The Relationship between Extracellular Volume Compartments and Matrix Metalloproteinases-2 in Left Ventricular Remodeling after Myocardial Infarction. / A Relação entre Compartimentos de Volume Extracelular e Matriz Metaloproteinase 2 na Remodelação do Ventrículo Esquerdo após o Infarto do Miocárdio.

BACKGROUND: Matrix metalloproteinases (MMPs) can affect myocardial extracellular volume (ECV) and its compartments, and this can provide more detailed information about the mechanism of adverse left ventricular (LV) remodeling (AR) after acute myocardial infarction (MI). OBJECTIVES: To investigate the role of changes (Δ) in ECV compartments (matrix volume (MVi) and cell volume (CVi)) in the development of AR after MI, and their relationship with MMP-2 expressions. METHODS: Ninety-two first MI patients who underwent 3 Tesla cardiovascular magnetic resonance imaging performed 2 weeks (baseline) and 6 months post-MI. We measured T1 mapping with MOLLI sequences. ECV was performed post-gadolinium enhancement. ECV and LV mass were used to calculate MVi and CVi. AR was defined as an increase of ≥ 12% in LV end-diastolic volume in 6 months. MMPs were measured using a bead-based multiplex immunoassay system at first day (baseline) and 2 weeks post-MI. P <0.05 was accepted as statistically significant. RESULTS: Mean ECV and mean MVi baseline levels were higher in AR group compared to without AR group (42.9±6.4 vs 39.3±8.2%, p= 0.037; 65.2±13.7 vs 56.7±14.7 mL/m2, p=0.010; respectively). CVi levels was similar between groups. A positive correlation was found between baseline levels of MMP-2 and baseline levels of ECV (r=0.535, p<0.001) and MVi (r=0.549, p<0.001). Increased ΔMVi levels was independently predictor of AR (OR=1.03, p=0.010). ΔMVi had superior diagnostic performance compared to ΔECV in predicting AR (ΔAUC: 0.215±0.07, p<0.001). CONCLUSION: High MVi levels are associated with AR, and ΔMVi was independently predictor of AR. This may be associated with MMP-2 release due to increased inflammatory response.

FUNDAMENTO: As matrizes metaloproteinases (MMPs) podem afetar o volume extracelular (VEC) e seus compartimentos, e isso pode oferecer informações mais detalhadas sobre o mecanismo de remodelação adversa (RA) do ventrículo esquerdo (VE) após o infarto agudo do miocárdio (IM). OBJETIVOS: Investigar o papel que as alterações (Δ) nos compartimentos de VEC (volume matriz (MVi) e volume celular (CVi)) desempenham no desenvolvimento de RA após o IM, e sua relação com as expressões de MMP-2. MÉTODOS: Um total de noventa e dois pacientes com primeiro IM passaram por exames de imagens por ressonância magnética cardiovascular 3 Tesla realizados 2 semanas (linha de base) e 6 meses após o IM. Medimos o mapeamento T1 com sequências MOLLI. O VEC foi obtido após o realce pelo gadolínio. O VEC e a massa do VE foram usados para calcular o MVi e o CVi. A RA foi definida como um aumento de ≥ 12% no volume diastólico final do VE em 6 meses. As MMPs foram medidas usando-se um sistema de imunoensaio multiplex em grânulos no primeiro dia (linha de base) e 2 semanas após o IM. Um P valor <0,05 foi aceito como estatisticamente significativo. RESULTADOS: Os níveis de linha de base de MVi média e VEC médio foram mais altos no grupo com RA em comparação com o grupo sem RA (42,9±6,4 vs. 39,3±8,2 %, p= 0,037; 65,2±13,7 vs. 56,7±14,7 mL/m2, p=0,010; respectivamente). Os níveis de CVi eram semelhantes entre os grupos. Foi encontrada uma correlação positiva entre os níveis de linha de base de MMP-2 e os níveis de linha de base de VEC (r=0,535, p<0,001) e MVi (r=0,549, p<0,001). O aumento dos níveis de ΔMVi foi um preditor independente da RA (RC=1,03, p=0,010). O ΔMVi teve um desempenho diagnóstico superior quando comparado ao ΔVEC na previsão do (ΔAUC: 0,215±0,07, p<0,001). CONCLUSÃO: Níveis altos de MVi estão associados à RA, e o ΔMVi foi um preditor independente de RA. Isso pode estar associado à liberação de MMP-2 devido ao aumento da resposta inflamatória.

A Relação entre Compartimentos de Volume Extracelular e Matriz Metaloproteinase 2 na Remodelação do Ventrículo Esquerdo após o Infarto do Miocárdio / The Relationship between Extracellular Volume Compartments and Matrix Metalloproteinases-2 in Left Ventricular Remodeling after Myocardial Infarction

Resumo Fundamento: As matrizes metaloproteinases (MMPs) podem afetar o volume extracelular (VEC) e seus compartimentos, e isso pode oferecer informações mais detalhadas sobre o mecanismo de remodelação adversa (RA) do ventrículo esquerdo (VE) após o infarto agudo do miocárdio (IM). Objetivos: Investigar o papel que as alterações (Δ) nos compartimentos de VEC (volume matriz (MVi) e volume celular (CVi)) desempenham no desenvolvimento de RA após o IM, e sua relação com as expressões de MMP-2. Métodos: Um total de noventa e dois pacientes com primeiro IM passaram por exames de imagens por ressonância magnética cardiovascular 3 Tesla realizados 2 semanas (linha de base) e 6 meses após o IM. Medimos o mapeamento T1 com sequências MOLLI. O VEC foi obtido após o realce pelo gadolínio. O VEC e a massa do VE foram usados para calcular o MVi e o CVi. A RA foi definida como um aumento de ≥ 12% no volume diastólico final do VE em 6 meses. As MMPs foram medidas usando-se um sistema de imunoensaio multiplex em grânulos no primeiro dia (linha de base) e 2 semanas após o IM. Um P valor <0,05 foi aceito como estatisticamente significativo. Resultados: Os níveis de linha de base de MVi média e VEC médio foram mais altos no grupo com RA em comparação com o grupo sem RA (42,9±6,4 vs. 39,3±8,2 %, p= 0,037; 65,2±13,7 vs. 56,7±14,7 mL/m2, p=0,010; respectivamente). Os níveis de CVi eram semelhantes entre os grupos. Foi encontrada uma correlação positiva entre os níveis de linha de base de MMP-2 e os níveis de linha de base de VEC (r=0,535, p<0,001) e MVi (r=0,549, p<0,001). O aumento dos níveis de ΔMVi foi um preditor independente da RA (RC=1,03, p=0,010). O ΔMVi teve um desempenho diagnóstico superior quando comparado ao ΔVEC na previsão do (ΔAUC: 0,215±0,07, p<0,001). Conclusão: Níveis altos de MVi estão associados à RA, e o ΔMVi foi um preditor independente de RA. Isso pode estar associado à liberação de MMP-2 devido ao aumento da resposta inflamatória.

Abstract Background: Matrix metalloproteinases (MMPs) can affect myocardial extracellular volume (ECV) and its compartments, and this can provide more detailed information about the mechanism of adverse left ventricular (LV) remodeling (AR) after acute myocardial infarction (MI). Objectives: To investigate the role of changes (Δ) in ECV compartments (matrix volume (MVi) and cell volume (CVi)) in the development of AR after MI, and their relationship with MMP-2 expressions. Methods: Ninety-two first MI patients who underwent 3 Tesla cardiovascular magnetic resonance imaging performed 2 weeks (baseline) and 6 months post-MI. We measured T1 mapping with MOLLI sequences. ECV was performed post-gadolinium enhancement. ECV and LV mass were used to calculate MVi and CVi. AR was defined as an increase of ≥ 12% in LV end-diastolic volume in 6 months. MMPs were measured using a bead-based multiplex immunoassay system at first day (baseline) and 2 weeks post-MI. P <0.05 was accepted as statistically significant. Results: Mean ECV and mean MVi baseline levels were higher in AR group compared to without AR group (42.9±6.4 vs 39.3±8.2%, p= 0.037; 65.2±13.7 vs 56.7±14.7 mL/m2, p=0.010; respectively). CVi levels was similar between groups. A positive correlation was found between baseline levels of MMP-2 and baseline levels of ECV (r=0.535, p<0.001) and MVi (r=0.549, p<0.001). Increased ΔMVi levels was independently predictor of AR (OR=1.03, p=0.010). ΔMVi had superior diagnostic performance compared to ΔECV in predicting AR (ΔAUC: 0.215±0.07, p<0.001). Conclusion: High MVi levels are associated with AR, and ΔMVi was independently predictor of AR. This may be associated with MMP-2 release due to increased inflammatory response.

Low sCD163/TWEAK Ratio at First Day After Acute Myocardial Infarction Associated with Adverse Cardiac Remodeling in Non-Elderly Patients.

Aim    In this study, we aimed to investigate the role of sCD163 / tumor necrosis factor-like weak apoptosis-inducing (TWEAK) ratio in cardiac remodeling in non-elderly patients diagnosed with first acute myocardial infarction (MI).Material and Methods    Forty-four patients (age ranges: 40-64 years) diagnosed with first-time acute ST-elevation MI in the emergency department were evaluated with cardiac magnetic resonance (CMR) imaging. Adverse remodeling (AR) was defined the increases of left ventricular end-diastolic volume by ≥12 % by CMR at 6­month post-MI TWEAK and sCD163 were measured at the first day (baseline), 2 weeks and 6 weeks post-MI.Results    The average age of patients included in the study was 53.6±5.1 years. AR was detected in 18 patients at the 6 months post-MI. At the first day post-MI, median sCD163 concentration (116 069 vs 86 394 pg / mL, p=0.040) and median TWEAK concentration (759.4 vs 220.1 pg / mL, p<0.001) were higher in AR group compared to group without AR (the non-AR group), median sCD163 / TWEAK ratio (101.4 vs. 406.8; p<0.001) was lower. At the first day post-MI, concentrations of TWEAK and sCD163 showed a positive correlation in AR group and group without AR s. At 2 weeks post-MI, positive correlation continued in the non-AR group, but no significant correlation was found in the AR group. At the first day post-MI, sCD163 / TWEAK ratio was higher diagnostic performance compared to TWEAK and sCD163.Conclusion    In the early phase post-MI, the relationship between sCD163 - TWEAK may have an important role in AR pathogenesis. A lower sCD163 / TWEAK ratio on the first day after MI was associated with an increase in left ventricular end-diastolic volume after 6 months of follow-up.

De novo interstitial deletion of 11q14.3q22 in a boy with mild intellectual disability and short stature.

BACKGROUND: Interstitial deletions of the 11q region are infrequent. Nonrecurrent chromosomal rearrangements are observed with high variability in size and precise breakpoints of the deleted area. Moreover heterogeneous clinical findings are observed in those harboring 11q interstitial deletions. Main clinical features associated with these deletions include mild dysmorphic findings intellectual disability and moderate developmental or speech delay . METHOD: Conventional high-resolution karyotyping along with microarray studies were performed for the index patient who was found to be a carrier of a de novo interstitial deletion in the long arm of chromosome 11 which is located between the 11q14 and 11q22 band regions. We also investigated the homologous chromosome with next-generation sequencing technology to search for unmasked recessive variants in genes on the nondeleted contralateral allele. RESULTS: Cytogenetic analysis revealed a de novo interstitial deletion on the long arm of chromosome 11 46 XY del(11) (q14q22). Microarray analysis confirmed the deletion of 11.2 Mb in length mapping from 11q14.3 to 11q22.2 [arr (GRCh37) 11q14.3q22.1(90549863_101833022)x1 dn]. Whole-exome sequencing did not detect any other genetic variant (single nucleotide variant ) on the nondeleted allele. CONCLUSION: This study gave us the opportunity for an attempt to define the smallest region of overlap for frequently observed clinical findings by reviewing the literature.

The Role of Interferons in Cardiac Remodeling after Acute Myocardial Infarction.

OBJECTIVE: To determine the relationship of serial interferon (IFN) measurements and adverse cardiac remodeling (AR) after myocardial infarction (MI). STUDY DESIGN: Observational multi-centre study. PLACE AND DURATION OF STUDY: Departments of Cardiology of Diskapi Yildirim Beyazit Training and Research Hospital, Ataturk Training and Research Hospital, Numune Training and Research Hospital, and Dr. Nafiz Sincan Korez State Hospital, Turkey, from June 2015 to June 2020. METHODOLOGY: Forty-seven patients with acute MI were included. IFN levels were measured on the first day and at 14 days and 45 days post-MI. Reverse cardiac remodeling (RR) and AR were defined as the reduction of left ventricular end-diastolic volume by ≥12% and increases of ≥12% by cardiac magnetic resonance imaging at the 6-month follow-up. Statistical significance was accepted as p<0.05. RESULTS: Median IFN-α (50.1 vs. 34.8 pg/mL, p=0.035), IFN-ß (39.1 vs. 23.0 pg/mL, p=0.013), and IFN-γ (26.7 vs. 18.5 pg/mL, p=0.023) levels on the first day post-MI were higher in the AR group compared to the RR group. At 14 days post-MI, IFN levels had decreased in the AR group, while they had not changed in the RR group. At 45 days post-MI, IFN levels were similar between the AR and RR groups. High IFN-α level on the first-day post-MI was an independent predictor of AR (OR: 1.23, 95% CI: 1.06-1.43, p=0.008). CONCLUSION: High IFN levels in the acute phase post-MI are associated with AR. Among IFNs, IFN-α is an important predictor of AR. Stable IFN levels appear to be associated with cardiac healing. KEY WORDS: Cardiac remodeling, Interferons, Inflammation, Myocardial infarction.

Determination of microRNAs associated with adverse left ventricular remodeling after myocardial infarction.

Increasing evidence indicates that microRNA (miRNA) regulated mechanisms in myocardial healing and ventricular remodeling following acute myocardial infarction (AMI). We aim to comprehensively investigate changes of exosomal miRNA profile during the post-MI period and determine potential miRNAs associated to adverse left ventricular remodeling (ALVR). We prospectively evaluated ST-elevated MI patients with cardiac magnetic resonance imaging at the 2 weeks and 6 months after AMI (n = 10). ALVR was defined as an increase in LV end-diastolic and end-systolic volume > 13%. The blood samples were taken for miRNA measurements at the baseline, 2 and 6 weeks after AMI. In the miRNA profile assessment, 8 miRNAs were identified that were associated ALVR (miR-199a-5p, miR-23b-3p, miR-26b-5p, miR-301a-3p, miR-374a-5p, miR-423-5p, miR-483-5p and miR-652-3p). Three of them (miR-301a-3p, miR-374a-5p and miR-423-5p) differed significantly between patients with and without ALVR during follow-up period and the rest of them during the acute phase of AMI. The detection of these miRNAs, which have different role in various pathways, necessitate future mechanistic studies unravel the complex remodeling process after AMI.

The role of temporal changes of pro-inflammatory cytokines in the development of adverse cardiac remodeling after ST-elevation myocardial infarction.

Introduction: Increasing evidence supports the view that pro-inflammatory cytokines play a role in fibrosis after myocardial infarction (MI). It has been suggested that interleukin (IL)-12p40, a pro-inflammatory cytokine, can induce interferon γ (IFN-γ) and matrix metalloproteinase (MMP). However, the role of IL-12p40 in adverse cardiac remodeling (AR) after ST-elevation MI (STEMI) is unclear. Aim: To examine the role of temporal changes of pro-inflammatory cytokines in the development of post-STEMI AR. Material and methods: A total of 43 patients with STEMI for the first time ever were prospectively analyzed. In cardiac magnetic resonance imaging at 6 months after STEMI, a decrease of left ventricular end-diastolic volume by ≥ 12% was defined as reverse cardiac remodeling (RR), and a 12% increase was defined as AR. Cytokine concentrations were measured on the first day (baseline) and 2 weeks after STEMI. Results: Mean IL-12p40 (59.1 ±14.5 vs. 46.7 ±9.1 pq/ml, p = 0.001), median IFN-γ (20.4 vs. 16.2 pq/ml, p = 0.048) and median MMP-2 (33866 vs. 20691 pq/ml, p = 0.011) baseline concentrations were higher in AR than RR. In patients with AR, IL-12p40 level was lower at 2 weeks than baseline (p < 0.001). There was a positive correlation between the baseline concentrations of IL-12p40, IFN-γ, MMP-2, C-reactive protein and infarct size (p < 0.05). Increased IL-12p40 and MMP-2 baseline levels were independently associated with AR (OR = 1.14, p = 0.010; OR = 1.08, p = 0.035). Conclusions: In the initial phase of MI, greater release of pro-inflammatory cytokines was associated with increased MMP-2 levels. Elevated expression of IL-12 and MMP-2 had an independent association with AR. This may be related to the excessive inflammatory response in the initial phase of MI.

Double Heterozygous Mutations in the BRCA2 and ATM Genes: A Case Report and Review of the Literature.

INTRODUCTION: Germline mutations of the BRCA1 and BRCA2 genes are responsible for about a quarter of hereditary breast cancers (BCs). In this study, we aimed to determine the importance of rare double heterozygous (DH) pathogenic variant carriership in BRCA2and ATM genes in a patient diagnosed with BC and pancreas cancer (PC). CASE REPORT: A 54-year-old female patient was diagnosed with BC at the age of 34 years and with PC at the age of 48 years. The multigene panel and next-generation sequencing technique were used to evaluate the status of the patient's cancer susceptibility genes. Pathogenic variants c.537dup (p.Ile180Tyrfs*3) in the BRCA2 gene and c.5065C>T (p.Gln1689Ter) in the ATM gene were detected as DH in the patient. Co-segregation analysis was performed on the relatives of the patient using Sanger sequencing. DISCUSSION/CONCLUSION: Multiple primary malignant neoplasms can be encountered more frequently in DH pathogenic variant carriers, and the diagnosis of malignancies can be made at an earlier age through surveillance guided by genetic testing. In this rare case, more patient studies are needed to determine the contribution of DH in BRCA2 and ATM genes to the phenotype.

Higher levels of TWEAK and matrix metalloproteinase-3 during the acute phase of myocardial infarction are associated with adverse left ventricular remodeling.

INTRODUCTION: It is known that the levels of tumor necrosis factor-like weak inducer of apoptosis (TWEAK/TNFSF12) increase after myocardial infarction (MI) and that it interacts with sCD163. It has also been argued that TWEAK can induce matrix metalloproteinases (MMPs) in macrophages. AIM: To investigate the roles of TWEAK, sCD163, and MMPs in left ventricular (LV) adverse remodeling (AR) in the early post-MI period. MATERIAL AND METHODS: Forty-six patients with ST-elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention were enrolled in the study. Post-MI LV functions and volumes were assessed by cardiac magnetic resonance imaging at 2 weeks and 6 months. Cytokines and MMPs were measured using a bead-based multiplex immunoassay system at 1 day (baseline) and 2 weeks post-MI. AR was defined as an increase in LV end-diastolic volume of ≥ 10% at the 6-month follow up. RESULTS: The TWEAK, MMP-2, and MMP-3 baseline levels were higher in the patients with AR than those without AR. At 2 weeks post-MI, these expression levels were similar in patients with and without AR, but sCD163 expression was increased in patients without AR. The TWEAK and MMP levels were positively correlated in the early period post-MI. At first day post-MI, higher levels of TWEAK and MMP-3 were predictors of AR (OR = 1.03, p = 0.006; OR = 1.08, p = 0.015; respectively). CONCLUSIONS: TWEAK can induce MMPs in the early period post-MI, and these higher levels contribute to development of AR. Increased sCD163 levels at 2 weeks post-MI seem to be associated with the healing process through neutralizing the excessive inflammatory effects of TWEAK.

Renpenning Syndrome in a Turkish Patient: de novo Variant c.607C>T in PACS1 and Hypogammaglobulinemia Phenotype.

Renpenning syndrome is an X-linked intellectual disability syndrome caused by mutations in the human polyglutamine binding protein 1 (PQBP1) gene characterized by intellectual disability (ID), microcephaly, and dysmorphic facial features. We report a Turkish child with a novel pathogenic variant in PQBP1 and a likely pathogenic variant in the PACS1 gene presenting with growth restriction, microcephaly, ID, micropenis, bilateral iris coloboma, and hypogammaglobulinemia. Cytogenetic investigations, including a high-resolution-banded karyotype, were normal. Clinical exome sequencing was performed. We found the novel PQBP1 variant, c.640C>T; p.(Arg214Trp), and the known PACS1 variant, c.607C>T; p.(Arg203Trp), in the proband. The patient's hypogammaglobulinemia did not respond to treatment. This condition was detected for the first time in a patient with Renpenning syndrome.

Association of vitamin D receptor gene FokI and TaqI polymorphisms and risk of RDS.

Background: Vitamin D and its receptor (VDR) have important roles in perinatal lung development. The objective of this study was to investigate the possible association between VDR FokI and TaqI polymorphism and development of respiratory distress syndrome (RDS) in preterm infants.Method: A total of 173 premature infants <34 weeks: 82 with RDS and 91 without RDS were enrolled. Genotyping of VDR polymorphisms was assayed by real-time PCR. Serum 25-hydroxyvitamin D (25-OHD) levels were measured by ELISA in blood samples that were obtained at the time of admission to the neonatal intensive care unit.Results: Gestational age (GA) was significantly lower in the RDS group compared with the controls. In univariate analysis, VDR TaqI CT and CC genotypes were associated with the increased risk of RDS (OR = 3.264, p = .001, 95% CI = 1.597-6.672 and OR = 5.222, p < .001, 95% CI = 2.165-12.597, respectively); while VDR FokI showed no association with RDS. In multivariate logistic regression analysis, variant TaqI genotype increased risk of RDS (p = 0.001, OR = 3.464, 95% CI = 1.655-7.251) independent of gestational age, birth weight and gender. 25-OHD levels in the RDS group were significantly lower compared with those in without the RDS group (p = .002). Serum 25-OHD levels were not significantly different among the different FokI and TaqI genotypes in RDS group.Conclusions: This is the first report of association of VDR polymorphism with RDS development in preterm neonates. Current study suggests that VDR TaqI polymorphism may be involved in predisposition to RDS in premature neonates. Further studies are needed to assess the contribution of vitamin D and VDR signaling to the pathogenesis RDS.

Novel BRCA2 pathogenic genotype and breast cancer phenotype discordance in monozygotic triplets.

BRCA1/2 genes with high-penetrance are tumor suppressor and tumor susceptibility genes that play important roles in the homologous recombination mechanism in DNA repair and increase breast cancer risk. Variants in BRCA1 or BRCA2 are the main causes of familial and early-onset breast cancer. This study investigated pathogenic variant belonging to the BRCA2 gene splice region in monozygotic triplets. A 44-year-old woman was diagnosed with breast cancer when she was 32 years old. Her monozygotic sister had a history of breast cancer. No malignancy was detected in the third one of the monozygotic triplets. Sanger sequencing was used to evaluate the BRCA1/2 gene status of the patient and family members. It was figured out that they had the same genetic variant, a heterozygous germ-line splice region variant (c.7008-1G > C) in the BRCA2 gene. This novel splice region variant may be a new pathogenic variant of the BRCA2 gene. Its association with breast cancers needs to be further verified in more patient cases.

HNF1A gene p.I27L is associated with co-existing preeclampsia in gestational diabetes mellitus.

The association of the FTO gene and HNF1α gene on gestational diabetes mellitus (GDM) and preeclampsia remains unclear. This is the first study to examine whether HNF1α gene and FTO gene were associated with having GDM and preeclampsia in Turkish women. Healthy pregnant women (n = 101) and women with GDM (n = 169) were included. GDM was divided into two groups as GDM-only (n = 90) and GDM-preeclampsia (n = 79). Genotyping of HNF1α gene p.I27L, p.A98V, and p.S487N, and FTO gene rs9939609 SNPs were performed using RT-PCR. The frequency of p.S487N, p.A98V, and FTO genotype were similar between the groups (p > .05). p.I27L GG-wild, GT, and TT genotype were 56.5%, 36.6%, and 6.9% in controls; 40.0%, 51.1%, and 8.9% in GDM-only; and 26.6%, 51.9%, and 21.5% in GDM-preeclampsia (p = .034). TT and GT genotype was more frequent in GDM-preeclampsia than in controls (p < .05). GT genotype was increased in GDM-only compared with controls (p < .05). TT genotype was more frequent in GDM-preeclampsia than in GDM-only (p < .05). p.I27L TT genotype was independently associated with increased blood pressure (BP) and urinary protein. p.I27L TT genotype was associated with increased preeclampsia risk in patients with GDM by increasing BP and urinary protein.

Maternal genetic contribution to pre-pregnancy obesity, gestational weight gain, and gestational diabetes mellitus.

INTRODUCTION: Pre-pregnancy obesity, gestational diabetes mellitus (GDM), and gestational weight gain (GWG) are associated with each other. This is the first study to investigate whether genetic variants were associated with having GDM, and whether genetic variants-related GDM were associated with adiposity including pre-pregnancy obesity and excessive GWG in Turkish women. PATIENTS AND METHODS: Women with GDM (n = 160) and without GDM (n = 145) were included in case-controlled study. Genotyping of the HNF1A gene (p.I27L rs1169288, p.98V rs1800574, p.S487N rs2464196), the VDR gene (p.BsmI rs1544410, p.ApaI rs7975232, p.TaqI rs731236, p.FokI rs2228570), and FTO gene (rs9939609) SNPs were performed by using RT-PCR. RESULTS: The FTO AA genotype was associated with an increased risk of having GDM (AA vs. AT + TT, 24.4% vs. 12.4%, OR = 2.27, 95% CI [1.23-4.19], p = 0.007). The HNF1A p.I27L GT/TT genotype was associated with increased GDM risk (GT + TT vs. GG-wild, 79.4% vs. 65.5%, OR = 2.02, 95% CI 1.21-3.38], p = 0.007). However, all VDR gene SNPs and the HNF1A p.A98V, p.S487N were not associated with having GDM (p > 0.05). The FTO AA genotype was associated with an increased risk for pre-pregnancy overweight/obesity (OR = 1.43, 95% CI [1.25-3.4], p = 0.035), but not associated with excessive GWG after adjusting for pre-pregnancy weight (p > 0.05). Pre-pregnancy weight, weight at delivery, and GWG did not differ in both VDR and HNF1A gene carriers (p > 0.05). HOMA-IR and HbA1c were increased in both p.I27L TT and FTO AA genotype carriers (p < 0.05). CONCLUSION: The adiposity-related gene FTO is associated with GDM by the effect of FTO on pre-pregnancy obesity. The diabetes-related p.I27L gene is associated with GDM by increasing insulin resistance.

HNF1A gene p.I27L is associated with early-onset, maturity-onset diabetes of the young-like diabetes in Turkey.

BACKGROUND: The molecular basis of the Turkish population with suspected maturity-onset diabetes of the young (MODY) has not been identified. This is the first study to investigate the association between HNF1A-gene single-nucleotide polymorphisms (SNPs) and having early-onset, MODY-like diabetes mellitus in the Turkish population. METHODS: All diabetic patients (N = 565) who presented to our clinic between 2012 and 2015 with a clinical suspicion of MODY were included in the study. Analysis of HNF1A, HNFB, HNF4A, GCK gene mutations was performed using real-time polymerase chain reaction sequencing. After genetic analysis, diabetics (n = 46) with HNF1A, HNF1B, HNF4A, GCK gene mutations (diagnosed as MODY) and diabetics (n = 30) with HNF1B, HNF4A, GCK gene SNPs were excluded. Patients with early-onset, MODY-like diabetes (n = 486) and non-diabetic controls (n = 263) were included. Genetic analyses for the HNF1A gene p.S487 N (rs2464196), p.A98V (rs1800574) and p.I27L (rs1169288) SNPs were performed using Sanger-based DNA sequencing among the control group. RESULTS: p.S487 N and p.A98V was similar between the diabetics and controls in dominant and recessive models with no association (each, p > 0.05). p.I27L GT/TT carriers (GT/TT vs. GG, OR = 1.68, 95% CI: [1. 21-2.13]; p = 0.035) and p.I27L TT carriers had increased risk of having MODY-like diabetes (GT/GG vs. TT, OR = 1.56, 95% CI: [1. 14-2.57]; p = 0.048). Family inheritance of diabetes was significantly more common in patients with the p.I27L TT genotype. The p.I27L SNP was modestly associated with having diabetes after adjusting for body mass index and age (ß = 1.45, 95% CI: [1. 2-4.2]; p = 0.036). CONCLUSIONS: The HNF1A gene p.I27L SNP was modestly associated with having early-onset, MODY-like diabetes in the Turkish population. HNF1A gene p.I27L SNP might contribute to age at diabetes diagnosis and family inheritance.

The VDR gene FokI polymorphism is associated with gestational diabetes mellitus in Turkish women.

BACKGROUND: The association between the vitamin D receptor (VDR) gene and gestational diabetes mellitus (GDM) has not been investigated in Turkish pregnant women. We aimed to investigate associations between VDR gene BsmI (rs15444410), ApaI (rs7975232), FokI (rs19735810), and TaqI (rs731236) single nucleotide polymorphisms (SNPs) and GDM. MATERIAL-METHODS: This case-control study comprised 100 women with GDM and 135 pregnant women without GDM. The VDR polymorphism was evaluated using Sanger-based DNA sequencing. RESULT: VDR gene ApaI, BsmI, and TaqI SNPs did not differ between women with and without GDM (each, p > 0.05). ApaI, BsmI, and TaqI were not associated with GDM risk. The VDR gene FokI CT/TT genotype was associated with an increased GDM risk (CT vs. CC, OR = 1.84, 95% CI: [1.05-3.23], p = 0.031; TT vs. CC, OR = 3.95, 95% CI: [1.56-9.96], p = 0.002; CT/TT vs. CC, OR = 2.29, 95% CI: [1.35-3.89], p = 0.002; and CT/CC vs. TT, OR = 3.02, 95% CI: [1.23-7.38], p = 0.012). The FokI-TT genotype was more associated with younger age and higher glucose, HbA1c, and HOMA-IR than the CC and CT genotype. FokI-T was positively correlated with log-HOMA-IR (r = 0.326, p = 0.004). FokI SNPs were independently associated with GDM after adjusting for BMI and age (ß = 1.63, 95% CI: [1. 2-4.2], p = 0.012). There were no associations between the FokI, ApaI, BsmI and TaqI haplotypes and GDM. CONCLUSION: VDR gene FokI SNPs were independently associated with having GDM in Turkish women. VDR gene FokI SNPs might contribute to insulin resistance of developing GDM.

Melanocortin 3 receptor gene polymorphism is associated with polycystic ovary syndrome in Turkish population.

Polycystic ovary syndrome (PCOS) is a frequent complex disorder with an ill-defined etiology. Genetic factors seem rather effective at the occurrence of the disease, however, the evidence of established various studies results are unsatisfied. We aimed to make a contribution to the genetic baseline of the disease by investigating melanocortin 3 receptor gene polymorphism in affected patients. 101 PCOS patients and 162 age-matched healthy volunteered control subjects recruited to the study. PCOS patients classified according to their BMI class and insulin resistance situation. Anthropometric measurements, physical examination results, laboratory findings, and hormone levels were recorded for each participant and analysis of two SNPs on the MC3R gene; rs3746619 and rs3827103 were performed. Although no significant difference was observed in rs3827103 polymorphism between PCOS patients and controls; rs3746619 polymorphism was determined associated with PCOS in the heritage of dominant (AA + AC) and co-dominant (AA) genotypes. Two polymorphisms did not found related to obesity and insulin resistance in PCOS subgroups analysis. MC3R gene rs 3746619 polymorphism was found associated with PCOS in the Turkish population and may make a contribution to the genetic baseline of the disease.

Comparison of non-invasive tests with invasive tests in the diagnosis of celiac disease.

BACKGROUND/AIMS: Today, invasive diagnostic tests are necessary for definite diagnosis of adult celiac disease (CD). However, in selected children patients, the need for invasive tests is ceased. In this study, we evaluated adult patients according to the ESPGHAN (European Pediatric Gastroenterology Hepatology and Nutrition Society) criteria. METHODS: Thirty-nine patients (aged 17-66) with symptoms of CD were included. Serum samples were tested for total IgA, tTG-IgA (antitissue transglutaminase), tTG-IgG, DGP-IgA (antideamidated gliadin peptide), DGP-IgG, and EMA (endomysial antibodies). HLA-DQ typing was studied with PCR-SSP (sequence-specific primers) method. Biopsy samples were evaluated according to Marsh scoring. RESULTS: In CD patients, 71.4% (15/21) of the patients were diagnosed without biopsy according to the EPSGHAN criteria but when ESPGHAN's IgA tTG threshold value for children was taken into consideration (>200 IU/mL), the sensitivity decreased to 81%. Celiac disease diagnosed and control groups were compared in terms of HLA tissue types. DQ2.5 homozygous or DQ2.5/DQ2.2 was significantly higher in CD group, and DQ2- or DQ8-negative HLA tissue type was significantly higher in control group. CONCLUSION: When serological tests, HLA typing, and clinical symptoms are all in favor of CD, biopsy may not be performed in selected adult CD patients.

VDR gene FokI polymorphism as a poor prognostic factor for papillary thyroid cancer.

This is the first study to investigate the effect of vitamin D receptor ( VDR) gene single-nucleotide polymorphisms on the clinicopathologic features of papillary thyroid cancer in Turkey. A total of 165 patients with papillary thyroid cancer and 172 controls were included in this case-control study. VDR gene single-nucleotide polymorphisms FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) were evaluated using reverse-transcription polymerase chain reaction. VDR gene polymorphisms BsmI, ApaI, and TaqI did not differ between the papillary thyroid cancer group and control group (p > 0.05, each). BsmI, ApaI, and TaqI were not associated with papillary thyroid cancer risk. The VDR gene FokI CT/TT genotype was associated with an increased papillary thyroid cancer risk (CT vs CC: odds ratio = 1.71, 95% confidence interval = 1.15-2.76, p = 0.028; TT vs CC: odds ratio = 2.44, 95% confidence interval = 1.29-4.62, p = 0.005; CT/TT vs CC: odds ratio = 1.88, 95% confidence interval = 1.20-2.96, p = 0.006; CT/CC vs TT: odds ratio = 1.80, 95% confidence interval = 1.05-3.20, p = 0.041). VDR gene polymorphisms were not in linkage disequilibrium. The FokI TT genotype was associated with having T3 and T4, stage III/IV, extra-thyroidal invasion. The FokI CT/TT or TT genotype was associated with developing N1 status, multifocality, tumor size ≥10 mm, and treatment with radioiodine therapy. Persistence/recurrence did not differ between the FokI genotypes. Carriers of the FokI T allele were at an increased risk of more advanced tumor-node-metastasis stage, greater tumor size, multifocality, and extra-thyroidal invasion of papillary thyroid cancer compared with the CC genotype. VDR gene FokI T allele and TT genotype correlated with aggressiveness of papillary thyroid cancer; thus, FokI could be useful as a poor prognostic factor to assess the high risk of papillary thyroid cancer.

Cytokine, C-Reactive Protein, and Heat Shock Protein mRNA Expression Levels in Patients with Active Behçet's Uveitis.

BACKGROUND To investigate the gene expression levels of interleukin 10 (IL10), IL18, interferon gamma (IFNG), IFN-gamma receptor (IFNGR), C-reactive protein (CRP), and heat shock protein 70 (HSP70) in patients with active Behçet's uveitis. MATERIAL AND METHODS Forty patients with Behçet's disease diagnosed according to the International Study Group criteria and 30 healthy individuals were included in the study. IL10, IL18, IFNG, IFNGR, CRP, and HSP70 gene expression levels were compared. RESULTS Expression levels of IL18, IFNG, IFNGR, and CRP were significantly higher in patients with active Behçet's uveitis than in control subjects (P<0.01 for all), whereas no significant differences were found in IL10 and HSP70 gene expression levels (P>0.01 for both). CONCLUSIONS IL18, IFNG, IFNGR, and CRP gene expression is significantly increased in active Behçet's uveitis. There was no significant difference between active Behçet's uveitis patients and controls in terms of IL10 and HSP70 gene expression levels. We conclude that drugs prescribed to Behçet's patients with active uveitis downregulate gene expression.