Identification of molecular heterogeneity in telomere maintenance pathway of aplastic anemia.

AIM: Aplastic anemia (AA) is a hematological disorder accompanying with hypocellular marrow and heterogenous characteristics of bi or pancytopenia. This study was undertaken to identify the genetic and epigenetic heterogeneity in telomere maintenance pathway in AA. MATERIALS AND METHODS: Peripheral blood samples were collected from idiopathic AA cases (n = 60) and age-matched healthy subjects (n = 43). To evaluate genetic factors, whole exome and targeted resequencing was performed among AA cases and age-matched healthy subjects. Differential gene expression of telomere maintenance pathway and evaluation of predicted miRNA, hsa-miR-1202 was assessed through SYBR green based quantitative real-time PCR. The results were then correlated with clinical parameters. RESULTS: Majority (95%) of AA cases exhibited significantly reduced average telomere length (p value < 0.001) compared to age-matched healthy subjects except 5% of AA cases. 25 genetic variations in 15 genes were observed exclusively among AA cases with shorter telomere, that may be associated with pathogenesis of Aplastic anemia. Specifically, a heterozygous deleterious variation in TMEM173 gene (NM_198282: exon7: c. G878A: p. R293Q, rs7380824) was found exclusively among cases with short telomere that might be used as a possible marker to identify the pathogenic scenarios of bone marrow. Positive correlation of upregulated hsa-miR-1202 was found to be associated with their target genes (RAPGEF5 and MANEA). Additionally, these altered genes and the miR1202 also have a significant negative correlation with platelet count. CONCLUSION: Estimation of average telomere length, genetic variation and gene expression pattern might indicate a novel diagnostic approach towards new treatment regimen of idiopathic AA cases with an emphasis on telomere maintenance pathway.