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Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

Gliptins act by increasing endogenous incretin levels. Glucagon-like peptide-1 receptor ( GLP1R) and glucose-dependent insulinotropic peptide receptor ( GIPR) are their indirect drug targets. Variants of GLP1R and GIPR have previously been associated with the incretin effect. The aim of the present pilot study was to examine associations of the GLP1R and GIPR gene variants with the glycaemic response to gliptins. A total of 140 consecutive patients with type 2 diabetes were followed-up 6 months after initiation of gliptin treatment. GLP1R rs6923761 ( Gly168Ser) and GIPR rs10423928 genotyping was performed using real-time PCR, with subsequent high-resolution melting analysis. The main study outcome was reduction in glycated haemoglobin ( HbA1c) after treatment. GLP1R Gly168Ser variant was significantly associated with reduction in HbA1c in an additive model (β = −0.33, p = 0.011). The mean reduction in HbA1c in Ser/Ser homozygotes was significantly lower compared with Gly-allele carriers [0.12 ± 0.23% vs. 0.80 ± 0.09% (1.3 ± 2.5 mmol/mol vs. 8.7 ± 1.0 mmol/mol); p = 0.008]. In conclusion, GLP1R missense variant was associated with a reduced response to gliptin treatment. The genotype-related effect size of ∼0.7% (8 mmol/mol) is equal to an average effect of gliptin treatment and makes this variant a candidate for use in precision medicine. [ABSTRACT FROM AUTHOR]

An improved nucleic acid amplification test (NAAT) to detect Chlamydia trachomatis infections, based on PCR amplification within its cryptic plasmid (CT1/CT2 Test) was developed. DNA was extracted from urogenital swabs and a 594-bp long DNA fragment from the cryptic plasmid (pCT) was amplified. The sensitivity and specificity of the CT1/CT2 Test were determined to be 100 and 99 %, respectively, when directly compared with current amplification kit for sexually transmitted diseases (MPCR). Basic epidemiological data related to the patients attending gynecological and/or urological clinics are also provided. The overall prevalence rate in this group of patients suspected for C. trachomatis infection was determined to be about 95 per 1000 (88 and 107 per 1000 in females and males, respectively). It demonstrates that the CT1/CT2 Test is suitable for epidemiological screening and/or diagnostic practice. [ABSTRACT FROM AUTHOR]

A simple nucleic acid amplification test (NAAT) was developed for detection of Ureaplasma urealyticum infection based on the PCR amplification of the urease gene (UU1/UU2 Test). DNA was extracted from urogenital swabs and a 225-bp long DNA fragment was amplified by PCR. NAAT was compared to the commercial amplification kit for sexually transmitted disease reference assay. The sensitivity and specificity of the UU1/UU2 Test were determined to be 100 and 98.9 %, respectively. The overall prevalence rate in this group of patients was found to be about 236 per 1000 (283 and 166 per 1000 in females and males, respectively). These data demonstrate that UU1/UU2 Test is suitable for effective epidemiological screening and/or diagnostic practice. [ABSTRACT FROM AUTHOR]

Background: There is no doubt that genetic factors have the potential to predict the therapeutic outcomes of antidepressants in patients with major depressive disorder (MDD). This study investigated the association between genetic variants involved in serotonin signaling and brain-derived neurotrophic factor (BDNF) with the response to escitalopram treatment in patients with MDD. We focused on examining the influence of 5-HTTLPR (ins/del), HTR2A rs9316233, BDNF rs962369, CYP2C19 and CYP2D6 on the clinical response to escitalopram., Methods: The patients were recruited from outpatient psychiatric clinics in Košice between 2020 and 2022. Patients received escitalopram for 12 weeks at a fixed dose of 10 mg daily. Clinical assessment was done at baseline and after 4, 8, and 12 weeks using the 21-item Hamilton Depression Rating Scale (HAMD-21)., Results: At the end of week 12, 57 (65%) patients were defined as responders to escitalopram treatment, while 31 (35%) patients were non-responders. Genotyping revealed that carriers of the short allele (S) of 5-HTTLPR exhibit a significantly lower therapeutic response to escitalopram measured by HAMD-21 than the long allele (L) carriers (p = 0.01). Adjusting for CYP2C19 and CYP2D6 metabolizer genotypes did not modify the observed relationship between 5-HTTLPR and treatment response. No significant associations were found for HTR2A rs9316233 or BDNF rs962369 variants and the treatment response., Conclusions: These findings underscore the utility of 5-HTTLPR genotyping in guiding escitalopram therapy for MDD patients. Further research with larger cohorts is warranted to validate these results and elucidate additional genetic determinants of antidepressant efficacy., (© 2024. The Author(s).)

Aim: We examined associations of eight SNPs in/near seven candidate genes with glycemic response to 6 month treatment with DPP4 inhibitors. Patients & methods: 206 patients with type 2 diabetes (116 men and 90 women) were treated with sitagliptin or vildagliptin (both 100 mg/day) in combination with metformin or metformin/sulphonylurea over 6 months, and the reduction in glycated hemoglobin (HbA 1c ) was measured. Results: Rs6923761 in GLP1R was significantly associated with a reduction in HbA 1c (adjusted p = 0.006). Homozygotes for the minor A allele had smaller reduction in HbA 1c by 0.4% (4 mmol/mol) than the G allele carriers (p = 0.016). Conclusion: The missense variant rs6923761 in the  GLP1R gene was associated with a smaller glycemic response to 6 month gliptin therapy in diabetic patients of central European origin.

Aim: To assess the effects of single nucleotide polymorphisms (SNPs) on blood pressure control in patients with obstructive sleep apnea (OSA)., Methods: This prospective observational cohort study, conducted between 2004 and 2014, examined the associations of SNPs of JAG1, GUCY1A3-GUCY1B3, SH2B3, and NPR3-C5orf23 genes with systolic and diastolic blood pressure (SBP, DBP) in 1179 adults evaluated for OSA with overnight polysomnography. Genotyping was performed by unlabeled probe melting analysis., Results: The patients were predominantly male (69.6%, mean age 52±11 years, apnea-hypopnea index 34±31 episodes/h). Only JAG1 genotype was associated with SBP and DBP: compared with AA homozygotes, G allele carriers (pooled GG and AG genotype) had significantly higher morning SBP (132±19 vs 129±18 mm Hg; P=0.009) and morning and evening DBP (85±11 vs 83±10 mm Hg, P=0.004; 86±10 vs 84±10 mm Hg, P=0.012, respectively); the differences remained significant after the correction for multiple SNPs testing. In multivariate analyses, oxygen desaturation index and JAG1 genotype independently predicted morning SBP (P=0.001, P=0.003, respectively) and DBP (P<0.001, P=0.005, respectively), and evening SBP (P=0.019, P=0.048, respectively) and DBP (P=0.018, P=0.018, respectively)., Conclusion: This is the first replication study of the SNPs recently linked to arterial hypertension in general population by genome-wide association studies. Our findings suggest that JAG1 genotype is related to blood pressure control in OSA: G allele was associated with higher morning and evening SBP and DBP.

Aims: Only afew gene variants were associated with the response to dipeptidylpeptidase-4 inhibitors (DPP4I). KCNQ1 gene variants were previously related both to type 2 diabetes (T2D) and incretin effect. We hypothesized that T2D related KCNQ1 variants would be associated with smaller glucose-lowering effect of DDP4I., Methods: We performed a retrospective study in 137 Caucasian subjects with T2D who were followed for 6months after initiation of DPP4I treatment. Genotyping for KCNQ1 rs163184 and rs151290 was performed using PCR-HRMA and PCR-RFLP methods, respectively. The main clinical outcome was reduction in HbA1c (ΔHbA1c) after 6-month DPP4I treatment., Results: KCNQ1 rs163184 T>G variant was associated with the response to DPP4I treatment in genetic additive model (β=-0.30, p=0.022). For each G allele in the rs163184 genotype, we observed a 0.3% (3.3mmol/mol) less reduction in HbA1c during treatment with a DPP4I. Both the GG homozygotes and G-allele carriers had significantly smaller HbA1c reduction in comparison with the TT homozygotes., Conclusions: KCNQ1 rs163184 T>G variant was associated with a reduced glycaemic response to DPP4I. The difference of 0.6% (6.5mmol/mol) in HbA1c reduction between the TT and GG homozygotes might be of clinical significance if replicated in further studies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: High variability in clinical response to metformin is often observed in type 2 diabetes (T2D) patients, and it highlights the need for identification of genetic components affecting the efficiency of metformin therapy. Aim of this observational study is to evaluate the role of tagSNPs (tagging single nucleotide polymorphisms) from genomic regions coding for six metformin transporter genes with respect to the short-term efficiency., Design: 102 tagSNPs in 6 genes coding for metformin transporters were genotyped in the group of 102 T2D patients treated with metformin for 3 months., Methods: Most significant hits were analyzed in the group of 131 T2D patients from Slovakia. Pharmacokinetic study in 25 healthy nondiabetic volunteers was conducted to investigate the effects of identified polymorphisms., Results: In the discovery group of 102 patients, minor alleles of rs3119309, rs7757336 and rs2481030 were significantly nominally associated with metformin inefficiency (P = 1.9 × 10 -6 to 8.1 × 10 -6 ). Effects of rs2481030 and rs7757336 did not replicate in the group of 131 T2DM patients from Slovakia alone, whereas rs7757336 was significantly associated with a reduced metformin response in combined group. In pharmacokinetic study, group of individuals harboring risk alleles of rs7757336 and rs2481030 displayed significantly reduced AUC ∞ of metformin in plasma., Conclusions: For the first time, we have identified an association between the lack of metformin response and SNPs rs3119309 and rs7757336 located in the 5' flanking region of the genes coding for Organic cation transporter 2 and rs2481030 located in the 5' flanking region of Organic cation transporter 3 that was supported by the results of a pharmacokinetic study on 25 healthy volunteers., (© 2016 European Society of Endocrinology.)

Purpose: The aim of the present study was to investigate possible associations of the single-nucleotide variants in six genes encoding the key molecules mediating the metformin pharmacodynamic effect with the response to treatment with metformin in patients with type 2 diabetes., Methods: One hundred forty-eight drug-naïve patients with type 2 diabetes were included in the study. PRKAA1 rs249429, STK11 rs741765, PCK1 rs4810083, PPARGC1A rs10213440, HNF1A rs11086926, and CAPN10 rs3792269 variants were genotyped. The outcomes of the study were treatment success defined by achieving HbA1c <7 % and absolute reduction in HbAlc after 6-month metformin therapy. The relationships between genotypes and outcomes were evaluated in multivariate logistic and linear models. The level of statistical significance after Bonferroni correction was predefined as p<0.0083., Results: The minor G-allele of CAPN10 rs3792269 A>G polymorphism was significantly associated with less treatment success with an odds ratio of 0.27 (95 % CI 0.12-0.62, p=0.002) per variant allele. When the reduction in HbA1c was analyzed as a quantitative trait, G-allele was nominally associated with a smaller reduction in HbA1c (per allele β=-0.26, 95 % CI -0.50 to -0.02, p=0.032). The reduction in HbA1c in minor allele carriers (24 % of study population) was smaller by 0.3 % in comparison with the major allele homozygotes., Conclusions: The present study provides the first observation of an association between a variant in CAPN10 gene and the response to metformin therapy in patients with type 2 diabetes. This observation needs to be replicated in further studies in different populations.

N-acetyltransferase 2 (NAT2) is an enzyme involved in the biotransformation of xenobiotics, mainly aromatic and heterocyclic amines and hydrazines, all of which represent an important class of carcinogens found in tobacco smoke. Polymorphism in NAT2 gene is reported to be associated with susceptibility to various types of cancer. This study investigated the relationship between the NAT2 polymorphism and the risk of prostate cancer with reference to the link between cigarette smoking and the xenobiotic-metabolizing enzyme NAT2. Overall, 281 cases and 395 controls from Slovakia were studied using polymerase chain reaction-restriction fragment length polymorphism assay. We found no statistically significant association between NAT2 genotypes and prostate cancer risk (slow acetylation vs. rapid acetylation: OR 1.13; 95 % CI 0.83-1.55). We report here a statistically significant correlation between the NAT2*5C/NAT2*6A slow acetylator genotype and the risk for developing prostate cancer (OR 2.91; 95 % CI 1.43-5.94; p = 0.003) when compared with the rapid phenotype. Smokers with NAT2 rapid phenotype had a five percent (5 %) reduced risk of prostate cancer compared with non-smokers carrying the rapid acetylator genotype. The association was reversed among smokers and non-smokers with NAT2 slow phenotype. On the basis of the foregoing, we conclude that the NAT2 phenotypes whether alone or in association with smoking do not correlate with susceptibility to prostate cancer within the Slovak population.

Previous studies showed associations between variants in TCF7L2 gene and the therapeutic response to sulfonylureas. All sulfonylureas stimulate insulin secretion by the closure of ATP-sensitive potassium (KATP) channel. The aim of the present study was to compare TCF7L2 genotype specific effect of gliclazide binding to KATP channel A-site (Group 1) with sulfonylureas binding to AB-site (Group 2). A total of 101 patients were treated with sulfonylureas for 6 months as an add-on therapy to the previous metformin treatment. TCF7L2 rs7903146 C/T genotype was identified by real-time PCR with subsequent melting curve analysis. Analyses using the dominant genetic model showed significantly higher effect of gliclazide in the CC genotype group in comparison with combined CT + TT genotype group (1.32 ± 0.15% versus 0.73 ± 0.11%, P (adj) = 0.005). No significant difference in ΔHbA1c between the patients with CC genotype and the T-allele carriers was observed in Group 2. In the multivariate analysis, only the TCF7L2 genotype (P = 0.006) and the baseline HbA1c (P < 0.001) were significant predictors of ΔHbA1c. After introducing an interaction term between the TCF7L2 genotype and the sulfonylurea type into multivariate model, the interaction became a significant predictor (P = 0.023) of ΔHbA1c. The results indicate significantly higher difference in ΔHbA1c among the TCF7L2 genotypes in patients treated with gliclazide than in patients treated with glimepiride, glibenclamide, or glipizide.

Background & Aim: Hepatitis C is a liver disease caused by the hepatitis C virus. Interferon and ribavirin combination therapy has been a standard treatment of chronic hepatitis C. But only about 50% of patients have positive response to treatment and achieve so called sustained virological response. Recent studies indicate association of several single nucleotide polymorphisms near IL28B gene and response of hepatitis C patients to combined interferon/ribavirin treatment. In this study, rapid, specific and cost-effective small amplicon genotyping method for the two clinically important polymorphisms, rs12979860 C > T and rs8099917 T > G, near the IL28B gene is described., Methods: The distribution of genotypes of 181 HCV-uninfected Slovak Caucasians was analyzed using this novel method, based on a real-time melting analysis of the small amplicon., Results and Conclusions: The frequency of wild-type (TT) homozygotes for rs8099917 was 66.30%, frequency of heterozygotes (TG) was 30.94% and we found only 2.76% subjects homozygous for risk G allele (allelic frequencies: T = 81.77%, G = 18.23%) were found. The frequency of wild-type genotype (CC) for rs12979860 was 49.72%, frequencies of heterozygous (CT) and risk-allele homozygous genotypes (TT) were 39.78% and 10.50%, respectively (allele frequencies: C = 69.61%, T = 30.39%). Statistically significant differences in the distribution of the alleles between the men and the women were not found. The novel method developed in our laboratory proved to be simple and highly customizable., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Follicular lymphoma (FL) is one of the most common Non-Hodgkin lymphoma (NHL) subtype. Only small number of studies concerning NHL and DNA reparation gene polymorphisms has been performed so far. Hence, we have assessed the effect of 4 selected polymorphisms with possible influence on risk of FL development in a case-control study in Slovak population. We have genotyped polymorphisms in the RAG1 (K820R), LIG4 (T9I), BRCA2 (N372H), and WRN (V114I) genes in 108 patients with histologically proven FL diagnosis and 127 healthy controls. For discrimination between the allelic variants, we have established the genotyping by real-time melting analysis of an unlabeled probe. The most notable finding was related to polymorphism N372H in the BRCA2 gene. Compared with the wild-type genotype (NN), the homozygous variant genotype (HH) was associated with an increased FL risk (OR = 2.91, 95% CI: 0.96-8.81), although on the borderline of statistical significance (P = 0.050). However, after stratification by gender and age, the FL risk was significantly increased in men with variant-containing genotypes (OR = 2.79, 95% CI: 1.20-6.45) and even severalfold significantly increased among men with homozygous variant BRCA2 genotype (OR = 21.18, 95% CI: 2.46-182.2). No significant associations with FL risk were identified for other polymorphisms.

N-acetyltransferase 2 (NAT2) is phase II enzyme with major roles in catalyzing the detoxification of aromatic amines, which are known risk factors for bladder cancer, and are ubiquitously present in the environment. We assessed the association between common polymorphisms in NAT2 gene and the risk of bladder cancer in 90 Slovak patients and 274 ethnicity-matched healthy controls. Effect modifications by smoking, age and gender were also evaluated. Overall, NAT2 slow acetylation was associated with significantly increased risk of bladder cancer (OR = 1.90; 95% CI, 1.15-3.16). In stratified analyses by age and gender, the elevated risk conferred by slow acetylator genotype was evident in older individuals (OR = 3.55; 95% CI, 1.77-7.35) and males (OR = 4.65; 95% CI, 1.68-16.10), with further increasing in NAT2*5B/*6A genotype carriers. Smoking was confirmed to be important risk factor, moreover, the risk was markedly increased in smokers with NAT2 slow acetylator genotype, and NAT2*5B/*6A carriers especially. In summary, these findings are consistent with previous literature suggesting that individual susceptibility to bladder cancer may be modulated by NAT2 polymorphisms, particularly in interaction with relevant environmental exposures such as smoking.