Person: PİRİM, DİLEK
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PİRİM
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DİLEK
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Publication Apolipoprotein E-C1-C4-C2 gene cluster region and inter-individual variation in plasma lipoprotein levels: A comprehensive genetic association study in two ethnic groups(Public Library Science, 2019-03-26) Pirim, Dilek; Radwan, Zaheda H.; Wang, Xingbin; Niemsiri, Vipavee; Hokanson, John E.; Hamman, Richard F.; Feingold, Eleanor; Bunker, Clareann H.; Demirci, F. Yesim; Kamboh, M. Ilyas; PİRİM, DİLEK; Bursa Uludağ Üniversitesi/Edebiyat Fakültesi/Moleküler Biyoloji ve Genetik Bölümü; 0000-0002-0522-9432; ABA-4957-2020; HTP-6233-2023The apolipoprotein E-C1-C4-C2 gene cluster at 19q13.32 encodes four amphipathic apolipo proteins. The influence of APOE common polymorphisms on plasma lipid/lipoprotein profile, especially on LDL-related traits, is well recognized; however, little is known about the role of other genes/variants in this gene cluster. In this study, we evaluated the role of common and uncommon/rare genetic variation in this gene region on inter-individual variation in plasma lipoprotein levels in non-Hispanic Whites (NHWs) and African blacks (ABs). In the variant discovery step, the APOE, APOC1, APOC4, APOC2 genes were sequenced along with their flanking and hepatic control regions (HCR1 and HCR2) in 190 subjects with extreme HDL-C/TG levels. The next step involved the genotyping of 623 NHWs and 788 ABs for the identified uncommon/rare variants and common tagSNPs along with additional relevant SNPs selected from public resources, followed by association analyses with lipid traits. A total of 230 sequence variants, including 15 indels were identified, of which 65 were novel. A total of 70 QC-passed variants in NHWs and 108 QC-passed variants in ABs were included in the final association analyses. Single-site association analysis of SNPs with MAF>1% revealed 20 variants in NHWs and 24 variants in ABs showing evidence of association with at least one lipid trait, including several variants exhibiting independent associations from the established APOE polymorphism even after multiple-testing correction. Overall, our study has confirmed known associations and also identified novel associations in this genomic region with various lipid traits. Our data also support the contribution of both common and uncommon/rare variation in this gene region in affecting plasma lipid profile in the general population.Publication Association study of coronary artery disease-associated genome-wide significant SNPS with coronary stenosis in Pakistani population(Hindawi, 2020-01-23) Cheema, Asma Naseer; Pirim, Dilek; Wang, Xingbin; Ali, Jabar; Bhatti, Attya; John, Peter; Feingold, Eleanor; Demirci, F. Yeşim; Kamboh, M. Ilyas; PİRİM, DİLEK; Bursa Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Moleküler Biyoloji ve Genetik Bölümü.; 0000-0002-0522-9432; ABA-4957-2020Genome-wide association studies (GWAS) of coronary artery disease (CAD) have revealed multiple genetic risk loci. We assessed the association of 47 genome-wide significant single-nucleotide polymorphisms (SNPs) at 43 CAD loci with coronary stenosis in a Pakistani sample comprising 663 clinically ascertained and angiographically confirmed cases. Genotypes were determined using the iPLEX Gold technology. All statistical analyses were performed using R software. Linkage disequilibrium (LD) between significant SNPs was determined using SNAP web portal, and functional annotation of SNPs was performed using the RegulomeDB and Genotype-Tissue Expression (GTEx) databases. Genotyping comparison was made between cases with severe stenosis (>= 70%) and mild/minimal stenosis (<30%). Five SNPs demonstrated significant associations: three with additive genetic modelsPLG/rs4252120 (p=0.0078),KIAA1462/rs2505083 (p=0.005), andSLC22A3/rs2048327 (p=0.045) and two with recessive modelsSORT1/rs602633 (p=0.005) andUBE2Z/rs46522 (p=0.03).PLG/rs4252120 was in LD with two functionalPLGvariants (rs4252126 and rs4252135), each with a RegulomeDB score of 1f. Likewise,KIAA1462/rs2505083 was in LD with a functional SNP,KIAA1462/rs3739998, having a RegulomeDB score of 2b. In the GTEx database,KIAA1462/rs2505083,SLC22A3/rs2048327,SORT1/rs602633, andUBE2Z/rs46522 SNPs were found to be expression quantitative trait loci (eQTLs) in CAD-associated tissues. In conclusion, five genome-wide significant SNPs previously reported in European GWAS were replicated in the Pakistani sample. Further association studies on larger non-European populations are needed to understand the worldwide genetic architecture of CAD.Publication In silico identification of putative roles of food-derived xeno-mirs on diet-associated cancer(Routledge Journals, Taylor & Francis Ltd, 2019-10-01) Pirim, Dilek; Doğan, Berkcan; Pirim, Dilek; PİRİM, DİLEK; Bursa Uludağ Üniversitesi/Tıp Fakültesi; 0000-0002-0522-9432; ABA-4957-2020; HTP-6233-2023Aim: Dietary miRNAs in foods were recently suggested to be absorbed into the human circulation and engage in human gene regulation. This started a debate on their possible impacts on human diseases which need further investigation. In this study, we aimed to identify the putative functions and possible implications of selected Xeno-miRs in human diseases by using bioinformatic tools. Methods: Seventy-five human absorbable Xeno-miR candidates were selected from literature and narrowed down the list to miRNAs that share sequence homologies with human miRNAs. Sixteen distinct Xeno-miRs of animal species (cow, pig, chicken) were identified to have homologs in human and they were subsequently analyzed with target prediction, functional and pathway analysis tools. Results and Conclusion: Thirteen human genes were common targets of the miRNA sets grouped by species and shown evidence of associations with various cancer categories, specifically in large intestine adenocarcinoma by Ingenuity Pathway Analysis. miRNA functional enrichment analyses also highlighted the putative involvements of the dietary miRNAs in cancer pathways. Our effort provides ?in silico? evidence for implications of animal-derived dietary miRNAs in cancer-associated pathways, and this shed on light the necessities of future translational research design to investigate the roles of dietary Xeno-miRs in cancer pathophysiology and nutrition-based interventions towards cancer management.Publication Hepatic lipase (LIPC) sequencing in individuals with extremely high and low high-density lipoprotein cholesterol levels(Public Library Science, 2020-12-16) Bunker, Clareann H.; Hokanson, John E.; Hamman, Richard F.; Demirci, F. Yesim; Kamboh, M. Ilyas; Pirim, Dilek; PİRİM, DİLEK; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Moleküler Biyoloji ve Genetik.; 0000-0002-0522-9432; ABA-4957-2020; HTP-6233-2023Common variants in the hepatic lipase (LIPC) gene have been shown to be associated with plasma lipid levels; however, the distribution and functional features of rare and regulatory LIPC variants contributing to the extreme lipid phenotypes are not well known. This study was aimed to catalogue LIPC variants by resequencing the entire LIPC gene in 95 non-Hispanic Whites (NHWs) and 95 African blacks (ABs) with extreme HDL-C levels followed by in silico functional analyses. A total of 412 variants, including 43 novel variants were identified; 56 were unique to NHWs and 234 were unique to ABs. Seventy-eight variants in NHWs and 89 variants in ABs were present either in high HDL-C group or low HDL-C group. Two non-synonymous variants (p.S289F, p.T405M), found in NHWs with high HDL-C group were predicted to have damaging effect on LIPC protein by SIFT, MT2 and PP2. We also found several non-coding variants that possibly reside in the circRNA and lncRNA binding sites and may have regulatory potential, as identified in rSNPbase and RegulomeDB databases. Our results shed light on the regulatory nature of rare and non-coding LIPC variants as well as suggest their important contributions in affecting the extreme HDL-C phenotypes.Publication Hsa-miR-584-5p as a novel candidate biomarker in Turkish men with severe coronary artery disease(Springer, 2019-12-21) Çoban, Neslihan; Pirim, Dilek; Erkan, Ayçan Fahri; Doğan, Berkcan; Ekici, Berkay; PİRİM, DİLEK; DOĞAN, BERKCAN; Bursa Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Moleküler Biyoloji ve Genetik Bölümü; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Genetik Anabilim Dalı; 0000-0002-0522-9432; 0000-0001-8061-8131; HTP-6233-2023; AAD-5249-2020; ABA-4957-2020Coronary artery disease (CAD) is still the preliminary cause of mortality and morbidity in the developed world. Identification of novel predictive and therapeutic biomarkers is crucial for accurate diagnosis, prognosis and treatment of the CAD. The aim of this study was to detect novel candidate miRNA biomarker that may be used in the management of CAD. We performed miRNA profiling in whole blood samples of angiographically confirmed Turkish men with CAD and non-CAD controls with insignificant coronary stenosis. Validation of microarray results was performed by qRT-PCR in a larger cohort of 62 samples. We subsequently assessed the diagnostic value of the miRNA and correlations of miRNA with clinical parameters. miRNA-target identification and network analyses were conducted by Ingenuity Pathway Analysis (IPA) software. Hsa-miR-584-5p was one of the top significantly dysregulated miRNA observed in miRNA microarray. Men-specific down-regulation (p = 0.040) of hsa-miR-584-5p was confirmed by qRT-PCR. ROC curve analysis highlighted the potential diagnostic value of hsa-miR-584-5p with a power area under the curve (AUC) of 0.714 and 0.643 in men and in total sample, respectively. The expression levels of hsa-miR-584-5p showed inverse correlation with stenosis and Gensini scores. IPA revealed CDH13 as the only CAD related predicted target for the miRNA with biological evidence of its involvement in CAD. This study suggests that hsa-miR-584-5p, known to be tumor suppressor miRNA, as a candidate biomarker for CAD and highlighted its putative role in the CAD pathogenesis. The validation of results in larger samples incorporating functional studies warrant further research.Publication A novel mirsnp at the IGF1 3′utr may modulate the mirna-mediated gene expression in cardiovascular disease(Elsevier, 2018-08-01) Pirim, Dilek; Çoban, Neslihan; Erkan, Ayça Fahri; Ekici, Berkay; Erginel-Unaltuna, Nihan; Diker, İrem Yağmur; Özuynuk, Aybike Sena; PİRİM, DİLEK; Çoban, Neslihan; Erkan, Ayça Fahri; Ekici, Berkay; Erginel-Unaltuna, Nihan; Diker, İrem Yağmur; Özuynuk, Aybike Sena; Bursa Uludağ Üniversitesi; 0000-0002-0522-9432; 0000-0002-9469-7149; 0000-0002-1681-9622; ABA-4957-2020; AAN-5880-2021; HTP-6233-2023; AAB-8792-2020; A-4885-2018; GXV-9750-2022; AAB-8766-2020; ETX-5416-2022