The Relationship of RAGE Gene Polymorphism With Type I Diabetes in Egyptian Patients
Condition: Type1diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional

Summary: 
      Type I Diabetes Mellitus (TIDM) is a chronic metabolic disorder caused by the immune-mediated
      T-cell and macrophages that typically affects insulin-producing β-cells of Langerhans leading
      to cell destruction and absolute insulin deficiency. This study aimed to investigate the
      correlation of RAGE gene polymorphism rs1800625 with the incidence of type I diabetes
      mellitus in the Egyptian patients with the activity and the severity of the disease and to
      assess their association with inflammatory reactions in TIDM patients (IL-6, TNF-α). Also,
      this study investigated the relation between MiRNA-34, MiRNA-146, to TID severity and
      activity
    

Detailed description: 
      Type I diabetes mellitus (TIDM) is also called autoimmune diabetes, juvenile-onset or
      insulin-dependent diabetes mellitus . It is representing 10% of diabetes cases, estimated
      that most of these patients are less than 15 years old. The pathophysiology of TIDM is a
      complex and available data proposed the important cause for this disease such as autoimmune
      disease and some genetic factors TIDM is a chronic disease caused by the immune-mediated
      T-cell and macrophages attack on insulin-producing β-cells of Langerhans leading to cell
      destruction and absolute insulin deficiency. This will produce high blood sugar
      (hyperglycemia) and change in the proteins and lipids metabolism TIDM is usually
      characterized by the presence of anti-glutamic acid decarboxylase, islet of β-cell or insulin
      antibodies which identify the autoimmune processes, leads to β-cell destruction .

      Type I diabetes mellitus is account for only a minority of the total burden of diabetes in a
      population, however it is considered the major type of diabetes in younger age .

      Treatment of TIDM is more complex than other types of diabetes, as it cannot be regulated
      only by dietary interventions, as it is usually accompanied by severe complications, and has
      extreme variability due to the diverse ages of diagnosis. Primary treatment for TIDM include
      immune-suppressive drugs and continuous exogenous insulin that cover the primary
      pathophysiology of TIDM Currently, diabetes mellitus is diagnosed when hemoglobin A1C (HbA1c)
      is ≥6.5% or fasting plasma glucose (FPG) is ≥ 126 mg/dl or 2 hour postprandial plasma glucose
      is ≥ 200 mg/dl during an oral glucose tolerance test or a random plasma glucose is ≥ 200
      mg/dl plus symptoms of diabetes .

      Advanced glycation end products (AGEs) Advanced glycation end products (AGEs) are defined as
      a heterogeneous group of irreversibly reactive derivatives. They are formed by non-enzymatic
      glycation with tissue proteins, and shown to accumulate on long-lived proteins in diabetes
      mellitus . They generate oxidative stress and induce inflammation and they have been tied to
      be a factor in the development an unfavorable pro-inflammatory state implicated in many
      degenerative diseases, such as autoimmune diseases, diabetes, atherosclerosis, chronic renal
      failure, metabolic syndrome and its complications, and neurological diseases such as
      Alzheimer's disease, cardiovascular diseases (Kuzan and Aleksandra 2021). These harmful
      compounds can affect every type of cell in the body and are thought to be one factor in some
      age-related chronic diseases. Receptor for advanced glycation end products (RAGE) is a
      multi-ligand cell surface receptor that belongs to the immunoglobulin superfamily. RAGE
      activation by various ligands have been reported to induce LDL deposition, resulting in foam
      cell formation . Furthermore, it increase oxidative stress generation and subsequently
      increase inflammatory, proliferative, angiogenic, fibrotic, thrombogenic, and apoptotic
      reactions in numerous cell types via activation of many intracellular signaling pathways such
      as nuclear factor-κB (NF-κB) . RAGE expression is usually low in the majority of healthy
      adult tissues, but its levels are elevated under pathological conditions such as diabetes .

      RAGE is a highly polymorphic gene, with around ten polymorphisms being predominantly studied.
      The genetic variations of RAGE should be considered as responsible for the development of
      many diseases (Serveaux et al., 2019). In addition, combining RAGE-circulating protein levels
      and RAGE polymorphisms may be used as a useful clinical tool to predict risk of vascular
      diseases. Indeed, sRAGE could be a valuable biomarker in many pathological states. It
      increases in patients with decreased renal function, and decreases in diabetic complications
      and coronary artery disease, but also elevated levels of sRAGE are often associated with
      end-stage disease . The genetic background of RAGE demonstrated that some gene polymorphisms
      are implicated in various pathological states, for example, diabetes complications,
      amplification of the inflammatory response, gastric cancer, and breast cancer . Recently,
      five main RAGE polymorphisms described (rs2070600, rs1800624, rs184003, and a 63 bp deletion)
      were not associated with either type 1 or type 2 diabetes . In this study, we focused on the
      principal RAGE polymorphism (rs1800625) and their potential pathological effect depending on
      the study of the Egyptian population with TIDM.

      Rs1800625 Polymorphism The rs1800625 SNP (- 429 T > C) located in the upstream region and was
      found to increase the transcription of RAGE around twofold in vitro and so increase the RAGE
      expression, which might influence the pathogenesis of many diseases such as autoimmune and
      inflammatory diseases (Ahuja el al., 2022). In the presence of rs1800625 polymorphism, it is
      not only a higher expression of sRAGE but also, there is an increase of AGEs. Studies on
      different pathologies (inflammatory disease, cancer, coronary artery disease, lung disease,
      and myocardial infarction) focused on rs1800625, but with conflicting results. However the
      rs1800625 SNP was studied in different types of cancer but founded to be not involved in the
      pathogenesis of pancreatic cancer like RAGE is implicated There were numerous studies of SNP
      rs1800625 in diabetic patients, but with conflicting results. The rs1800625 SNP was
      significantly increased in type 2 diabetes subjects with retinopathy, compared to those
      without . Many studies demonstrated a correlation between rs1800625 polymorphism and diabetic
      complications. The rs1800625 and rs3134940 were founded to be increase (+65%) the risk of
      developing diabetic nephropathy and was associated with its early onset. The rs1800625 SNP
      was also associated with the development of insulin resistance, and in a Brazilian population
      there was a two-fold increase in the incidence of rs1800625 when subjects were diabetic. An
      analysis in infants with type I diabetes from the Finn Diane cohort reported that rs1800625
      was more prevalent in type I diabetic patients than in controls . In diabetic subjects,
      rs1800625 was associated with higher HbA1c levels, with an increased incidence of type 1
      diabetes.

      The association of rs1800625 with cardiovascular risk has been evaluated, with again
      controversial results. The rs1800625 was associated with higher levels of circulating form of
      (RAGE) and an increased risk of developing coronary artery disease, especially in diabetic
      patients
    

Intervention name(s): Detection of RAGE gene polymorphism (rs1800625)
Intervention type(s): Genetic
Intervention description(s): Detection of RAGE gene polymorphism (rs1800625) By Molecular analysis (real time PCR)
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Screening