Person: EREN, FATİH
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EREN
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FATİH
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Publication Metadata only A Systems Genetics Approach to Dyslipidemia in Children and Adolescents(MARY ANN LIEBERT, INC, 2015) EREN, FATİH; White, Marquitta J.; Eren, Fatih; Agirbasli, Deniz; Chen, Jane; Hu, Ting; Moore, Jason H.; Williams, Scott M.; Agirbasli, MehmetElevated triglycerides (TG) or low high density lipoprotein cholesterol (HDL-C) levels are common cardiometabolic risk factors in children. From a systems genetics standpoint, Visualization of Statistical Epistasis Networks (ViSEN) is a nonparametric entropy-based method that can characterize the global structure of interacting genetic factors. We identified a novel set of connected genetic and cardiometabolic risk factors with strong and significant interaction effects on two important dyslipidemia phenotypes (low HDL-C and high TG) in children and adolescents. Study participants were recruited from five schools in Istanbul, Turkey (n=360; 170 boys, 190 girls). Participants with TG levels >= 75th and HDL-C levels <= 25th percentile were defined as 'high TG' and 'low HDL-C', respectively. We genotyped participants for six single nucleotide polymorphisms (SNPs) in five genes with known associations to lipid levels (rs328 in LPL, rs708272 in CETP, rs1800588 in LIPC, rs1800977 in ABCA1, rs1799941 and rs6257 in SHBG gene). ViSEN was used to identify associations with dyslipidemia phenotypes. There were 71 (50 males, 21 females) and 93 (60 males and 33 females) subjects with low HDL-C and high TG, respectively. Biological variables including age, gender, and BMI were significantly associated with both phenotypes (p<0.001). Importantly, a single SNP, rs708272, was associated with low HDL-C (IG=2.24%, p=0.026). Pairwise and higher order interaction analyses in the full dataset for low HDL-C and high TG revealed the largest effects in the models containing rs1800977, rs708272, age (IG=6.20%, p=0.046) and rs1800588, age, BMI (IG, 3.06%, p=0.022), respectively. In conclusion, the present study brings us a step closer to a systems genetic approach in understanding lipid phenotypes in children. Further efforts can integrate population and laboratory-based studies, hence accelerate the preventive medicine efforts.Publication Metadata only Serum osteopontin levels as a predictor of portal inflammation in patients with nonalcoholic fatty liver disease(ELSEVIER SCIENCE INC, 2013) EREN, FATİH; Yilmaz, Yusuf; Ozturk, Oguzhan; Alandab, Yesim Ozen; Senates, Ebubekir; Colak, Yasar; Doganay, Hamdi Levent; Coskunpinar, Ender; Oltulu, Yasemin Musteri; Eren, Fatih; Atug, Ozlen; Tuncer, Ilyas; Imeryuz, NeseBackground: Osteopontin is a secreted phosphorylated glycoprotein that is expressed by a variety of cell types and that mediates numerous and diverse biological functions. Osteopontin knockout mice are protected from obesity-induced hepatic steatosis. In the present study, we sought to investigate whether serum osteopontin concentrations are associated with liver histology in patients with nonalcoholic fatty liver disease. Methods: Serum levels of osteopontin were measured by enzyme-linked immunosorbent assay in 179 Well-characterized patients with nonalcoholic fatty liver referred for liver histology and 123 control subjects. Results: Serum osteopontin levels were markedly higher in patients with nonalcoholic fatty liver disease than in controls (p < 0.001). Multivariable analysis showed that osteopontin levels were strongly and independently associated with both portal inflammation (beta = 0.294, p < 0.01) and serum aminotransferase levels (aspartate aminotransferase: beta = 0.295, p < 0.01; alanine aminotransferase; beta = 0.285, p < 0.01). Conclusion: In summary, these data demonstrate that serum levels of osteopontin are elevated in nonalcoholic fatty liver disease and are a significant independent predictor of portal inflammation in this clinical entity. (C) 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.Publication Metadata only Potential clinical variants detected in mitochondrial DNA D-loop hypervariable region I of patients with non-alcoholic steatohepatitis(SPRINGER INTERNATIONAL PUBLISHING AG, 2019) EREN, FATİH; Hasturk, Burcu; Yilmaz, Yusuf; Eren, FatihPurpose Non-alcoholic steatohepatitis (NASH) is a mitochondrial disease. However, the underlying role of mitochondrial genetics has not yet been completely elucidated. Evaluation of D-loop nucleotide variations with respect to statistical significance and clinical data distribution. Methods Genomic DNAs were extracted from the peripheral blood samples of patients with biopsy-proven 150 NASH as well as from 150 healthy individuals to explore the functional D-loop region responsible for the replication and transcription of the mitochondrial genome. DNA sequencing by capillary electrophoresis analysis was performed for the D-loop region of mitochondrial DNA containing the hypervariable region I, and restriction fragment length polymorphism with MnlI analysis was performed for the m.16189 T/C D-loop variant. Results The m.A16318C variant was detected only in patients with NASH and approached significance level. Based on clinical data, six variants associated with histological subgroups of NASH and NASH-complicated diseases were identified. In patients with NASH, the m.16129 AA genotype was associated with advanced-stage fibrosis; the m.16249 CC genotype was associated with advanced lobular inflammation and advanced-stage histological steatosis; the m.16296 TT genotype was associated with hypothyroidism; the m.16163 GG and m.16294 TT genotypes were associated with metabolic syndrome; and the m.16256 TT+CT genotypes were associated with type II diabetes. In patients with NASH, microRNAs were estimated by targeting the significant variants identified in this study. Conclusion These findings suggest that NASH may be associated with D-loop nucleotide variations and that microRNA-based in vitro and/or in vivo studies may be developed by targeting the D-loop variants.Publication Metadata only Familial Mediterranean fever gene (MEFV) mutations and disease severity in systemic lupus erythematosus (SLE): implications for the role of the E148Q MEFV allele in inflammation(SAGE PUBLICATIONS LTD, 2015) ERZİK, CAN; Deniz, R.; Ozen, G.; Yilmaz-Oner, S.; Alibaz-Oner, F.; Erzik, C.; Aydin, S. Z.; Inanc, N.; Eren, F.; Bayalan, F.; Direskeneli, H.; Atagunduz, P.Objective Observed low prevalence of SLE among familial Mediterranean fever (FMF) patients in several large cohorts suggests a possible protective effect of the MEFV mutations from SLE. In contrast, SLE patient carriers for the common MEFV mutations had rather complex disease expression with an increased frequency of febrile episodes and pleurisy and a decreased renal complication rate. Our aim was to investigate the prevalence of MEFV gene mutations in patients with SLE and their effect on organ involvement in a well-defined group of biopsy-proven SLE nephritis patients. Material and method The prevalence of four MEFV gene mutations (M694V, M680I, V726A and E148Q) was investigated in 114 SLE patients and effect on disease severity was analyzed in patients with biopsy-proven SLE nephritis. Results None of the SLE patients fulfilled the revised Tel-Hashomer criteria. Fourteen of 114 SLE patients (12.2%) were found to carry at least one MEFV mutation. A single patient in the SLE-Nephritis group was compound heterozygous for M694V/M680I mutations and only one patient in the SLE-Mild group was homozygous for E148Q mutation. Carrier frequency was similar to controls in SLE patients (12.2 vs 18.8%, p=0.34). After the exclusion of the less penetrant E148Q mutation, re-analysis revealed an association between exon 10 mutations and SLE nephritis (p=0.050, odds ratio (OR)=4.16, 95% confidence interval (CI)=1.04-16.6). Carrier rate for the E148Q mutation decreased in the SLE group (controls vs. SLE=20/186 vs. 3/114, p=0.08) and E148Q mutation was absent in SLE nephritis (controls vs. SLE nephritis=20/186 vs. 0/47, p=0.016, OR=11.69, 95% CI=0.69-197.13). Conclusions Carrier rate for the studied MEFV mutations was slightly lower in the SLE group, which is in agreement with previous observations that FMF may confer some protection from SLE. Exon 10 mutations were associated with SLE nephritis after the exclusion of the E148Q mutation. The significance of the E148Q as a disease-causing mutation is controversial, and whether E148Q substitution is a polymorphism generally affecting inflammatory pathways is not addressed in the current literature. In this regard, absence of the E148Q mutation in SLE nephritis may serve as a clue for further investigation into its role as a general modulatory polymorphism for inflammation. This clarification is necessary to conclude whether other more penetrant MEFV gene mutations confer susceptibility to nephritis in SLE.Publication Metadata only Hepatic expression and serum levels of syndecan 1 (CD 138) in patients with nonalcoholic fatty liver disease(INFORMA HEALTHCARE, 2012) ÇELİKEL, ÇİĞDEM; Yilmaz, Yusuf; Eren, Fatih; Colak, Yasar; Senates, Ebubekir; Celikel, Cigdem Ataizi; Imeryuz, NeseBackground and aims. Syndecan-1 (CD 138) is a transmembrane heparan sulfate proteoglycan expressed in the liver which may exert metabolic effects by mediating the hepatic clearance of triglyceride-rich lipoproteins. In the present study, we assayed serum levels and the hepatic expression of syndecan-1 and examined their association with clinical, biochemical, and histologic phenotypes in patients with histology-proven nonalcoholic fatty liver disease (NAFLD). Methods. A total of 59 patients with biopsy-proven NAFLD and 54 matched controls were enrolled. The analysis of syndecan-1 expression in liver biopsies was performed by immunohistochemistry on formalin-fixed, paraffin-embedded samples. Serum syndecan-1 levels were measured by ELISA. Results. NAFLD patients had significantly higher serum syndecan-1 levels [median: 61 ng/mL (interquartile range: 36-97 ng/mL)] than controls [median: 37 ng/mL (interquartile range: 25-59 ng/mL, Mann Whitney U test, p < 0.001]. However, we did not find any significant association between serum syndecan-1 and the mean syndecan-1 immunohistochemical score (n = 59, r = 0.064, p = 0.63). Interestingly, the syndecan-1 immunohistochemical score was an independent predictor of HDL cholesterol in NAFLD patients (beta = 0.27; t = 1.99, p < 0.05). Conclusions. Our data suggest that serum syndecan-1 levels are raised in patients with NAFLD. Moreover, the syndecan-1 immunohistochemical score in the liver is independently associated with HDL cholesterol in this group of patients. These pilot results support further investigation of this molecule in metabolic liver diseases.Publication Metadata only Serum Levels of Adipokines in Patients with Chronic HCV Infection: Relationship with Steatosis and Fibrosis(ELSEVIER SCIENCE INC, 2009) ÇELİKEL, ÇİĞDEM; Tiftikci, Arzu; Atug, Ozlen; Yilmaz, Yusuf; Eren, Fatih; Ozdemir, Filiz Ture; Yapali, Suna; Ozdogan, Osman; Celikel, Cigdem Ataizi; Imeryuz, Nese; Tozun, NurdanBackground and Aims. Hepatic steatosis and fibrosis are common histological findings in patients with chronic hepatitis C virus (HCV) infection. In this study we sought to determine whether serum levels of three adipokines (leptin, adiponectin and resistin) show any biochemical correlation with hepatic steatosis and fibrosis in patients with chronic HCV infection. Methods. We examined a total of 51 patients with chronic HCV infection (22 males and 29 females, mean BMI: 27.4 +/- 5 kg/m(2)) and 24 healthy control subjects (10 males and 14 females, mean BMI: 23.2 +/- 3 kg/m(2)). Liver steatosis and fibrosis were scored on biopsies. Serum levels of leptin, adiponectin and resistin were determined by ELISA. Results. HCV genotypes were 1b in 41 patients (80.4%), 3a in three patients (5.9%), 2a in two patients (3.9%), 1 a in two patients (3.9%), 1 c in one patient (2%), and 2b in one patient (2%). Serum levels of leptin, resistin, and the leptin-to-adiponectin ratio were significantly higher in patients with chronic HCV infection than in controls. Steatosis and fibrosis were detected in 33.3% and 70.5% of chronic HCV patients, respectively. No significant association with serum adipokine levels and degree of steatosis was evident. Low serum levels of resistin were associated with the presence of fibrosis independently of potential confounders. Conclusions. Patients with chronic HCV infection display elevated levels of adipokines in their sera. Reduced concentrations of resistin may be a biochemical marker of fibrosis in this patient group. (C) 2009 IMSS. Published by Elsevier Inc.Publication Metadata only Serum galectin-3 levels in patients with nonalcoholic fatty liver disease(PERGAMON-ELSEVIER SCIENCE LTD, 2011) EREN, FATİH; Yilmaz, Yusuf; Eren, Fatih; Kurt, Ramazan; Yonal, Oya; Polat, Zulfikar; Senates, Ebubekir; Bacha, Mohammad; Imeryuz, NeseObjectives: Galectin-3 might serve as a biomarker of human metabolic alterations. We measured serum levels of galectin-3 in patients with nonalcoholic fatty liver disease (NAFLD) and examined their association with clinical and histological phenotypes. Design and methods: Serum levels of galectin-3 were assayed in 71 patients with biopsy-proven NAFLD and 39 controls. Results: Serum galectin-3 levels did not differ in patients with NAFLD (median 4.1 ng/mL; interquartile range: 1.5-5.5 ng/mL) compared with healthy controls (median 3.1 ng/mL; interquartile range: 0.8-7.5 ng/mL, P = 0.93). Among patients with NAFLD, however, serum galectin-3 levels correlated significantly with BMI (r = 0.267, P<0.05). This association persisted after adjustment for potential confounders (beta = 0.30; t = 2.11, P<0.05). Conclusions: Although galectin-3 was modestly associated with BMI, our results do not support the hypothesis that levels of this molecule are altered in patients with NAFLD. (C) 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.Publication Open Access Multi-Locus Candidate Gene Analyses of Lipid Levels in a Pediatric Turkish Cohort: Lessons Learned on LPL, CETP, LIPC, ABCA1, and SHBG(MARY ANN LIEBERT, INC, 2013-12) EREN, FATİH; Agirbasli, Mehmet; Eren, Fatih; Agirbasli, Deniz; White, Marquitta J.; Williams, Scott M.Cardiovascular risk factors and atherosclerosis precursors were examined in 365 Turkish children and adolescents. Study participants were recruited at five different state schools. We tested single and multi-locus effects of six polymorphisms from five candidate genes, chosen based on prior known association with lipid levels in adults, for association with low (10(th) percentile) high density lipoprotein cholesterol (HDL-C) and high (90(th) percentile) triglycerides (TG), and the related continuous outcomes. We observed an association between CETP variant rs708272 and low HDL-C (allelic p=0.020, genotypic p=0.046), which was supported by an independent analysis, PRAT (PRAT control p=0.027). Sex-stratified logistic regression analysis showed that the B2 allele of rs708272 decreased odds of being in the lower tenth percentile of HDL-C measurements (OR=0.36, p=0.02) in girls; this direction of effect was also seen in boys but was not significant (OR=0.64, p=0.21). Logistic regression analysis also revealed that the T allele of rs6257 (SHBG) decreased odds of being in the top tenth percentile of TG measurements in boys (OR=0.43, p=0.03). Analysis of lipid levels as a continuous trait revealed a significant association between rs708272 (CETP) and LDL-C levels in males (p=0.02) with the B2B2 genotype group having the lowest mean LDL-C; the same direction of effect was also seen in females (p=0.05). An effect was also seen between rs708272 and HDL-C levels in girls (p=0.01), with the B2B2 genotype having the highest mean HDL-C levels. Multi-locus analysis, using quantitative multifactor dimensionality reduction (qMDR) identified the previously mentioned CETP variant as the best single locus model, and overall model, for predicting HDL-C levels in children. This study provides evidence for association between CETP and low HDL-C phenotype in children, but the results appear to be weaker in children than previous results in adults and may also be subject to gender effects.