatory regions might play an important role in various pathways like, for example, in the control of development processes, hematopoietic cell differentiation, apoptosis, cell proliferation and organ growth, but also in several pathologies. There is an increasing evidence in favor of an involvement of miRNAs in diabetes development [89,90] as well as in diabetic complications (i.e. diabetic retinopathy, nephropathy, neuropathy and cardiovascular disease) [91]. While different studies analyzed the levels of miRNAs expression in diabetic complications [92,93], in our recent study we evaluated a possible contribution of genetic polymorphisms present in miRNA regions in susceptibility to DPN and CAN [94]. Nine polymorphisms in miRNA genes were studied in a sample of 132 type 2 diabetic patients analyzed for DPN and 128 type 2 diabetic patients analyzed for CAN. The study highlighted an association of the rs2910164 (G>C) in MIR146A and rs11888095 (C>T) in MIR128A with DPN susceptibility. Indeed, the variant allele of rs2910164 SNP in MIR146A was associated with a significantly lower risk of developing DPN (OR: 0.46; p = 0.032), whereas the T allele of rs11888095 SNP in MIR128A was associated with a higher risk (OR: 2.91; p = 0.007). The association with MIR128A remained significant after correction for BMI, age, disease duration, HbA1c and gender (ORadj: 4.89 and Padj = 0.002), while MIR146A showed only a trend of association after adjustment (ORadj: 0.49 and Padj = 0.092).

15. A genome-wide approach on neuropathic pain: GFRA2 gene The genome-wide association study (GWAS) is a useful and efficient method to identify potential candidate genes for

diabetes research and clinical practice

common complex disorders using DNA chips [95]. The DNA chips can genotype hundreds of thousands of SNPs in individuals, comparing variants’ frequency between cases and controls. This approach has been used in a recent study to identify the genetic factors associated with neuropathic pain in diabetes [96]. Neuropathic pain was defined as pain directly caused by a lesion or a disease affecting the somatosensory system [97]. The authors recruited 572 cases of neuropathic pain and 2491 diabetic controls (without neuropathic pain). The study results highlighted a significant SNPs cluster in Chr8p21.3 next to GFRA2 gene, with a p-value of 1.77
107 at rs17428041. GFRA2 encodes a glycosylphophatidylinositol (GPI)-linked cell surface receptor for neurotrophic factors that are involved in the control of neuron survival and differentiation, such as GDNF (cell line-derived neurotrophic factor) and NTN (neurturin). Thus, the study showed that the C allele of rs1742041 could be a protective variant with regard to the development of painful DPN, since the C allele showed an OR: 0.67. This study provided support that SNPs next to GFRA2 in the Chr8p21.3 may be associated with neuropathic pain in diabetes.

16.

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In a future perspective, it is crucial to perform replication of significant SNPs in independent and larger cohorts and to focus upon the molecular mechanisms that may be responsible for the association signals. Moreover, new genomic approaches such as Next Generation Sequencing might be useful to better understand the genetic basis for diabetic neuropathies. In conclusion, no definite information is available on genetic biomarkers for diabetic neuropathy, although available data support genetic susceptibility and might provide useful insights into pathogenetic mechanisms of this troublesome complication of diabetes.

Conflict of interest The authors declare no conflict of interest.

Acknowledgments This study was supported by grants from Fondazione Roma 2013.

Discussion R E F E R E N C E S

Both DPN and CAN are common and disabling complications of diabetes with complex, multifactorial pathogenetic mechanisms, which are still far from being completely understood. Given their multifactorial nature, many genetic and environmental factors could contribute to diabetic neuropathy susceptibility, with a modest contribution. In any case, the identification of genetic factors, that may potentially become genetic biomarkers, could be useful in identifying patients more prone to develop these serious neuropathic conditions. This issue represents a topical subject to deserve attention in the diabetes field, so that a recent review already reported associations with several kinds of diabetes complications, including diabetes neuropathy [98]. In this review, we have tried to represent major data from literature regarding the current knowledge about genetic susceptibility implicated in diabetic neuropathies. Several genes have been studied as candidate genes for diabetic neuropathy susceptibility, although, only very few genes have been extensively investigated in different populations and in large cohorts, such as the ACE gene polymorphisms and the MHTFR polymorphisms. The majority of other genes have been analysed in a small number of studies. Moreover, most of the published studies on diabetic neuropathy susceptibility are underpowered in terms of their ability to detect the contributory role of common alleles because of the insufficient number of investigated patients. In order to increase the statistical power required to identify potential susceptibility genes, larger sample sizes are clearly essential in future studies. Another issue with these studies is the definition of phenotype: the diagnosis of DPN should be confirmed by nerve conduction studies or skin biopsy, but in many studies this is not the case. Therefore, it is evident that not only large scale sample sizes are needed but also well-defined phenotypes in order to minimize heterogeneity.

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