👤 Khalid K Alharbi

Acute myeloid leukemia (AML) is a complex hematologic malignancy with multiple disease subgroups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here, we perform a meta-analysis of 4 published GWAS plus 2 new GWAS, totaling 4710 AML cases and 12 938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P = 1.35 × 10-8; EFR3B, POMC, DNMT3A, and DNAJC27), which also significantly associates with patient survival (P = 6.09 × 10-3). Our analysis also identifies 3 new genome-wide significant risk loci for disease subgroups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P = 7.0 × 10-10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P = 3.28 × 10-8; PARD3B) and 2p21 (rs79918355; P = 1.60 × 10-9; EPCAM). We also investigated loci previously associated with the risk of clonal hematopoiesis (CH) or CH of indeterminate potential and identified several variants associated with the risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease subgroup specific risk loci. Show less

Among various epithelial-to-mesenchymal transition (EMT)-related transcription factors (TFs), altered expression levels of Snail-1, Snail-2/Slug, Twist, and ZEB1 have shown a significant association in different cancers having a higher risk of metastasis. However, their role in the circulation of endometriosis patients is not well understood. Hence, the present study was designed to evaluate the crucial role of these TFs in defining the molecular pathogenesis for endometriosis progression and differentiation from control subjects. The qualitative and quantitative expression analysis of Snail-1, Snail-2/Slug, Twist, and ZEB1 were analyzed in peripheral blood samples of 75 different stages of endometriosis patients and compared with 50 control subjects. Total RNA was extracted and converted into complementary DNA (cDNA) for relative quantification of each gene transcript using SYBRGreen-based reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). The Livak method of relative quantification was used for calculating the fold change in each TF compared with endogenous control. All four selected TFs showed significantly upregulated expression levels in endometriosis patients compared with control subjects. A three-fold increase was observed for Snail-1 (p = 0.0001), and a two-fold increase was observed for Snail-2 (p = 0.01), Twist (p = 0.0002), and ZEB1 (p = 0.001) in stage III and IV compared with stage I and II of endometriosis patients. The present study revealed that EMT-related TFs play a crucial role in the pathogenesis and differentiating different stages of endometriosis patients through expression analysis of specific molecular cascades using non-invasive tools. Show less

Colorectal cancer is a major health concern as it ranks third in incidence and second major cause of cancer-related deaths worldwide. A leading cause of treatment failure has been attributed to cancer stem cells that can invariably resist existing chemotherapeutic regimens. Notch signaling pathway has been involved in the maintenance of stem cells besides being crucial in cell fate decision and embryonic development. This pathway has also been implicated in several human malignancies including colorectal cancer. We investigated mRNA expression of four Notch receptors (Notch1-4), five ligands (Jag1, Jag2, Dll1, Dll3, and Dll4), and four target genes (Hes1, Hes5, Hey1, and Hey2) using highly specific TaqMan gene expression assays in colorectal adenomas and cancers. Upregulated expression of Notch receptors ranged between 29 and 73% in colorectal cancers and between 11 and 56% in adenomas. Expression of Notch3 and Notch4 receptors was significantly higher in colorectal cancers compared to normal and adenoma tissues. The Jagged and Delta-like ligands were overexpressed between 25 and 52% in colorectal cancers, while in adenomas, it ranged between 0 and 33%. Combining the data for upregulation of receptors and ligands suggests that 86% colorectal cancers and 56% adenomas exhibited overexpression of Notch pathway genes in our cohort. Notch target genes were upregulated between 24 and 33% in colorectal cancers and between 11 and 22% in adenomas. Collating upregulation of Notch receptors and ligands with the target genes showed concordance in 58% colorectal tumors. Additionally, we evaluated expression of Notch receptors, ligands, and target genes with prognosis using the TCGA mRNA expression dataset. Patients overexpressing Notch3, Notch4, and Hey1 had significantly poorer overall survival relative to those having lower levels of these genes. Taken together, Notch signaling components are aberrantly overexpressed in colorectal tumors, and development of therapeutics targeting the Notch pathway may prove to be beneficial in the management of colorectal cancers. Show less

Apolipoprotein C3 (ApoC3) is a major constituent of VLDL and is a modulator of triglyceride metabolism. Recent genetic studies have implicated several ApoC3 gene polymorphisms in the development of insulin resistance and type 2 diabetes mellitus (T2DM). Considering the high prevalence of T2DM in Saudi Arabia, we sought to examine the possible association of ApoC3 gene variants with diabetes risk in Saudi population. The 3238C>G and -482C>T polymorphisms of ApoC3 gene were studied in 268 T2DM patients and 255 healthy controls by TaqMan probe based real time polymerase chain reaction assays. Diabetic patients displayed significantly increased systolic blood pressure, fasting plasma glucose, insulin resistance, and dyslipidemia compared to control. Patients also had markedly elevated plasma VLDL levels. Genotype distribution of 3238C>G polymorphism was significantly different between patients and control. Consistently, this variant was found to be significantly associated with T2DM risk. Contrastingly, no significant relationship was found between -482C>T polymorphism and T2DM risk. Association of disease risk with 3238C>G polymorphism remained significant even after accounting for the established risk factors. Genotype-based stratification revealed a significant correlation of GG genotype of 3238C>G with elevated plasma triglycerides, insulin resistance, and VLDL, whereas the TT genotype of -482C>T correlated with elevated triglyceride and VLDL levels. Thus, 3238C>G polymorphism of ApoC3 gene appears to augment the propensity to develop T2DM, while -482C>T to negatively affect lipid metabolism in Saudi subjects. Show less