Executive Summary : | Type 2 Diabetes (T2D) is an inflating global health concern and a major cause of diabetes-related deaths worldwide. As per IDF data, India will see a dramatic rise (~134.3 million) in T2D individuals by 2045. The relative risk of developing T2D in first-degree relatives is 3 to 6 times higher if both parents are affected. To date, ~144 genetic variants found to be associated with T2D. These genes and variants explain ~20% of the heritability (attributed to the genetic factors mainly involved in the insulin pathways) of the T2D regardless of all the advancement and successive identification methodology. Therefore, the need to explore other signaling pathways and genetic factors that contribute to the pathogenesis of T2D is a prerequisite. An important factor recently found to be associated with T2D is Somatomedin B and Thrombospondin Type 1 Domain Containing (SBSPON) gene.
SBSPON (8q21.11) of the thrombospondin (TSP) family, comprised of 61,012 bases, encodes a 264 amino acids protein, believed to play a very important role in the metabolism and O-glycosylation pathways. mRNA expression in normal human tissues from the GTEx and cbio portal data exhibit the gene expression in several tissues (whole blood, brain, heart, skeletal muscle, adipocyte, kidney, pancreas). The data suggested its secretory role and the protein expression in the exocrine pancreatic glandular cells. Any mutation in the gene or abnormal protein function can lead to pancreatitis and diabetes.
A number of transcription factor binding sites are observed in the gene region which is linked to T2D like TCF7L2 (robustly associated with T2D worldwide), SPI1(insulin resistance, highly expressed in adipocytes), JUND factor (upregulated in the human islets which are exposed to the metabolic stress), TFAP2C (involved in the protein metabolism, transcriptional regulation). The variants (rs2291219 & rs2291220), linked with the Telomere Repeat Binding Factor 1 (TERF1) however, are located in the SBSPON gene exon (4 & 5) are associated with T2D and telomere length attrition. Therefore, it is not specified how the gene is playing role in T2D etiology, and might be possible that it is involved in telomere length regulation further needs experimental validation. The GTEx data revealed that rs2291219 & rs2291220 significantly down-regulates the SBSPON gene expression in pancreas (p-value = 1.9E-6) & skeletal muscle (p-value = 0.02) respectively.
To date, no perspective data is available on the SBSPON gene. However, it can be anticipated that gene plays an important role in physiological pathways. The study aims to determine the role of this gene in T2D etiology by using knockdown, Co-IP, gene expression, and sequencing approaches. Screening of the Indian population for the genetic variations in the gene in association with T2D will provide more insight into the pathophysiology of the disease. Further, the study will offer new pathways to explore for therapeutic purposes and personalized medicine. |