Gly Allele Research Articles

Abstract B035: Investigating the roles of GLI transcription factors in the pancreatic cancer microenvironment

Abstract Pancreatic ductal adenocarcinoma (PDA) remains a difficult cancer to treat due to an extensive and complex tumor microenvironment. In particular, intercellular signaling between tumor cells, fibroblasts and immune cells is a key contributor to pancreatic tumor growth. One of these signals, the Hedgehog (HH) pathway, is a known feature of PDA. Pancreatic tumor cells secrete HH ligands, which signal in a paracrine fashion to fibroblasts in the tumor microenvironment. Notably, the role of HH signaling is complicated, with reports suggesting both tumor-promoting and tumor-restraining functions in pancreatic cancer. GLI proteins (GLI1-3) are the transcriptional effectors of the HH pathway; their contribution to pancreatic tumor growth is equally complex. This study seeks to investigate the contribution of GLI1-3 in PDA progression. Our lab has demonstrated that Gli1-3 are expressed in pancreatic fibroblasts and that all three Glis functionally contribute to pancreatic cancer progression through effects on immune cell infiltration. To further explore the mechanisms of GLI function, we have generated a novel mouse model carrying endogenous, epitope-tagged Gli alleles (Gli1FLAG/FLAG;Gli2HA/HA;Gli3V5/V5). This model will allow us to define GLI protein processing and localization as well as the identification of target genes to elucidate the contribution of GLI-driven transcriptional programs that regulate tumor immune infiltration in PDA. Citation Format: Paola Isabel Medina-Cabrera, Michael Scales, Nina Steele, Benjamin Allen, Marina Pasca di Magliano. Investigating the roles of GLI transcription factors in the pancreatic cancer microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B035.

The role of Toll-like receptor 4 gene polymorphism in the development of organ dysfunction in patients with severe pneumonia associated with A/H1N1 influenza

The aim of the study. To identify the frequency of occurrence of TLR4 Asp299Gly (rs4986790) gene polymorphism and to establish its contribution to the development of organ dysfunction in patients with severe pneumonia associated with A/H1N1 influenza.Materials and methods. The study included 55 patients with severe pneumonia associated with A/H1N1 influenza. Inclusion criteria: severe pneumonia; consolidation/ground-glass syndrome according to chest X-ray/CT. Exclusion criteria: unstable hemodynamics; body mass index > 30; diabetes mellitus; HIV; tuberculosis, oncopathology. Verification of the pathogen in the respiratory swab was carried out using PCR method: A/H1N1 influenza virus RNA was identified. The age of the patients was 47 [38; 62] years. Among all the patients the proportion of men was 47.8 %, of women – 52.2 %. Patients were divided into 2 groups: group 1 included patients with SOFA scale (Sequential Organ Failure Assessment) score ≥ 2 points; group 2 – patients with SOFA scale score ˂ 2 points. Gene SNPs were determined by PCR method using standard kits developed by Research and Production Company “Litekh” (Moscow). Amplification of the TLR4 gene fragments was carried out in a thermocycler Bis-M111 (Bis-N LLC, Novosibirsk). Genomic DNA isolated from whole blood leukocytes using the “DNA Express Blood” reagent was analyzed followed by an amplification reaction. The amplification product was detected in a 3% agarose gel.Results. Multiple organ dysfunction (SOFA scale score ≥ 2 points) in patients with severe pneumonia associated with A/H1N1 influenza was registered in 24 (43.6 %) cases. When analyzing the frequency of occurrence of the minor Gly allele, according to genetic models, the differences were established between patients of the groups 1 and 2 in codominant (p = 0.023; odds ratio (OR) – 8.82 (0.95–81.89)) and dominant (p = 0.005; OR = 12.35 (1.40–109.07)) models.Conclusion. Severe pneumonia associated with A/H1N1 influenza is accompanied by a high incidence of organ dysfunction. The risk of organ failure development is 2.1 times increased in patients with severe pneumonia with identified TLR4 Asp299Gly gene polymorphism, which probably requires further study.

The PPARGC1A Gly482Ser polymorphism is associated with elite long-distance running performance

ABSTRACT Success in long-distance running relies on multiple factors including oxygen utilisation and lactate metabolism, and genetic associations with athlete status suggest elite competitors are heritably predisposed to superior performance. The Gly allele of the PPARGC1A Gly482Ser rs8192678 polymorphism has been associated with endurance athlete status and favourable aerobic training adaptations. However, the association of this polymorphism with performance amongst long-distance runners remains unclear. Accordingly, this study investigated whether rs8192678 was associated with elite status and competitive performance of long-distance runners. Genomic DNA from 656 Caucasian participants including 288 long-distance runners (201 men, 87 women) and 368 non-athletes (285 men, 83 women) was analysed. Medians of the 10 best UK times (Top10) for 10 km, half-marathon and marathon races were calculated, with all included athletes having personal best (PB) performances within 20% of Top10 (this study’s definition of “elite”). Genotype and allele frequencies were compared between athletes and non-athletes, and athlete PB compared between genotypes. There were no differences in genotype frequency between athletes and non-athletes, but athlete Ser allele carriers were 2.5% faster than Gly/Gly homozygotes (p = 0.030). This study demonstrates that performance differences between elite long-distance runners are associated with rs8192678 genotype, with the Ser allele appearing to enhance performance.

The role of PPARGC1A and the RS8192678 polymorphism in determining the performance of athletes

Annotation. The impact of genetics on physiology and sports performance is one of the most controversial areas of sports medicine. Studies have shown that in addition to wild-type genes, almost 200 gene polymorphisms affect athletic performance, and more than 20 polymorphisms can determine the status of elite athletes. Sports results are manifested to a greater extent not only due to environmental factors, but also due to the athlete's own genotype, so the purpose of our review article is to study the effects of the PPARGC1A gene and its rs8192678 polymorphism on sports characteristics. For this purpose, we analyzed and processed the information known to date about a specific gene and the effects of its polymorphism, using the main databases. The PPARGC1A gene plays an important role in a number of physiological processes and is responsible for the metabolism of glucose and ATP, to a greater extent in muscle tissue; for oxidative processes in organs; and for switching one or another type of muscle fibers depending on the force load. It was proved that the expression of this gene can be induced under the influence of low temperatures. The PPARGC1A polymorphism has different effects on athletic performance, depending on its alleles. For example, the Gly allele, associated with muscle strength and endurance, favors athletic performance, while the Ser allele and the Ser-Gly genotype show no significant evidence. The results of our review are intended to help select a training strategy for each athlete in order to understand the role of environment and genotype in achieving athletic success.

Genetic Polymorphism of beta1-adrenergic Receptors and the Effect on the Clinical Efficacy of beta-adrenoblockers

Beta-adrenergic blockers are a valuable class of cardiovascular drugs and are widely used in the treatment of arterial hypertension (AH), coronary heart disease, chronic heart failure (CHF), cardiac arrhythmias, significantly improving the prognosis of patients. However, the clinical efficacy of betablockers is largely dependent on the genetic polymorphism of beta1-adrenergic receptors (ADRB1). The aim of the review was a systematic analysis of scientific data from pharmacogenetic studies on the role of beta1-adrenergic receptor polymorphism in the clinical efficacy of beta-blockers in the treatment of hypertension, chronic heart failure, and atrial fibrillation. The results of clinical trials and meta-analyzes were used. Of greatest importance is the genetic polymorphism of beta1-adrenergic receptors of two loci – Arg389Gly and Ser49Gly; the frequency of occurrence of variant and less functionally active alleles Gly389 and Gly49 in Europeans reaches 27% and 15%. The variant Gly389 allele has reduced functional activity and carriers have a weak response to the use of beta-blockers. In carriers of variant alleles Gly389 and Gly49 a reduced hypotensive effect on the use of beta-blockers was observed, and in studies of long-term efficacy, carriage of variant alleles was accompanied by an increase in the frequency and risk of unfavorable outcomes of hypertension. In pharmacogenetic studies, a reduced effect of the effect on myocardial remodeling in patients with CHF for beta-blockers in carriers of the variant Gly389 allele were confirmed. According to two meta-analyzes of trials on use of beta-blockers in patients with CHF, the frequency of increased left ventricle ejection fraction was significantly higher in carriers of the wild Arg389Arg gene type (risk ratio=1.83, p=0,001). In contrast, in atrial fibrillation, the frequency of rhythm control with beta-blockers was achieved better in the presence of the variant allele Gly389 with “loss of function”. Another polymorphic Gly49 allele plays a role in desensitization and down-regulation of beta1-receptor activity, although clinically this effect has been less obvious and contradictory. However, in studies, a more pronounced clinical effect of beta-blockers was observed in carriers of the wild genotype Ser49Ser, as well as in carriers of the haplotype Ser49Ser/Arg389Arg. Thus, genetic polymorphism ADRB1 may be another important predictor of the effectiveness of beta-blockers in clinical practice, which must be taken into account in the treatment of cardiovascular diseases.

ROLE OF TLR2, TLR4 GENE POLYMORPHISM IN DEVELOPING MICROVASCULAR COMPLICATIONS IN ADOLESCENTS WITH TYPE 1 DIABETES MELLITUS

Long-term complications of type 1 diabetes mellitus (T1DM) in children and adolescents are an important problem in modern medicine. Recently, the role of immune mechanisms, in particular, chronic inflammation, in the development of both T1DM and its microvascular complications has been actively discussed. Activation of Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) leads to hyperproduction of proinflammatory cytokines, chemokines, adhesion molecules involved in the formation of diabetic microvascular complications. At the same time, TLR2 and TLR4 gene polymorphism alters the immune susceptibility to the endogenous ligands, which may increase the risk of diabetic microangiopathies. The aim of this study is to evaluate the frequency of genotypes and alleles of TLR2 and TLR4 genes distribution and to determine the content of TNFα, IL-1, VCAM-1, fractalkine, endothelin-1 in adolescents with T1DM with microvascular complications. We examined 139 adolescents with T1DM from 14 to 18 years old and 56 healthy teenagers. Patients with T1DM were divided into two groups: Group I – patients with poor glycemic control (HbA1C > 9.0%), (n = 64); Group II – patients with satisfactory glycemic control of T1DM (HbA1C ≤ 9.0%), (n = 75), including adolescents with optimal (HbA1C < 7.5%) and suboptimal glycemic control (7.5% ≤ HbA1C ≤ 9.0%) (ISPAD clinical practice consensus guidelines 2014). According to the presence of microvascular complications, the groups were subdivided into subgroups: Iа (n = 49), IIа (n = 38) – adolescents with verified microvascular disorders: diabetic retinopathy, nephropathy and neuropathy; Ib (n = 15), IIb (n = 37) – without microvascular complications. Allelic variants of TLR genes were determined using test systems GosNII genetics (Moscow). The content of cytokines in blood serum was carried out by the method of enzyme-linked immunosorbent assay “BIOSCIENCE”. Data were analyzed using software packages Statistica version 6.0. The assessment of TLR2 (Arg753Gln) and TLR4 (Thr399Ile) polymorphism distribution did not reveal significant differences between the observed subgroups and the control. In Ia and IIa subgroups (with complications) Asp299Gly variant was noted to be significantly less common when compared to subgroups Ib, IIb and controls. The presence of Gly allele in TLR4 gene was found to disrupt the expression of TNFα and VCAM-1 and can be considered protective for the development of microvascular complications.

ANALYSIS OF THE ASSOCIATION OF BRONCHIAL ASTHMA CLINICAL COURSE WITH Arg16Gly POLYMORPHIC VARIANT IN THE β2-ADRENOCEPTOR GENE

Relevance. The relevance of the study of Arg16Gly polymorphism of the β2-adrenoceptor (β2-AR) gene is due to the fact that a number of studies have proven its role in the development of bronchial asthma (BA), bronchial hyperactivity, the effectiveness of basic treatment. However, these associations show low reproducibility in various studies, so the question of the possibility of clinical application of the results of genetic testing for Arg16Gly polymorphic variant of the β2-AR gene remains unanswered. The main reasons why the clinical significance of this polymorphism is not confirmed in various studies are - population heterogeneity, insufficient sample size, improper characterization of comparison groups.
 Objective: to study the association of Arg16Gly polymorphism in the β2-adrenoceptor gene with BA clinical course taking into account the age of onset.
 Materials and methods. We examined 553 BA patients (group I included 282 patients with late-onset asthma and group II included 271 patients with early-onset asthma) and 95 apparently healthy individuals. The study has been approved by the Bioethics Committee of Medical Institute of Sumy State University. Arg16Gly polymorphism in the β2-АR gene (rs1042713) was determined using polymerase chain reaction-restriction fragment length polymorphism analysis. Statistical analysis of obtained results was performed using SPSS–17 program.
 Results. There was no significant difference in the distribution of genotypes for Arg16Gly polymorphism in the β2-AR gene depending on asthma severity with no regard for the age of onset (χ2 = 5.14; p = 0.27). With regard for the age of onset, we found out that early-onset BA was linked to a difference in genotype distribution for this polymorphic variant in patients with severe and non-severe course (χ2 = 14.76; р = 0.001). The frequency of Gly/Gly genotype was higher in patients with severe course (41.4%) as compared to patients with mild course (16.4%), while the frequency of Arg/Arg (32.9%) and Arg/Gly (50.7%) genotypes was higher in patients with mild asthma as compared to patients with severe course (24.3% and 34.3%). There was no significant difference in the distribution of genotypes in patients with late-onset asthma with regard to course severity (χ2 = 4.94; p = 0.084).
 The relative risk of severe course for early-onset asthma was 3.84 times higher (95% CI 2.11–7.36; p = 0.001) in the recessive model, 2.58 times higher (95% CI 1.53–4,37, p = 0.001) in the dominant model, and 2.16 times (95% CI 1.56–3.04) higher in the additive model. In patients with late-onset asthma, no association was found in all models.
 Conclusions. There was no significant difference in the distribution of genotypes for Arg16Gly polymorphism in the β2-AR gene depending on asthma severity with no regard for the age of onset. When adjusted for the age of onset, the analysis revealed a difference in genotype distribution for this polymorphic variant in patients with severe and non-severe course having early-onset BA (р = 0.001). The frequency of Gly/Gly genotype was higher in patients with severe course as compared to patients with mild course. For patients with late-onset asthma, no differences were found (p = 0.084). Heterozygous and homozygous Gly allele carriers have a higher risk of early-onset asthma only.

Differential β‐arrestin2 binding of the human β 1 ‐adrenoceptor Arg389Gly polymorphic variants in cardiac myocytes

Rationale The β1-adrenergic receptor (AR) is the primary receptor in cardiomyocytes through which catecholamines increase cardiac function, i.e. contractility and heart rate (positive inotropy and chronotropy). The human β1AR gene (Adrb1), which encodes a G protein-coupled receptor (GPCR), displays high nucleotide sequence variability. One of its several non-synonymous polymorphisms identified to date is the Gly/Arg variation at aminoacid position 389 (C1165G in the open reading frame's nucleotide sequence), with the Arg389 variant being much less frequent in African-Americans than in Caucasians (58% vs. 73%, respectively). Since amino acid 389 is located in the intracellular C-terminus of the encoded receptor, this polymorphism is expected, and has been shown to affect both signaling/function and desensitization of the β1AR. Indeed, Arg389 β1AR has been found to be hyperfunctional, compared to its Gly389 counterpart, in transfected cell lines and in cardiomyocytes in vitro. It is also known to affect the response of individuals to the cardiac stimulant (β1AR-agonist) dobutamine, as well as the responses of heart failure patients to several β-blockers (β1AR-antagonists), including carvedilol, to which the Arg allele confers greater responses. Consistent with this, homozygous Arg389 heart failure patients seem to fare much better than their homozygous Gly389 or heterozygous Arg389Gly counterparts when treated with the same β-blocker drug, a finding that has led to the idea of utilizing genotyping for the β1AR Arg389Gly polymorphism for the purposes of stratification of heart failure patients and of tailoring their b-blocker therapy. Objective To examine the interaction of the two β1AR variants with the signal transducers β-arrestins in neonatal rat ventricular myocytes (NRVMs), in order to identify molecular mechanisms underlying their functional differences. Methods We tested the interaction of the polymorphic β1ARs with β-arrestins via β1AR immunoprecipitation followed by β-arrestin immunoblotting in NRVM protein extracts. Results The β-arrestin1 isoform binds both variants equally well in NRVMs. Conversely, the potentially beneficial in the heart β-arrestin2 isoform interacts only with the Arg389 receptor (not with the Gly389 allele) in NRVMs. Conclusion Arg389 confers unique β-arrestin2-interacting properties to the β1AR in cardiac myocytes, potentially underlying this variant's gain-of-function phenotype.

Ser49Gly Beta1-Adrenergic Receptor Genetic Polymorphism as a Death Predictor in Brazilian Patients with Heart Failure.

Background The role of Ser49Gly beta1-adrenergic receptor genetic polymorphism (ADBR1-GP-Ser49Gly) as a predictor of death in heart failure (HF) is not established for the Brazilian population. Objectives To evaluate the association between ADBR1-GP-Ser49Gly and clinical outcomes in individuals with HF with reduced ejection fraction. Methods Secondary analysis of medical records of 178 patients and genotypes of GPRβ1-Ser49Gly variants, classified as Ser-Ser, Ser-Gly and Gly-Gly. To evaluate their association with clinical outcome. A significance level of 5% was adopted. Results Cohort means were: clinical follow-up 6.7 years, age 63.5 years, 64.6% of men and 55.1% of whites. HF etiologies were predominantly ischemic (31.5%), idiopathic (23.6%) and hypertensive (15.7%). The genetic profile was distributed as follows: 122 Ser-Ser (68.5%), 52 Ser-Gly (28.7%) and 5 Gly-Gly (2.8%). There was a significant association between these genotypes and mean NYHA functional class at the end of follow-up (p = 0.014) with Gly-Gly being associated with less advanced NYHA. In relation to the clinical outcomes, there was a significant association (p = 0.026) between mortality and GPRβ1-Ser49Gly: the number of deaths in patients with Ser-Gly (12) or Gly-Gly (1) was lower than in those with Ser-Ser (54). The Gly allele had an independent protective effect maintained after multivariate analysis and was associated with a reduction of 63% in the risk of death (p = 0.03; Odds Ratio 0.37 - CI 0.15-0.91). Conclusion The presence of β1-AR-GP Gly-Gly was associated with better clinical outcome evaluated by NYHA functional class and was a predictor of lower risk of mortality, regardless of other factors, in a 6.7-year of follow-up. (Arq Bras Cardiol. 2020; 114(4):613-615).

Association between Superoxide Dismutase 2 p.(Ala16Val) and Superoxide Dismutase 3 p.(Arg213Gly) Genetic Variants and Risk of Peripheral Neuropathy in Children and Adolescents with Type 1 Diabetes

Diabetic neuropathy (DN) is one of the microvascular complications of diabetes. Marked increase in oxygenfree radicals (OFR) results in oxidative stress that leads to development of DN. Antioxidant enzymes playa major role in protection against progression of DN, by reducing OFR. This study aimed to investigatethe association between superoxide dismutase 2 SOD2:p.(Ala16Val) and superoxide dismutase 3 SOD3:p.(Arg213Gly) genetic variants and the risk of neuropathy in Type 1 Diabetes children and adolescent. Thestudy included 80 children with type 1 diabetes divided into 2 groups, group 1 of 40 patients with clinicalDN and group 2 of 40 patients without DN. HbA1c levels were measured and genetic variants of SOD2:p.(Ala16Val) and SOD3:p.(Arg213Gly) were assessed by Taqman Real time Polymerase Chain Reaction(PCR) for both groups. The frequency of Ala/Ala genotype (OR=0.28 with 95% CI of 0.11-0.71) and Alaallele (OR=0.33 with 95% CI of 0.17-0.65) of SOD2:p. (Ala16Val) were significantly lower in group 1(27.5%, 50% respectively) than group 2 (57.5%, 75% respectively) (p=0.007, p=0.001 respectively). Incontrast the frequency of Val/Val genotype (OR=4.68 with 95% CI of 1.19-18.3) and Val allele (OR=3 with95% CI of 1.54-5.86) were significantly higher in group 1 (27.5%, 50% respectively) than group 2 (7.5%,25% respectively) (p=0.019 and p=0.001 respectively). Regarding SOD3:p.(Arg213Gly) gene variants thefrequency of Arg/Arg genotype and Arg allele were higher in group 1 (100%,100% respectively) than group2 (90%,95% respectively) but with statistical insignificance (P=0.06, P=0.058 respectively), however thefrequency of Arg/Gly genotype and Gly allele were higher in group 2 (10%, 5% respectively) than group 1(0%, 0% respectively) but also with no statistical significance (P=0.058 and P=0.06 respectively). There isa possible association between SOD2:p.(Ala16Val), but not with SOD3:p.(Arg213Gly) genetic variants andthe occurrence of DN in patients with type 1 diabetes mellitus.

Association of Elite Sports Status with Gene Variants of Peroxisome Proliferator Activated Receptors and Their Transcriptional Coactivator.

Background: Although the scientific literature regarding sports genomics has grown during the last decade, some genes, such as peroxisome proliferator activated receptors (PPARs), have not been fully described in terms of their role in achieving extraordinary sports performance. Therefore, the purpose of this systematic review was to determine which elite sports performance constraints are positively influenced by PPARs and their coactivators. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used, with a combination of PPAR and sports keywords. Results: In total, 27 studies that referred to PPARs in elite athletes were included, where the Ala allele in PPARG rs1801282 was associated with strength and power elite athlete status in comparison to subelite athlete status. The C allele in PPARA rs4253778 was associated with soccer, and the G allele PPARA rs4253778 was associated with endurance elite athlete status. Other elite status endurance alleles were the Gly allele in PPARGC1A rs8192678 and the C allele PPARD rs2016520. Conclusions: PPARs can be used for estimating the potential to achieve elite status in human physical performance in strength and power, team, and aerobic sports disciplines. Carrying specific PPAR alleles can provide a partial benefit to achieving elite sports status, but does not preclude achieving elite status if they are absent.

PREDICTORS OF HIV INFECTION PROGRESSION BEFORE PRESCRIPTION AND ON ART

The search for predictors of the progression of HIV infection to the clinical stage IV in patients before prescription and on antiretroviral therapy (ART) is an urgent scientific and practical task. The study aimed to identify predictors of the progression of HIV infection to the clinical stage IV in patients before prescribing and on the background ART based on the determination of clinical and genetic markers. A retrospective cohort study of 181 HIV-infected patients was conducted. For statistical data processing, regression analysis was used. Independent predictors of the progression of HIV infection to clinical stage IV in HIV-infected patients prior to ART were: male (p = 0,037), parenteral HIV transmission (p = 0,004), conclusion experience (p = 0,020), body mass index (BMI) less than 18.5 kg / m2 (p = 0,040), initial viral load (HV) of HIV> 1.0 x 105 copies / ml (p = 0,034), initial level of CD4 + T-lymphocytes <350 cells / μl (p = 0,000), hemoglobin level below 100 g/l (p = 0,001), the presence of which increases the risk of HIV progression to the clinical stage IV prior to prescribing ART. Independent predictors of the progression of HIV infection to the clinical stage IV in HIV-infected patients receiving ART were: parenteral transmission of HIV infection (p = 0,053), previous incarceration (p = 0,043), low adherence to ART (p = 0,028) , the initial level of CD4 + T-lymphocytes <350 cells/μl (p = 0,020), hemoglobin level below 100 g/l (p = 0,015) and carriage of the 299 Gly allele of the TLR4 gene (p = 0,016).

Association of PPARGC1A Gly428Ser (rs8192678) polymorphism with potential for athletic ability and sports performance: A meta-analysis.

BackgroundGenetics plays a role in determining potential for athletic ability (AA) and sports performance (SP). In this study, AA involves comparing sedentary controls with competitive athletes in power and endurance activities as well as a mix between the two (SP). However, variable results from genetic association studies warrant a meta-analysis to obtain more precise estimates of the association between PPARGC1A Gly482Ser polymorphism and AA/SP.MethodsMulti-database literature search yielded 14 articles (16 studies) for inclusion. Pooled odds ratios (ORs) and 95% confidence intervals (CI) were used to estimate associations. Summary effects were modified based on statistical power. Subgroup analysis was based on SP (power, endurance and mixed) and race (Caucasians and Asians). Heterogeneity was assessed with the I2 metric and its sources examined with outlier analysis which dichotomized our findings into pre- (PRO) and post-outlier (PSO).ResultsGly allele effects significantly favoring AA/SP (OR > 1.0, P < 0.05) form the core of our findings in: (i) homogeneous overall effect at the post-modified, PSO level (OR 1.13, 95% CI 1.03–1.25, P = 0.01, I2 = 0%); (ii) initially homogeneous power SP (ORs 1.22–1.25, 95% CI 1.05–1.44, P = 0.003–0.008, I2 = 0%) which precluded outlier treatment; (iii) PRO Caucasian outcomes (ORs 1.29–1.32, 95% CI 1.12–1.54, P = 0.0005) over that of Asians with a pooled null effect (OR 0.99, 95% CI 0.72–1.99, P = 0.53–0.92) and (iv) homogeneous all > 80% (ORs 1.19–1.38, 95% CI 1.05–1.66, P = 0.0007–0.007, I2 = 0%) on account of high statistical power (both study-specific and combined). In contrast, none of the Ser allele effects significantly favored AA/SP and no Ser-Gly genotype outcome favored AA/SP. The core significant outcomes were robust and showed no evidence of publication bias.ConclusionMeta-analytical applications in this study generated evidence that show association between the Gly allele and AA/SP. These were observed in the overall, Caucasians and statistically powered comparisons which exhibited consistent significance, stability, robustness, precision and lack of bias. Our central findings rest on association of the Gly allele with endurance and power, differentially favoring the latter over the former.

Meta-analyses of the association between the PPARGC1A Gly482Ser polymorphism and athletic performance.

Peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) encoded by the PPARGC1A gene is a vital regulator of glucose and fatty acid oxidation, mitochondrial biogenesis, and skeletal muscle fibre conversion. Several studies have investigated the association between PPARGC1A Gly482Ser polymorphism and athletic performance in humans. However, the results were contradictory. In the present study, two meta-analyses were performed to assess the association between the Gly482Ser polymorphism and endurance or power athletic performance to resolve this inconsistency. Ten articles were identified, including a total of 3,708 athletes and 6,228 controls. Higher frequencies of the Gly/Gly genotype (OR, 1.26; 95% CI, 1.11–1.42) and the Gly allele (OR, 1.29; 95% CI, 1.09–1.52) were observed in Caucasian endurance athletes. Furthermore, higher incidences of the Gly/Gly genotype (OR, 1.30; 95% CI, 1.16–1.46) and the Gly allele (OR, 1.22; 95% CI, 1.12–1.33) were observed in power athletes compared to controls. This finding demonstrates that the Gly/Gly genotype and the Gly allele of the PPARGC1A Gly482Ser polymorphism may facilitate athletic performance regardless of the type of sport, as well as providing solid evidence to support the possible influence of genetic factors on human athletic performance.

ADRB2 polymorphism Arg16Gly modifies the natural outcome of heart failure and dictates therapeutic response to \u03b2-blockers in patients with heart failure

We sought to investigate the association of single nucleotide polymorphisms (SNPs) of the genes involved in βAR signaling with the response of patients to βAR blockers. A total of 2403 hospitalized patients with chronic heart failure (HF) were enrolled in a multicenter observational study as the first cohort and followed up for a mean period of 20 months. Genes for β1AR, β2AR, and the major cardiac G-protein-coupled receptor kinases (GRKs) GRK2 and GRK5 were analyzed to identify SNPs, and patients were stratified according to genotypes. A second independent cohort enrolling 919 patients with chronic HF was applied to validate the observed associations. The signaling properties of the key identified SNPs were assessed in vitro. Our data showed that HF patients harboring the Gly16 allele in the gene for β2AR (ADRB2) had an increased risk of the composite end point relative to patients who were homozygous for Arg16. Notably, these patients showed a beneficial response to βAR-blocker treatment in a G allele-dose-dependent manner, whereas Arg16 homozygotes had no response to βAR-blocker therapy. This Arg16Gly genotype-dependent heterogeneity in clinical outcomes of HF was successfully validated in the second independent population. Besides, the in vitro experiments revealed that G allele carriers were defective in β2AR-coupled inhibitory adenylate cyclase g (Gi) protein signaling.

A catalog of gliadin alleles: Polymorphism of 20th-century common wheat germplasm

A new, improved version of the catalog of 182 alleles at the six Gli loci of common wheat (T. aestivum L.) shown in electrophoregrams of 128 standard genotypes was used for analysis of 1060 cultivars and lines bred in the 20th century. The most frequent alleles in the studied germplasm occurred with frequencies of 18%–40%, with 30 unique alleles, one in each cultivar. Extremely high genetic diversity was found (average H for the six main Gli loci was 0.870±0.046), nearly identical in winter (H=0.831) and spring (H=0.856) wheats but differing among 28 groups of cultivars released in 22 countries. Each country or region was characterized by its own specific set of the most frequent Gli alleles, and the 28 cultivar groups formed five main relationship clusters if polymorphism at the six Gli loci was considered. However, different levels of similarity between groups of cultivars were found if polymorphism of the A, B, or D genomes of common wheat was tested separately. In general, the 20th century germplasm of common wheat was differentiated and structured by country or region and cultivar type (spring or winter). Each elemental genome (in particular, A and D) contributed to the structure of the polymorphism studied. We propose that the structure of the wheat germplasm was a result of natural selection under the eco-climatic conditions of cultivation specific to each country or region. As many as 27.4% of cultivars studied violated the requirement of the DUS rules for uniformity, being represented by mixtures of two or more closely related genotypes. However, the composition of a cultivar as a set of related but different genotypes may contribute to its adaptivity, and thereby to the known high plasticity of common wheat.

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease.

DRD3 Ser9Gly Polymorphism and Its Influence on Risperidone Response in Autistic Children.

Autism, a neuropsychiatric illness, is a complex ailment of mainly indefinite cause. Although precise pathophysiological mechanism is unclear but the role of genetics is undeniable therefore pharmacogenetics may assist to a better management of symptoms. Risperidone is widely used in autism. Considering the significance of dopaminergic system in psychological and neurological diseases and its association with autism, the hypothesis that genetic variant of dopamine receptor (DRD3), Ser9Gly (rs6280), may influence treatment of autism may be assumed. In the present study, 56 autistic Persian children within the age range of 2.5 to 14 years were included. Diagnosis of autism was based on DSM-V criteria and the severity degree was measured by ABC-C checklists at base line and after 8 weeks of treatment with risperidone. Based on their scores patients were categorized as responsive and non-responsive groups. DRD3 Ser9Gly (rs6280) was determined by PCR-RFLP. Carriers of Gly allele as well as carriers of Gly/Gly and Ser/Gly genotypes showed significantly better response to risperidone compared with carriers of Ser allele and Ser/Ser genotype (P=0.027; OR= 4.18; 95%CI=1.16-15.03 and P=0.014; OR=6.825; 95%CI=1.36-34.13). Our results advocate the possible influence of genetic variation of DRD3 in clinical response to antipsychotics like risperidone in autistic individuals.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

The Gly16 Allele of the G16R Single Nucleotide Polymorphism in the β 2 -Adrenergic Receptor Gene Augments the Glycemic Response to Adrenaline in Humans.

Cerebral non-oxidative carbohydrate consumption may be driven by a β2-adrenergic mechanism. This study tested whether the 46G > A (G16R) single nucleotide polymorphism of the β2-adrenergic receptor gene (ADRB2) influences the metabolic and cerebrovascular responses to administration of adrenaline. Forty healthy Caucasian men were included from a group of genotyped individuals. Cardio- and cerebrovascular variables at baseline and during a 60-min adrenaline infusion (0.06 μg kg−1 min−1) were measured by Model flow, near-infrared spectroscopy and transcranial Doppler sonography. Blood samples were obtained from an artery and a retrograde catheter in the right internal jugular vein. The ADRB2 G16R variation had no effect on baseline arterial glucose, but during adrenaline infusion plasma glucose was up to 1.2 mM (CI95: 0.36–2.1, P < 0.026) higher in the Gly16 homozygotes compared with Arg16 homozygotes. The extrapolated steady-state levels of plasma glucose was 1.9 mM (CI95: 1.0 –2.9, PNLME < 0.0026) higher in the Gly16 homozygotes compared with Arg16 homozygotes. There was no change in the cerebral oxygen glucose index and the oxygen carbohydrate index during adrenaline infusion and the two indexes were not affected by G16R polymorphism. No difference between genotype groups was found in cardiac output at baseline or during adrenaline infusion. The metabolic response of glucose during adrenergic stimulation with adrenaline is associated to the G16R polymorphism of ADRB2, although without effect on cerebral metabolism. The differences in adrenaline-induced blood glucose increase between genotypes suggest an elevated β2-adrenergic response in the Gly16 homozygotes with increased adrenaline-induced glycolysis compared to Arg16 homozygotes.

Beta2-adrenergic receptor gene haplotypes and bronchodilator response in Egyptian patients with chronic obstructive pulmonary disease

PurposeChronic obstructive pulmonary disease (COPD) is a multi-factorial disorder caused by environmental determinants and genetic risk factors. Understanding the genetic predisposition of COPD is essential to develop personalized treatment regimens. Beta2-adrenergic receptor (ADRB2) gene polymorphisms have been implicated in the pathogenesis of obstructive pulmonary diseases. This study was conducted to assess the genetic association between Arg16Gly and Gln27Glu polymorphisms and COPD in the Egyptian patients, and to analyze their impact on the clinical outcome and therapeutic response. Patients/methodsThe study population included 115 participants (61 COPD patients and 54 healthy controls) were genotyped for the Arg16Gly (rs1042713) and Gln27Glu (rs1042714) polymorphisms. Pulmonary function test was done and repeated in patients after salbutamol inhalation. ResultsThe Gly16 and Gln27 alleles represented 57% and 70% of the whole study population, and only 3 haplotypes were detected; Arg16/Gln27, Gly16/Gln27, and Gly16/Glu27. Genotypes and haplotypes homozygous for Arg16 and Gln27 were more likely to develop COPD (p<0.05). However, individuals carrying Glu27 allele conferred protection against COPD development (p=0.002). Furthermore, Arg16 genotypes and haplotypes were significantly associated with higher grades of dyspnea, more COPD symptoms and frequent exacerbations. In contrast, patients carrying Glu27 allele had better bronchial airway responsiveness to β2-agonists. ConclusionsOur findings suggested that the ADRB2 gene polymorphisms may have vital role in COPD risk, severity, and bronchodilator response among Egyptian population. Larger epidemiological studies are needed for results validation.