Mehmet Karaca

GSTM1, GSTP1, and GSTT1 genetic variability in Turkish and worldwide populations.

Glutathione S‐transferase (GST) variants have been widely investigated to better understand their role in several pathologic conditions. To our knowledge, no data about these genetic polymorphisms within the Turkish population are currently available. The aim of this study was to analyze GSTM1 positive/null, GSTT1 positive/null, GSTP1*I105V (rs1695), and GSTP1*A114V (rs1138272) variants in the general Turkish population, to provide information about its genetic diversity, and predisposition to GST‐related diseases.

Phenotypic and genotypic spectrum of Turkish patients with isovaleric acidemia.

We aim to investigate the genetic basis of isovaleryl-CoA dehydrogenase (IVD) gene mutations and genotype-phenotype correlations in Turkish patients. Accordingly, bi-directional sequencing was performed to screen 26 patients with isovaleric acidemia (IVA). Nine novels (c.145delC, c.234 + 3G > C, c.506_507insT, p.Glu85Gln, p.Met147Val, p.Ala268Val, p.Ile287Met, p.Gly346Asp and p.Arg382Trp) and six previously reported (c.456 + 2T > C, p.Arg21His, p.Arg21Pro, p.Arg363Cys, p.Arg363His p.Glu379Lys) pathogenic mutations were identified. Pathogenicity of the novel mutations was supported using computational programs. No clear genotype-phenotype correlation could be determined. One of the cases with the novel c.234 + 3G > C mutation has portoseptal liver fibrosis, the clinical condition that was first reported for IVA. This study is the first comprehensive report from Turkey related to IVA genetics that provides information about the high number of disease-causing novel mutations.

Allergy-specific Phenome-Wide Association Study for Immunogenes in Turkish Children

To dissect the role of immunogenetics in allergy and asthma, we performed a phenome-wide association study in 974 Turkish children selected from a cross-sectional study conducted using ISAAC (International Study of Asthma and Allergies in Children) Phase II tools. We investigated 9 loci involved in different immune functions (ADAM33, ADRB2, CD14, IL13, IL4, IL4R, MS4A2, SERPINE1, and TNF) with respect to 116 traits assessed through blood tests, hypertonic saline challenge tests, questionnaires, and skin prick tests. Multiple associations were observed for ADAM33: rs2280090 was associated with reduced MEF240% (i.e., the ratio of Mean Expiratory Flow after 240s of hypertonic saline inhalation with respect to the age- and ancestry-matched reference value) and with an increased risk of allergic bronchitis (p = 1.77*10−4 and p = 7.94*10−4, respectively); rs3918396 was associated with wheezing and eczema comorbidity (p = 3.41*10−4). IL4 rs2243250 was associated with increased FEV240 (Forced Expiratory Flow Volume after 240s of hypertonic saline inhalation; p = 4.81*10−4) and CD14 rs2569190 was associated with asthma diagnosis (p = 1.36*10−3). ADAM33 and IL4 appeared to play a role in the processes linked to allergic airway inflammation and lung function. Due to its association with wheezing and eczema comorbidity, ADAM33 may also be involved in the atopic march.

Haplotype analysis of non-HLA immunogenetic loci in Turkish and worldwide populations.

Immunogenes (i.e., genes related to the immune system and its functions) are involved in the predisposition to numerous traits and their variation contributes to the phenotypic variability observed among human groups. Turkish population presents particular genetic features since its genetic pool is an admixture of European, Middle-Eastern, and Central Asian ancestries. Here, we analyzed the haplotype structure of four immunogenetic loci (i.e., ADAM33; IL13-IL4; IL4R; MS4A2) in 482 subjects from five different regions of Turkey. Genotyping was performed using KASP technology. Turkish data were compared with the haplotype information available from the 1000 Genomes Project Phase 3 (26 human populations from 5 ancestry groups). We did not observe significant differences among Turkish groups. Comparing other ancestries, we identified haplotype similarity of Turkish subjects with European populations in IL13-IL4, IL4R, and ADAM33 loci; and with central Asians in MS4A2 region. Considering loci displaying Turkish-European haplotype similarity (i.e., IL13-IL4, IL4R, and ADAM33), we observed differences between Turkish subjects and northern/western Europeans. Conversely, no significant difference was determined in MS4A2 between Turkish and central Asian populations. Finally, we assessed the haplotypes responsible for the differences between Turkish and European samples and the potential functional effects on the immunogenetic loci investigated.

International warfarin genotype-guided dosing algorithms in the Turkish population and their preventive effects on major and life-threatening hemorrhagic events

AIM To determine the accuracy of international warfarin pharmacogenetic algorithms developed on large multiethnic cohorts (comprising more than 1000 subjects) to predict therapeutic warfarin doses in Turkish patients. MATERIALS & METHODS We investigated two Turkish warfarin-treated cohorts: patients with no history of hemorrhagic or thromboembolic event and patients with major and life-threatening hemorrhagic events. RESULTS International pharmacogenetic algorithms showed good performances in predicting the therapeutic dose of patients with no history of bleedings, but they did not significantly detect the incorrect warfarin dose of patients with major and life-threatening hemorrhagic events. CONCLUSION Although genetic information can predict the therapeutic warfarin dose, the accuracy of the international pharmacogenetic algorithms is not sufficient to be used for warfarin screening in Turkish patients.

Genetic diversity of disease-associated loci in Turkish population

Many consortia and international projects have investigated the human genetic variation of a large number of ethno-geographic groups. However, populations with peculiar genetic features, such as the Turkish population, are still absent in publically available datasets. To explore the genetic predisposition to health-related traits of the Turkish population, we analyzed 34 genes associated with different health-related traits (for example, lipid metabolism, cardio-vascular diseases, hormone metabolism, cellular detoxification, aging and energy metabolism). We observed relevant differences between the Turkish population and populations with non-European ancestries (that is, Africa and East Asia) in some of the investigated genes (that is, AGT, APOE, CYP1B1, GNB3, IL10, IL6, LIPC and PON1). As most complex traits are highly polygenic, we developed polygenic scores associated with different health-related traits to explore the genetic diversity of the Turkish population with respect to other human groups. This approach showed significant differences between the Turkish population and populations with non-European ancestries, as well as between Turkish and Northern European individuals. This last finding is in agreement with the genetic structure of European and Middle East populations, and may also agree with epidemiological evidences about the health disparities of Turkish communities in Northern European countries.

High prevalence of cerebral venous sinus thrombosis (CVST) as presentation of cystathionine beta-synthase deficiency in childhood: molecular and clinical findings of Turkish probands.

Classical homocystinuria is the most commonly inherited disorder of sulfur metabolism, caused by the genetic alterations in human cystathionine beta-synthase (CBS) gene. In this study, we present comprehensive clinical findings and the genetic basis of homocystinuria in a cohort of Turkish patients. Excluding some CBS mutations, detailed genotype-phenotype correlation for different CBS mutations has not been established in literature. We aimed to make clinical subgroups according to main clinical symptoms and discussed these data together with mutational analysis results from our patients. Totally, 16 different mutations were identified; twelve of which had already been reported, and four are novel (p.N93Y, p.L251P, p.D281V and c.829-2A>T). The probands were classified into three major groups according to the clinical symptoms caused by these mutations. A psychomotor delay was the most common diagnostic symptom (n=12, 46.2% neurological presentation), followed by thromboembolic events (n=6, 23.1% vascular presentation) and lens ectopia, myopia or marfanoid features (n=5, 19.2% connective tissue presentation). Pyridoxine responsiveness was 7.7%; however, with partial responsive probands, the ratio was 53.9%. In addition, five thrombophilic nucleotide changes including MTHFR c.677 C>T and c.1298 A>C, Factor V c.1691 G>A, Factor II c.20210 G>A, and SERPINE1 4G/5G were investigated to assess their contributions to the clinical spectrum. We suggest that the effect of these polymorphisms on clinical phenotype of CBS is not very clear since the distribution of thrombophilic polymorphisms does not differ among specific groups. This study provides molecular findings of 26 Turkish probands with homocystinuria and discusses the clinical presentations and putative effects of the CBS mutations.

Genotypic-phenotypic features and enzyme replacement therapy outcome in patients with mucopolysaccharidosis VI from Turkey

Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disorder (LSD) characterized by a chronic, progressive course with multiorgan involvement. In our study, clinical, biochemical, molecular findings, and response to enzyme replacement therapy (ERT) for at least 6 months were evaluated in 20 patients with MPS VI. Treatment effects on clinical findings such as liver and spleen sizes, cardiac and respiratory parameters, visual and auditory changes, joints’ range of motions, endurance tests and changes in urinary glycosaminoglycan excretions, before and after ERT were analyzed. ERT caused increased physical endurance and decreased urinary dermatan sulfate/chondroitin sulfate ratios. Changes in growth parameters, cardiac, respiratory, visual, auditory findings, and joint mobility were not significant. All patients and parents reported out an increased quality of life, which were not correlated with clinical results. The most prevalent mutation was p.L321P, accounting for 58.8% of the mutant alleles and two novel mutations (p.G79E and p.E390 K) were found. ERT was a safe but expensive treatment for MPS VI, with mild benefits in severely affected patients. Early treatment with ERT is mandatory before many organs and systems are involved.

Pleurodesis through Pleural Catheterization in Patients with Symptomatic Malignant Pleural Effusions: Which One is better? Talc, Bleomycin or Tetracycline?

Purpose: To analyze the results of pleurodesis through pleural catheterization using talc slurry, bleomycin, and tetracycline in patients with symptomatic malignant pleural effusion (MPE) and to compare the efficacy, reliability and outcomes of these agents. Methods: Talc (4 g), bleomycin (60.000 U) or tetracycline (1 g) was used for chemical pleurodesis in 271 patients. Successful pleurodesis was defined as no fluid build up and lack of recurrence of symptoms within the first 30 days after treatment. Data were analyzed using SPSS 15.0 for Windows. Results: Pleural catheterization was performed in a total of 368 patients. Eighteen patients were lost to follow-up. Seventy-nine patients were excluded due to either of the following factors; trapped lung syndrome or patient lost during the early post-catheterization period due to advanced disease. In 271 patients chemical pleurodesis was performed with talc slurry (17.3%), bleomycin (13.7%) or tetracycline (49.1%). In 19.9% of the patients, multiple chemical agents were used in different sessions as successful results were not obtained with one agent. Clinical and radiological success was achieved in 78.2% of patients. There was no significant difference among 4 groups (talc slurry, bleomycin, tetracycline and multiple agents) in terms of clinical success, complication rates and median symptom-free life periods. Conclusion: Talc slurry, bleomycin, or tetracycline administration through percutaneous pleural catheterization have comparable efficacy rates and safety profiles. If pleurodesis failure with one agent occurs, the attempt with other agents may result in success.