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Background: A 46-year-old Qatari female with a BMI of 25kg/m2 presented with hyperglycemia (blood glucose 13.5 mmol/l), hyperinsulinemia (21µU/mL) with elevated levels of HbA1c (10.3mmol/l). Biochemical investigations showed raised serum C-peptide (2.02ng/ml) and triglycerides (2.07mmol/L) and uric acid (104mg/dL), with normal BP. The objective of this case study is to validate this variant found through WGS in insulin receptor (INSR) gene that play a major cause of insulin resistant syndrome with different spectrums. Methods: Structural Variants discovered using custom multi-algorithm pipeline developed and optimized to run on HPC for short-read WGS data. In brief, 10 software packages applied (Breakdancer, Breakseq2, CNVnator, Delly, ERDS, Genomestrip, Manta, Speedseq, Svaba, WHAM), to existing short-read data. SVs annotated using AnnotSV and provides us functionally, regulatory and clinically relevant information. SVs analyzed based on their properties like pli-score, overlaps with known databases and OMIM annotations. This deletion was validated by ddPCR and the molecular docking performed by the autodock suit in order to understand the effect of deletion in the interaction between this receptor and insulin. Results: The patient was identified with 7.2k heterozygous deletion in exon 8 of INSR gene which play an essential role in the formation of extracellular alpha subunits in insulin receptor. molecular docking proved the decrease of catalytic activity of INSR and, hence signaling. Considering this and the phenotypic data from Qatar biobank, the patient developed features of type A insulin resistant syndrome as consequence of persistence hyperinsulinemia. The patient also exhibits severe Deterioration of glucose tolerant even with medication and unfortunately developed nephropathy. Conclusion: We highlighted the power of NGS in precise diagnosis and developing a potential and promising targeted therapeutics. Disclosure A.S. Akil: None. E.A.M. Yassin: None. S. Subash Padmajeya: None. L.A. Jerman: None. A. Fadda: None. W.H.O. Aamer: None. E.E. Aliyev: None. K. Fakhro: None.

A number of hyperglycemia- and dyslipidemia- triggered pathways, and numerous protein-encoding genes boosting the diabetic retinopathy (DR) progression. Evolving data suggests vast number of microRNAs(miRNAs) which exhibit no protein-coding capacity, are expressed and play key roles in DR pathogenesis. Purpose: of this pilot is to identify the miRNAs involved in pathways altered in lipid metabolism and dyslipidemia and to explore the association of dyslipidemia with the progression of DR. Methodology: 460 patients with diabetes type 2 (T2D) aged 23-77 years including 37 with DR and 490 matched healthy controls age range 18-74, from Qatar biobank cohort. The circulating miRNA profile was assessed in this pilot study. Logistic regression analysis was performed on the phenotypic data to investigate the level of association between A1C, low-density lipoproteins (LDL) and Triglycerides (TG) covariants and the miRNA expression profile in T2D with and without DR. Results: The most broadly characterized miRNAs in lipid metabolism are miR-33a/b; however, we identified another three miRNAs (miR-133b, miR-142-3p and miR-483-5p) shared between LDL and TG phenotypes. In particular, miR-133b appeared to be directly linked to retinal degeneration identified through our miRNA-target disease interaction network analysis. Our results indicated that all three miRNAs are significantly associated with VEGFR2 mediated vascular permeability, insulin signaling, apoptosis, EGFR, TGF-Beta signaling, cellular senescence and degradation pathways leading to the DR initiation than development. Conclusions: miRNAs are not only small regulators of lipid metabolism, but vital influencers in lipid homeostasis and lipoproteins formation and secretion. Dysregulation of these regulatory elements most likely augment the underlying metabolic flaws perceived in lipid disorders and related microvascular complications. Disclosure A. S. Akil: None. S. Subash padmajeya: None. L. A. Jerman: None. T. Habib: None. A. Al-kurbi: None. E. E. Aliyev: None. M. El anbari: None. K. Fakhro: None. Funding Qatar National Research Fund (NPRP9-229-3-041)

Background: In the light of growing global epidemic of T2D and related microvascular complications, it is important to find early detection marker for the disease. Circulating miRNAs serve as a potential biomarker for monitering the progression to DR in diabetic individuals. Hypothesis and Aims: miRNAs play a substantial role in metabolic homeostasis through regulation of multiple genes, and could serve as a prognostic biomarker in DR. This study aims to assess a functional role of selected miRNAs in the Qatari population recruited for the Qatar Genome Project through Qatar BioBank. Methods: Plasma samples from 470 T2D subjects with and without DR and 500 matched-healthy controls has been included in this study. Total RNA was extracted and the expression profiling of 56 miRNA that previously reported as a player in the pathogenesis of DR was performed using custom open array panel. The miRNA expression data were normalized using ath-mir159a. Statistical analysis was performed to study the association between the phenotypes (HbA1c, C-peptide, age, BMI) and miRNA. Results: The patients and controls phenotypic and miRNA expression data were analyzed to interepret the differential expression of the miRNA in DR subjects. Initial analysis by applying the generalized additive model reveals that six miRNA (hsa-miR-27a, hsa-miR-376c, hsa-miR-92a, hsa-miR-1 hsa-miR-223, and mmu-miR-451) were found to be significantly associated with DR (p>0.05). Furthermore, two differentially expressed miRNAs, (hsa-miR-1274A and hsa-miR-24) found to be associated with higher level of C-peptide in DR patients, which suggest the correlation of these miRNAs with the glucose hemostasis and DR. Conclusion: The etiology of DR is unclear, and present treatments have limited effectiveness. The biomarkers and downstream functional studies are required to deepen the understanding of this chronic diseases and its complications. Disclosure A.S. Akil: None. S. Subash Padmajeya: None. L.A. Jerman: None. A. Al-Kurbi: None. A.M. Hussein: None. A. Hardikar: None. M. Joglekar: None. T. Habib: None. M. El Anbari: None. K. Fakhro: None.

MicroRNAs (miRNAs/miRs) are implicated in the pathogenesis of type 2 diabetes (T2D) and its long-term complications such as retinopathy. miRNAs circulating levels have explored as possible biomarkers for the advancement of T2D. We examined the expression of customized set of miRNAs in T2D Qatari nationals with and without diabetic retinopathy (DR) from Qatar Biobank 1000 Qatar omics cohort. MiR-223 appeared to be significantly upregulated in T2D in comparison to the healthy controls. MiR-223 previously found to play a role in insulin resistant human adipose tissues, human and murine obesity and potential regulators of optic nerve regeneration. To further investigate the potential role of miR-223 in the development of DR, we established a zebrafish (ZF) model to functionally validate this potential correlation. Our aim is to investigate the miR-223 with hyperglycemia on the developing retina in the ZF as a vertebrate model. Mimic miR-223 was injected into single cell ZF embryos and incubated in normal and induced hyperglycemia conditions. We have examined the glucose ratios, eye morphology and vasculature structure in the developing model in comparison to the control groups. To understand the cellular mechanisms involved in DR; histological examination, cell apoptosis and proliferation have been performed and to be evaluated. miR-223 over expression resulted in an alteration of the glucose metabolism within the ZF model. Glucose ratio was significantly increased in ZF embryos injected with mimic miR-223. Increased miR-223 in the developing ZF larvae together with hyperglycemia affected the retinal development. The eye size was significantly reduced with degenerated vasculature and altered eye morphology. In conclusion, we have identified a novel correlation between DR development and miR-223. Targeting miR-223 in T2D patients may serve as promising therapeutic strategy to control DR in at risk T2D patients. Disclosure A. S. Akil: None. S. Da’as: None. L. A. Jerman: None. D. Abdelrahman: None. W. Hasan: None. K. Fakhro: None. Funding Qatar National Research Fund (NPRP9-229-3-041)