Genetic Contribution to the Pathophysiology of the Charcot Foot in Qatari Patients With Diabetes

Study Overview
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Brief Summary
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To assess the hypothesis that Charcot foot is associated with more vascular complications compared to matched diabetic patients without Charcot foot and to classify patients with Charcot foot according to the human genetic classification of the Qatari population.

Detailed Description
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Diabetes is a serious health issue for the Qatari population since approximately 1/5 of the population has Type 2 Diabetes, which is 2-3 times higher than the world average. Although much of the clinical studies of diabetes often focused on microvascular phenotypes such as retinopathy and nephropathy, and macrovascular diseases presenting clinically as myocardial infarction, stroke, and peripheral vascular disease, other rare complications such as Charcot foot disease confer a significant burden in Qatar diabetic population, leading to decreased life quality. Charcot foot is estimated to affect 0.8% to 8% of diabetic populations. It occurs most commonly in patients with diabetes complicated by severe peripheral neuropathy, often with coexisting sympathetic denervation, causing increased blood flow to the foot and increased bone resorption. Uncontrolled and inappropriate inflammation leading to bone resorption and deformation has been the hallmark of diabetic Charcot foot pathophysiology. There are two major theories that provide the likely mechanism of the disease. The neurovascular (French) theory suggests that increased blood flow, as a result of autonomic neuropathy, can lead to bone destruction and mechanical debilitation. On the other hand, the neurotraumatic (German) theory argues that the loss of protective sensation leads to unperceived injury and trauma in the insensate foot. One can argue that the pathogenesis of Charcot neuro-arthropathy is most likely a combination of these processes. For unknown reasons, Charcot foot is trigged only in some susceptible individuals with diabetes.

Official Title
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Genetic Contribution to the Pathophysiology of the Charcot Foot in Qatari Patients With Diabetes

Conditions
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Charcot Arthropathy, Type 2 Diabetes

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must provide informed consent Must hold Qatari passport Males or Females ages 30 years or older to minimize the potential confounding contribution of other forms of diabetes mellitus In patients with Diabetes, no concomitant diseases except for micro- and macrovascular complications of diabetes (nephropathy, retinopathy, peripheral arterial disease, coronary artery disease, neuropathy) or symptoms of the metabolic syndrome (hypertension, dyslipidemia and obesity). Not taking any chronic medications (except of the diabetes, cardiovascular related drugs, anti-inflammatory drugs and/or any other treatment used for Charcot foot). Exclusion Criteria: Other forms of diabetes (Type I, MODY, secondary diabetes) Active pregnancy Active infection or acute illness of any kind (except for Charcot foot) Chronic inflammation (auto-immune diseases) or infection Evidence of malignancy within the past 5 years Chronic hematological disorders known to affect HBA1C results such as hemoglobinopathies (e.g., sickle cell disease and thalassemia), increased red-cell turnover (e.g., hemolytic anemia and spherocytosis) Acute or critical limb ischemia. Osteomyelitis History of recent (within 6 months) immunosuppressive treatment including corticosteroids and anti-TNF-alpha compounds.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group I: T2D and Charcot foot<br>Individuals with confirmed diagnosis of type 2 diabetes, using the American Diabetes Association guidelines and confirmed diagnosis of Charcot foot, based on clinical and radiological evidence of Charcot foot. | |
| Group II: T2D neuropathy, no charcot<br>Individuals with type 2 diabetes and presence of neuropathy but the absence of Charcot foot. | |
| Group III: Control, non-diabetic<br>Individuals without history of type 2 diabetes. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Charcot Foot's vascular complications | Assess the hypothesis that Charcot Foot is associated with more vascular complications compared to match diabetic patients without Charcot foot | 6 months | 
| Charcot foot in monocyte epigenetics | Assess the hypothesis that Charcot foot disease reflects differences in monocyte epigenetics compared to other controls, particularly in genes involved in inflammation. | 6 months | 
| Assess the effect of initial methylation on kidney function in patients with type 2 diabetes mellitus, weather they have or not Charcot foot disease and for whom we have baseline kidney function, in a 2-year follow-up. |  | 6 months | 
| HBA1C >8.5% on total and gene-specific methylation. | Assess the effect of improving diabetes control in patients with type 2 diabetes (Charcot foot and non-charcot foot patients) and a HBA1C >8.5% on total and gene-specific methylation. | 6 months |