Association of Polymorphic Variants of TCF7L2 and PPARG Genes with Metabolic Markers in Patients with Early Disorders of Carbohydrate Metabolism.

We performed complex analysis of the association of polymorphic variants rs7903146 of the TCF7L2 gene and rs1801282 of the PPARG gene with metabolic parameters, insulin resistance, and ß-cell function in a group of patients with early signs of carbohydrate metabolism disturbances in a sample of Tyumen citizens. The study group consisted of 64 people (39 women, 25 men) aged 40-70 years. The distribution of frequencies of alleles and genotypes of the polymorphic markers rs7903146 and rs1801282 was analyzed and associations of carriage of major homozygous polymorphisms with various phenotypic traits were identified. Genotyping for polymorphic variants of TCF7L2 and PPARG genes was performed using allele-specific PCR with primers provided by Synthol company. Carriers of homozygotes for allele C of the polymorphic marker rs7903146 significantly differed from other respondents by a higher level of C-peptide, as well as by the presence of associations with waist circumference, elevated level of glycated hemoglobin, and arterial hypertension. Carriers of homozygotes for the allele C of the rs1801282 polymorphism of the PPARG gene differed from the group of carriers of homozygotes for the allele G and the group of heterozygote carriers by higher levels of triglycerides, as well as the presence of associations with waist circumference and the level of glycated hemoglobin.

Integrating Common Risk Factors with Polygenic Scores Improves the Prediction of Type 2 Diabetes.

We tested associations between 13 established genetic variants and type 2 diabetes (T2D) in 1371 study participants from the Volga-Ural region of the Eurasian continent, and evaluated the predictive ability of the model containing polygenic scores for the variants associated with T2D in our dataset, alone and in combination with other risk factors such as age and sex. Using logistic regression analysis, we found associations with T2D for the CCL20 rs6749704 (OR = 1.68, PFDR = 3.40 × 10-5), CCR5 rs333 (OR = 1.99, PFDR = 0.033), ADIPOQ rs17366743 (OR = 3.17, PFDR = 2.64 × 10-4), TCF7L2 rs114758349 (OR = 1.77, PFDR = 9.37 × 10-5), and CCL2 rs1024611 (OR = 1.38, PFDR = 0.033) polymorphisms. We showed that the most informative prognostic model included weighted polygenic scores for these five loci, and non-genetic factors such as age and sex (AUC 85.8%, 95%CI 83.7-87.8%). Compared to the model containing only non-genetic parameters, adding the polygenic score for the five T2D-associated loci showed improved net reclassification (NRI = 37.62%, 1.39 × 10-6). Inclusion of all 13 tested SNPs to the model with age and sex did not improve the predictive ability compared to the model containing five T2D-associated variants (NRI = -17.86, p = 0.093). The five variants associated with T2D in people from the Volga-Ural region are linked to inflammation (CCR5, CCL2, CCL20) and glucose metabolism regulation (TCF7L, ADIPOQ2). Further studies in independent groups of T2D patients should validate the prognostic value of the model and elucidate the molecular mechanisms of the disease development.

Genetic Predictors of Change in Episodic Verbal Memory by Cognitive Intervention: ACT, PICALM, BDNF, NRG1, APOE Genes and Their Interactions in Situations of Cognitive Demand.

BACKGROUND: Cognitive interventions (CIs) in the elderly are activities that seek to improve cognitive performance and delay its deterioration. Our objectives were to study potential genetic predictors of how a CI program may influence immediate and delayed episodic verbal memory (EVM). METHODS: 162 participants were elderly individuals without dementia who were randomized into parallel control and experimental groups. Participants underwent genetic testing to analyze the PICALM, ACT, NRG1, BDNF and APOE genes. We performed a broad neuropsychological assessment before and 6 months after the CI. The CI involved multifactorial training (30 sessions). The control group undertook the centre's standard activities. The main outcome measures were the genotype studied as a predictor of post-intervention changes in EVM. RESULTS: We found the CI was associated with improvements in several cognitive functions, including immediate and delayed EVM. While no individual gene was associated with any such change, the interaction between PICALM/ACT (p = 0.008; Eta2 = 0.23) and PICALM/NRG1 (p = 0.029; Eta2 = 0.19) was associated with improved immediate EVM, and the NRG1/BDNF interaction was associated with improved delayed EVM (p = 0.009; Eta2 = 0.21). The APOEε4 genotype was not associated with any change in EVM. CONCLUSIONS: Our study shows that the participants' genotype can have an impact on the results of CIs. Cognitive stress may stimulate the interaction of various genes and as such, different types of CI should be established for distinct groups of people taking into account the individual's characteristics, like genotype, to improve the results of this type of health prevention and promotion activity.

[Molecular genetic predictors of the development of urolithiasis].

Urolithiasis is one of the most urgent problems of clinical urology. Currently, there is no consensus on the causes of stone formation, as well as the role of various factors in the development of urolithiasis, however, increasingly, according to various studies, the leading role is given to genetic causes. The article presents a modern review of data on genetic polymorphisms associated with ICD: rs1801197 and rs6776158 of the CASR gene; TaqI of the VDR gene; rs1801197 of the CALCR gene, rs3752472, rs650439, rs2853744 of the Klotho gene.

[Possible Genetic Predictors of Cardiovascular Complications After Coronary Artery Bypass Surgery].

PURPOSE: to investigate associations of single nucleotide polymorphisms (SNPs) rs2046934, rs1126643, rs5918, rs6065, rs4244285; rs4986893 with cardiovascular complications (CVC) in patients after CABG. MATERIALS AND METHODS: We enrolled in this study 130 patients with stable functional class II-IV angina. After CABG 69 patients received ASA (100 mg of enteric form), 61 patients received dual antiplatelet therapy (ASA 100 mg + clopidogrel 75 mg). Mean follow up period was 10.9±5.2 months. The primary composite endpoint included all-cause mortality, myocardial infarction (MI), and ischemic stroke. The control group comprised 185 healthy volunteers. Platelet function was assessed using light transmission aggregometry with ADP (5µM) and arachidonic acid (1 mM). The following single nucleotide polymorphisms (SNPs) were identified by real-time PCR: rs2046934 (H1/H2) on P2RY12 [encoding platelet ADP receptor] (n=100); rs1126643 (C807T, Phe224Phe) on ITGA2 [encoding collagen receptor] (n=87); rs5918 (176T>C, Leu33Pro) on ITGB3 [encoding fibrinogen receptor) (n=91); rs6065 (Thr145Met) on GP1BA [encoding platelet receptor for Von Willebrand factor] (n=114); rs4244285 (*2) (n=84), and rs4986893 (*3) (n=83) on СYP2C19 [encoding cytochrome P450 activity]. RESULTS: The prevalence of rs5918, rs6065, rs4244285, rs4986893, rs2046934 did not differ significantly between patients and healthy volunteers. The mutant allele (T) of ITGA2 was detected more often in healthy volunteers: 67.2 % vs 51.7 % (р=0.021). Before and after CABG there was no significant difference in platelet aggregation between carries and non-carries of the mutant ITGA2 allele. Number of CVCs registered during follow-up was 12: 3 strokes, 6 MIs, 3 deaths. Patients with composite mutant alleles of ITGB3+СYP2C19*2 or СYP2C19*2+ITGA2, and with the mutant allele (*2) of СYP2C19 met end points more often than patients with other gene combinations (wild type homozygotes, presence of one mutant allele of ITGB3 or ITGA2, the composite of mutant alleles of ITGB3+ITGA2 or ITGB3+ITGA2+ СYP2C19*2) (hazard ratio 4.0, 95 % confidence interval 2,19-7.29, р=0.008). Carriers of ITGB3 mutant allele showed higher AA-induced platelet reactivity on the 1st-3rd day after CABG. Amplitude of platelet aggregation in carriers of mutant allele was 27.5 % vs 12.7 % in wild type (p=0.016). No differences in platelet reactivity among carriers of other mentioned mutant alleles and wild types were observed. CONCLUSION: Carriage of the combination of mutant alleles ITGB3+СYP2C19*2 or СYP2C19*2+ITGA2 or СYP2C19*2 is possible predictor of CVC in patients after CABG.

Sensorimotor Learning: Neurocognitive Mechanisms and Individual Differences.

Here we provide an overview of findings and viewpoints on the mechanisms of sensorimotor learning presented at the 2016 Biomechanics and Neural Control of Movement (BANCOM) conference in Deer Creek, OH. This field has shown substantial growth in the past couple of decades. For example it is now well accepted that neural systems outside of primary motor pathways play a role in learning. Frontoparietal and anterior cingulate networks contribute to sensorimotor adaptation, reflecting strategic aspects of exploration and learning. Longer term training results in functional and morphological changes in primary motor and somatosensory cortices. Interestingly, re-engagement of strategic processes once a skill has become well learned may disrupt performance. Efforts to predict individual differences in learning rate have enhanced our understanding of the neural, behavioral, and genetic factors underlying skilled human performance. Access to genomic analyses has dramatically increased over the past several years. This has enhanced our understanding of cellular processes underlying the expression of human behavior, including involvement of various neurotransmitters, receptors, and enzymes. Surprisingly our field has been slow to adopt such approaches in studying neural control, although this work does require much larger sample sizes than are typically used to investigate skill learning. We advocate that individual differences approaches can lead to new insights into human sensorimotor performance. Moreover, a greater understanding of the factors underlying the wide range of performance capabilities seen across individuals can promote personalized medicine and refinement of rehabilitation strategies, which stand to be more effective than "one size fits all" treatments.

Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review.

Drug hypersensitivity includes allergic (AR) and nonallergic reactions (NARs) influenced by genetic predisposition. We performed a systematic review of genetic predictors of IgE-mediated AR and NAR with MEDLINE and PubMed search engine between January 1966 and December 2014. Among 3110 citations, the search selected 53 studies, 42 of which remained eligible. These eligible studies have evaluated genetic determinants of immediate reactions (IR) to beta-lactams (n = 19), NAR against aspirin (n = 12) and other nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 8), and IR to biologics (n = 3). We reported two genomewide association studies and four case-control studies on candidate genes validated by replication. Genes involved in IR to beta-lactams belonged to HLA type 2 antigen processing, IgE production, atopy, and inflammation, including 4 genes validated by replications, HLA-DRA, ILR4, NOD2, and LGALS3. Genes involved in NAR to aspirin belonged to arachidonic acid pathway, membrane-spanning 4A gene family, histamine production pathway, and pro-inflammatory cytokines, while those involved in NAR to all NSAIDs belonged to arachidonic acid pathway and HLA antigen processing pathway. ALOX5 was a common predictor of studies on NAR to both aspirin and NSAIDs. Although these first conclusions could be drawn, this review highlights also the lack of reliable data and the need for replicating studies in contrasted populations, taking into account worldwide allele frequencies, gene-gene interactions, and contrasted situations of environmental exposure.

Mendelian Randomization Analysis Identifies Inverse Causal Relationship between External Eating and Metabolic Phenotypes.

Disordered eating contributes to weight gain, obesity, and type 2 diabetes (T2D), but the precise mechanisms underlying the development of different eating patterns and connecting them to specific metabolic phenotypes remain unclear. We aimed to identify genetic variants linked to eating behaviour and investigate its causal relationships with metabolic traits using Mendelian randomization (MR). We tested associations between 30 genetic variants and eating patterns in individuals with T2D from the Volga-Ural region and investigated causal relationships between variants associated with eating patterns and various metabolic and anthropometric traits using data from the Volga-Ural population and large international consortia. We detected associations between HTR1D and CDKAL1 and external eating; between HTR2A and emotional eating; between HTR2A, NPY2R, HTR1F, HTR3A, HTR2C, CXCR2, and T2D. Further analyses in a separate group revealed significant associations between metabolic syndrome (MetS) and the loci in CRP, ADCY3, GHRL, CDKAL1, BDNF, CHRM4, CHRM1, HTR3A, and AKT1 genes. MR results demonstrated an inverse causal relationship between external eating and glycated haemoglobin levels in the Volga-Ural sample. External eating influenced anthropometric traits such as body mass index, height, hip circumference, waist circumference, and weight in GWAS cohorts. Our findings suggest that eating patterns impact both anthropometric and metabolic traits.

Associations between behavioral and self-reported impulsivity, brain structure, and genetic influences in middle childhood.

Impulsivity undergoes a normative developmental trajectory from childhood to adulthood and is thought to be driven by maturation of brain structure. However, few large-scale studies have assessed associations between impulsivity, brain structure, and genetic susceptibility in children. In 9112 children ages 9-10 from the ABCD study, we explored relationships among impulsivity (UPPS-P impulsive behavior scale; delay discounting), brain structure (cortical thickness (CT), cortical volume (CV), and cortical area (CA)), and polygenic scores for externalizing behavior (PGSEXT). Both higher UPPS-P total scores and more severe delay-discounting had widespread, low-magnitude associations with smaller CA in frontal and temporal regions. No associations were seen between impulsivity and CV or CT. Additionally, higher PGSEXT was associated with both higher UPPS-P scores and with smaller CA and CV in frontal and temporal regions, but in non-overlapping cortical regions, underscoring the complex interplay between genetics and brain structure in influencing impulsivity. These findings indicate that, within large-scale population data, CA is significantly yet weakly associated with each of these impulsivity measures and with polygenic risk for externalizing behaviors, but in distinct brain regions. Future work should longitudinally assess these associations through adolescence, and examine associated functional outcomes, such as future substance use and psychopathology.

Comprehensive analysis and establishment of a prognostic model based on non-genetic predictors in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a systemic hematological malignancy usually incurable. The value of some important prognostic factors may gradually decrease. OBJECTIVE: We aimed to explore the non-genetic indexes, prognostic models, and significance of clinical staging systems of MM. METHODS: A retrospective analysis was conducted on clinical data from 110 patients with MM who first visit the First Affiliated Hospital of Guangzhou Medical University between September 2005 to December 2018. RESULTS: Bone marrow plasma cell percentage (BMPC%), cystatin C (CysC), and ß2 microglobulin (ß2-MG) were positively correlated with Durie-Salmon (D-S) and international staging system (ISS) stages, while red blood cell count (RBC) and hemoglobin volume (HGB) were negatively correlated (P< 0.05). Univariate analysis showed that ISS stage, treatment protocol, immunofixation electrophoresis (IFE), ratio of red cell distribution width to platelet count (RPR), monocyte count (MONO), lactate dehydrogenase, and immunoglobulin G were significantly associated with the three-year overall survival (OS). IFE, treatment protocol, and ß2-MG significantly affected progression-free survival (P< 0.05). Multivariate analysis showed that the treatment protocol, ISS stage, RPR, MONO, and IFE were independent prognostic factors for three-year OS (P< 0.05). CONCLUSIONS: BMPC%, CysC, and ß2-MG were positively correlated with both clinical staging systems and RBC and HGB were negatively correlated. RPR and MONO affect MM prognosis and the established prognostic model can guide patient prognosis.

Transcriptome Changes and Metabolic Outcomes After Bariatric Surgery in Adults With Obesity and Type 2 Diabetes.

Context: Bariatric surgery has been shown to be effective in inducing complete remission of type 2 diabetes in adults with obesity. However, its efficacy in achieving complete diabetes remission remains variable and difficult to predict before surgery. Objective: We aimed to characterize bariatric surgery-induced transcriptome changes associated with diabetes remission and the predictive role of the baseline transcriptome. Methods: We performed a whole-genome microarray in peripheral mononuclear cells at baseline (before surgery) and 2 and 12 months after bariatric surgery in a prospective cohort of 26 adults with obesity and type 2 diabetes. We applied machine learning to the baseline transcriptome to identify genes that predict metabolic outcomes. We validated the microarray expression profile using a real-time polymerase chain reaction. Results: Sixteen patients entered diabetes remission at 12 months and 10 did not. The gene-expression analysis showed similarities and differences between responders and nonresponders. The difference included the expression of critical genes (SKT4, SIRT1, and TNF superfamily), metabolic and signaling pathways (Hippo, Sirtuin, ARE-mediated messenger RNA degradation, MSP-RON, and Huntington), and predicted biological functions (ß-cell growth and proliferation, insulin and glucose metabolism, energy balance, inflammation, and neurodegeneration). Modeling the baseline transcriptome identified 10 genes that could hypothetically predict the metabolic outcome before bariatric surgery. Conclusion: The changes in the transcriptome after bariatric surgery distinguish patients in whom diabetes enters complete remission from those who do not. The baseline transcriptome can contribute to the prediction of bariatric surgery-induced diabetes remission preoperatively.

Incidence and predictors of anthracycline-related left ventricular dysfunction in acute myeloid leukemia.

INTRODUCTION: Anthracycline-related left ventricular dysfunction (ARLVD) is a concern in patients with acute myeloid leukemia (AML) undergoing anthracyclinecontaining induction chemotherapy. However, the incidence of ARLVD in the modern era of routine pretreatment left ventricular ejection fraction (LVEF) echocardiographic assessment, as well as the clinical and genetic predictors of ARLVD are not well understood. METHODS: Consecutive adult patients with AML receiving anthracycline-containing induction chemotherapy at the Dana-Farber Cancer Institute from 2014 to 2022 were studied. Inclusion criteria included availability of a pre and post chemotherapy echocardiogram to assess the LVEF, pre-treatment LVEF > 50 %, as well as comprehensive diagnostic next generation sequencing assessing for the presence of myeloid mutations. The primary endpoint was the incidence of ARLVD defined as LVEF < 50 % post-induction. RESULTS: Out of 419 patients meeting inclusion criteria, 34 (8%) patients developed ARLVD. Among the 122/419 patients who did not undergo planned allogeneic stem cell transplantation (allo-SCT), ARLVD was the deciding factor for ineligibility in 4 patients (1%). Baseline cardiovascular comorbidities (hypertension, diabetes mellitus, hyperlipidemia, smoking and coronary artery disease) and cumulative anthracycline dose were not predictive of post-induction ARLVD. However, the presence of a JAK2 mutation (but not other myeloid mutations) was associated with an increased risk of ARLVD in multivariable analysis (OR 8.34, 95 % CI 1.55-39.3, p = 0.007). DISCUSSION: In a group of AML patients with normal LVEF prior to anthracycline-containing induction chemotherapy, ARLVD was infrequent and did not commonly preclude post-remission allo-SCT consolidation. Genetic predictors of ARLVD require further investigation in a larger patient cohort.

Genetic Predictors of the Development of Complications after Coronary Stenting.

Due to the fact that there are scientific discussions about the significance of gene polymorphisms in the risk of developing cardiovascular complications after a percutaneous coronary intervention, it is of interest to evaluate the genetic predictors of the development of cardiovascular events. This study is a molecular genetic study. Association with the genes of biomarkers for inflammation and immune response increases the risk of cardiovascular events: rs1234313 (TNFSF4): (A/G, OR-4.57 (2.35-8.87), p ≤ 0.0001), (A/G-A/A, OR-3.14 (1.75-5.63), p ≤ 0.0001), and (A/G, OR = 4.01 (2.19-7.36), p ≤ 0.0001); rs3184504 (SH2D3); ATXN2: (C/T, OR-2.53 (1.28-5.01), T/T, OR-2.99 (1.13-7.92), p = 0.017)), (C/T-T/T, OR-2.61 (1.35-5.07), p = 0.000), and (OR-1.89 (1.15-3.09), p = 0.009)). According to the lipid metabolism biomarker genes, rs2943634: (A/C OR-2.57 (1.18-5.62), p = 0.013); according to the endothelial biomarker genes, rs2713604: (DNAJB8-AS1; GATA2): (C/T, OR-4.27 (2.35-7.76), p ≤ 0.0001), (C/T-C/C, OR-4.13 (2.31-7.40), p ≤ 0.0001), (OR-4.05 (2.24-7.30), p ≤ 0.0001), and (C/T, OR-3.46 (1.99-6.00), p ≤ 0.0001). The regression analysis found that in the presence of the rs2943634 gene polymorphism, the risk of late cardiovascular events increases by 4.007 times with 95% CI (1.502:10.692), p = 0.006. The genes of biomarkers for the risk of cardiovascular events are rs1234313(TNFSF4), rs3184504 (SH2D3; ATXN2), rs2943634, and rs2713604 (DNAJB8-AS1; GATA2). The only predictor of the development of new cardiovascular events was rs2943634, which belongs to the group of lipid metabolism biomarkers.

Novel Gene Mutations Regulating Immune Responses in Autoimmune Polyglandular Syndrome With an Atypical Course.

CONTEXT: Autoimmune polyglandular syndrome (APS) is a cluster of endocrine disorders arising from immune dysregulation, often combined with damage to nonendocrine organs. There are 2 types of APS: type 1 and type 2 (APS-1 and APS-2, respectively). In clinical practice, an atypical course of APS is often observed. OBJECTIVE: This work aims to find a novel genetic predictor of APS. METHODS: We performed exome sequencing in 2 patients with an atypical clinical APS picture and members of their families. Patient A presented with a manifestation of APS-2 in early childhood and patient B with a late manifestation of the main components of APS-1. RESULTS: In patient B, we identified inherited compound mutations as a novel combination of the c.769C > T and c.821delG alleles of AIRE and genetic variation in the CIITA gene. No homozygous or compound mutations in AIRE were found in patient A, but we did reveal mutations in genes encoding regulatory proteins of innate and acquired immunity in this patient. CONCLUSION: Our data revealed novel combination of mutations in the AIRE gene in atypical APS and imply that mutations in immune-related genes may modify the clinical manifestation of APS in AIRE-mutation carriers and contribute to the development of autoimmune pathology in non-AIRE carriers with atypical APS.

Recurrence of Graves' Disease: What Genetics of HLA and PTPN22 Can Tell Us.

Background: Approximately half of patients diagnosed with Graves' disease (GD) relapse within two years of thyreostatic drug withdrawal. It is then necessary to decide whether to reintroduce conservative treatment that can have serious side effects, or to choose a radical approach. Familial forms of GD indicate a significant genetic component. Our aim was to evaluate the practical benefits of HLA and PTPN22 genetic testing for the assessment of disease recurrence risk in the Czech population. Methods: In 206 patients with GD, exon 2 in the HLA genes DRB1, DQA1, DQB1 and rs2476601 in the gene PTPN22 were sequenced. Results: The risk HLA haplotype DRB1*03-DQA1*05-DQB1*02 was more frequent in our GD patients than in the general European population. During long-term retrospective follow-up (many-year to lifelong perspective), 87 patients relapsed and 26 achieved remission lasting over 2 years indicating a 23% success rate for conservative treatment of the disease. In 93 people, the success of conservative treatment could not be evaluated (thyroidectomy immediately after the first attack or ongoing antithyroid therapy). Of the examined genes, the HLA-DQA1*05 variant reached statistical significance in terms of the ability to predict relapse (p=0.03). Combinations with either both other HLA risk genes forming the risk haplotype DRB1*03-DQA1*05-DQB1*02 or with the PTPN22 SNP did not improve the predictive value. Conclusion: the DQA1*05 variant may be a useful prognostic marker in patients with an unclear choice of treatment strategy.

Factors affecting weight loss variability in obesity.

Current obesity treatment strategies include diet, exercise, bariatric surgery, and a limited but growing repertoire of medications. Individual weight loss in response to each of these strategies is highly variable. Here we review research into factors potentially contributing to inter-individual variability in response to treatments for obesity, with a focus on studies in humans. Well-recognized factors associated with weight loss capacity include diet adherence, physical activity, sex, age, and specific medications. However, following control for each of these, differences in weight loss appear to persist in response to behavioral, pharmacological and surgical interventions. Adaptation to energy deficit involves complex feedback mechanisms, and inter-individual differences likely to arise from a host of poorly defined genetic factors, as well as differential responses in neurohormonal mechanisms (including gastrointestinal peptides), metabolic efficiency and capacity of tissues, non-exercise activity thermogenesis, thermogenic response to food, and in gut microbiome. A better understanding of the factors involved in inter-individual variability in response to therapies will guide more personalized approaches to the treatment of obesity.

Genetic predictors of efficacy and toxicity of iguratimod in patients with rheumatoid arthritis.

Iguratimod (IGU) is a novel disease-modifying anti-rheumatic drug (DMARD) in rheumatoid arthritis (RA). Like other DMARDs, IGU exhibited significant differences in effectiveness and safety. AIM: The aim of this study was to identify genetic predictorsof efficacyand toxicity of IGU in patients with RA. MATERIALS & METHODS: Seven SNPs from IGU-metabolizing genes were genotyped in 272 IGU-treated patients with RA. Results: ABCG2 rs2231142 A allele conferred a higher response to IGU, while NAT2 rs1495742 G carriersconferred a lower response to IGU. CYP2C19*2 rs4244285 A carriers had higher risk for IGU-induced toxicity compared to the GG carriers. CONCLUSION: Our study suggests that the polymorphisms of ABCG2 (rs2231142), NAT2 (rs1495741)and CYP2C19*2 (rs4244285) may help to predict thetherapeutic effectiveness and toxicity of IGU in patients with RA.

The Prognostic Value of Combinations of Genetic Polymorphisms in the ITGB3, ITGA2, and CYP2C19*2 Genes in Predicting Cardiovascular Outcomes After Coronary Bypass Grafting.

AIM: To determine if there are any associations between the single nucleotide polymorphisms (SNPs): rs2046934, rs1126643, rs5918, rs6065, rs4244285; rs4986893 and the occurrence of cardiovascular events (CVE) in patients following coronary artery bypass grafting (CABG) surgery. MATERIALS AND METHODS: The study included 130 CABG patients with stable angina grades II-IV. After CABG 69 of the patients were treated with acetylsalicylic acid (ASA) alone, and 61 received dual antiplatelet therapy (ASA+clopidogrel). Platelet function was assessed by light transmission aggregometry with adenosinediphosphate and arachidonic acid. The SNPs were identified by real-time polymerase chain reaction (PCR) with electrophoretic detection. The mean follow-up period was equal to 10.9 ± 5.2 months. The primary end point included the composite of all-cause mortality, myocardial infarction (MI), and ischemic stroke. RESULTS: During the follow-up period 12 CVE were registered: 3 deaths, 6 MI, 3 strokes. Patients with composite mutant alleles of ITGB3+CYP2C19*2 or CYP2C19*2 + ITGA2, and with the mutant allele (*2) of CYP2C19, met end points more often than patients with other gene combinations (wild-type homozygotes, presence of one mutant allele of ITGB3 or ITGA2, the composite of mutant alleles of ITGB3+ITGA2 or ITGB3+ITGA2+CYP2C19*2; hazard ratio = 4, 95% confidence interval: 2.19-7.29, p = 0.008). CONCLUSION: Carriage of a combination of mutant alleles in multiple genes including ITGB3+CYP2C19*2 or CYP2C19*2 + ITGA2 or CYP2C19*2 are possible predictors of CVE in patients after CABG.

Identification of novel potential genetic predictors of urothelial bladder carcinoma susceptibility in Pakistani population.

Urothelial bladder carcinoma (UBC) is the most common among urinary bladder neoplasms. We carried out a preliminary study to determine the genetic etiology of UBC in Pakistani population, for this 25 sequence variants from 17 candidate genes were studied in 400 individuals by using polymerase chain reaction-based techniques. Multivariate logistic regression analysis was performed for association analysis of the overall data as well as the data stratified by smoking status, tumor grade and tumor stage. Variants of GSTM1, IGFBP3, LEPR and ACE were found to be associated with altered UBC risk in the overall comparison. CYP1B1 and CDKN1A variants displayed a risk modulation among smokers; IGFBP3 and LEPR variants among non-smokers while GSTM1 polymorphism exhibited association with both. GSTM1 and LEPR variants conferred an altered susceptibility to low grade UBC; GSTT1, IGFBP3 and PPARG variants to high grade UBC while ACE polymorphism to both grades. GSTM1 and LEPR variants exhibited risk modulation for non-muscle-invasive bladder cancer (NMIBC); GSTT1 and PPARG variants for muscle-invasive bladder cancer (MIBC), and ACE variant for NMIBC as well as MIBC. In general, the susceptibility markers were common for low grade and NMIBC; and distinct from those for high grade and MIBC indicating the distinct pathologies of both groups. In brief, our results conform to reports of previously associated variants in addition to identifying novel potential genetic predictors of UBC susceptibility.

Beyond Mendelian randomization: how to interpret evidence of shared genetic predictors.

OBJECTIVE: Mendelian randomization is a popular technique for assessing and estimating the causal effects of risk factors. If genetic variants which are instrumental variables for a risk factor are shown to be additionally associated with a disease outcome, then the risk factor is a cause of the disease. However, in many cases, the instrumental variable assumptions are not plausible, or are in doubt. In this paper, we provide a theoretical classification of scenarios in which a causal conclusion is justified or not justified, and discuss the interpretation of causal effect estimates. RESULTS: A list of guidelines based on the 'Bradford Hill criteria' for judging the plausibility of a causal finding from an applied Mendelian randomization study is provided. We also give a framework for performing and interpreting investigations performed in the style of Mendelian randomization, but where the choice of genetic variants is statistically, rather than biologically motivated. Such analyses should not be assigned the same evidential weight as a Mendelian randomization investigation. CONCLUSION: We discuss the role of such investigations (in the style of Mendelian randomization), and what they add to our understanding of potential causal mechanisms. If the genetic variants are selected solely according to statistical criteria, and the biological roles of genetic variants are not investigated, this may be little more than what can be learned from a well-designed classical observational study.