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

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

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.

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.

Inclusion Criteria:

1. Must provide informed consent
2. Must hold Qatari passport
3. Males or Females ages 30 years or older to minimize the potential confounding contribution of other forms of diabetes mellitus
4. 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).
5. 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:

1. Other forms of diabetes (Type I, MODY, secondary diabetes)
2. Active pregnancy
3. Active infection or acute illness of any kind (except for Charcot foot)
4. Chronic inflammation (auto-immune diseases) or infection
5. Evidence of malignancy within the past 5 years
6. 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)
7. Acute or critical limb ischemia.
8. Osteomyelitis
9. History of recent (within 6 months) immunosuppressive treatment including corticosteroids and anti-TNF-alpha compounds.