ABSTRACT
OBJECTIVE: Pulmonary tuberculosis (PTB) is a leading cause of morbidity and mortality. Macrophages play an important role in the immunopathogenesis of tuberculosis. Extracellular ATP induces macrophage bactericidal activity through activation of the purinergic P2X7 receptor. This case- control study assesses the association of -762 T/C, 1513A/C and 1729T/A P2X7 polymorphisms in patients with PTB and healthy controls to establish association if any with risk of developing the disease. MATERIALS AND METHODS: The genotyping for P2X7 was carried out using PCR and RFLP analysis in 256 individuals, which included 156 active PTB patients and 100 age and sex, matched healthy volunteers with no clinical symptoms or family history of PTB as controls. RESULTS: A chi square test showed a significant difference between the PTB patient and controls for -762 C allele; p=0.0051 (OR 1.6972, CI 95% 1.1839 to 2.4332) and 1729 T allele was found to be positively associated with the PTB; p < 0.0005 (OR- 2.4623, CI 95% 1.6376 to 3.7022). 1513A/C polymorphism did not show any significant difference between the two groups. SIGNIFICANCE: The study revealed a significant association of P2X7-762C allele and P2X7 1729T allele receptor polymorphisms with PTB in Asian Indian population. The use of these alleles as biomarkers for identifying individuals at high risk of developing TB needs to be ascertained.
Subject(s)
Asian People/genetics , Polymorphism, Single Nucleotide , Receptors, Purinergic P2/genetics , Tuberculosis, Pulmonary/ethnology , Tuberculosis, Pulmonary/genetics , Adolescent , Adult , Case-Control Studies , Child , Female , Gene Frequency , Genetic Markers , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Mycobacterium tuberculosis , Receptors, Purinergic P2X7 , Risk Assessment , Tuberculosis, Pulmonary/microbiologyABSTRACT
BACKGROUND: Diabetic nephropathy (DN) is a devastating complication of diabetes, the exact molecular pathophysiology of which is not well established. Hyperglycemia increases insulin-like growth factors (IGFs), especially IGF2, which acts via the IGF1 receptor present on renal cells. Elevated glucose levels damage the kidney, which is repaired by modulators such as secreted protein acidic and rich in cysteine (SPARC). Hence, it was hypothesized that IGF2 and SPARC may have an important role in the etiology of DN. METHODS: Human renal biopsies, histopathologically categorized as normal, early Type 2 diabetes mellitus (T2DM), or established DN, were analyzed for the localization and expression of IGF2, its negative regulator phosphatase and tensin homolog on chromosome 10 (PTEN), and SPARC. RESULTS: Expression of IGF2, PTEN, and SPARC was increased in renal biopsies from T2DM patients compared with normal samples. Although IGF2 protein was increased in biopsies from DN patients, PTEN and SPARC levels were decreased. Real-time reverse transcription-polymerase chain reaction indicated that transcript levels of IGF2 and PTEN were greater than those of ß-actin in all human renal biopsy samples. CONCLUSION: The results suggest the following molecular etiopathophysiology of DN: (i) hyperglycemia upregulates IGF2, which initiates PTEN, a regulator of IGF2 signaling; (ii) loss of this IGF2-PTEN feedback loop causes changes that are characteristic of DN; and (iii) lowered expression of the repair modulator SPARC results in the development and/or progression of DN. Hence, targeting relevant modulators, such as like IGF2, PTEN, and SPARC, may be important in the management of DN.
