Genetic Variants Of Proteins Research Articles

Genetic polymorphisms and major bleeding risk during vitamin K antagonists treatment: The BLEEDS case-cohort.

Major bleeding occurs annually in 1%-3% of patients on vitamin K antagonists (VKAs), despite close monitoring. Genetic variants in proteins involved in VKA response may affect this risk. To determine the association of genetic variants (cytochrome P450 enzymes 2C9 [CYP2C9] and 4F2 [CYP4F2], gamma-glutamyl carboxylase [GGCX]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit-1 (VKORC1). A case-cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613 years of follow-up and a random subcohort of 978 patients. We determined variants in CYP2C9, CYP4F2, GGCX, VKORC1 and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression. Genotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. CYP4F2-TT carriership was associated with a 1.6-fold (95% CI 0.9-2.8) increased risk of major bleeding compared with CC-alleles, albeit not statistically significant. For the CYP2C9 and GGCX variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in CYP2C9 (poor metabolizer), CYP4F2-TT, and VKORC1-AA was associated with a 4.0-fold (95%CI 1.4-11.4) increased risk, while carriers of both CYP4F2-TT and VKORC1-AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5-29.8) compared with carriers of CC alleles in CYP4F2 and GG in VKORC1. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively). CYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.

ANALYSIS OF THE INTERCONNECTION OF STALLION SEMEN INDICATORS WITH GENETIC MARKERS OF PROTEINS

The purpose of the research was to study the associations of genetic polymorphism of proteins and enzymes of blood serum (albumin, transferrin, and esterase) on the quality of freshly obtained and cryopreserved semen of breeding stallions, taking into account their breed characteristics. The authors divided horses into four breed groups, taking into account their characteristics – riding horses, Orlov trotters, prize-winning trotters, and draft horses. A comparative assessment of 154 stallions revealed no significant differences in the quality of semen from different breed groups. For the first time, the influence coefficient (Fisher coefficient) of different genetic variants of proteins and enzymes on the semen parameters of stallions was analyzed and calculated. At the same time, the authors revealed the multidirectional effect of the same alleles of albumin, transferrin, and carboxylesterase on semen activity in different breeds. Thus, the presence of the albumin allele B (ALBB) had a positive effect on the mobility of fresh semen of stallions of riding breeds but a negative effect on stallions of Orlov trotters and draft horses. The heterozygous state of alleles revealed a positive effect on semen parameters. The analysis of variance of all examined stallions showed the highest level of the esterase locus (ESI) on the mobility of fresh semen and the albumin locus (ALBA) – on the mobility of frozen-thawed semen. The reliability of it is close to a statistically significant value. The results obtained suggest that specific gene complexes and associations with productive traits are formed in breeds under the influence of breeding. It must be taken into account as additional criteria for controlling the breeding process.

Genetics of Pediatric Immune-Mediated Diseases and Human Immunity

Primary immunodeficiency diseases (PIDs) are a rapidly growing, heterogeneous group of genetically determined diseases characterized by defects in the immune system. While individually rare, collectively PIDs affect between 1/1,000 and 1/5,000 people worldwide. The clinical manifestations of PIDs vary from susceptibility to infections to autoimmunity and bone marrow failure. Our understanding of the human immune response has advanced by investigation and discovery of genetic mechanisms of PIDs. Studying patients with isolated genetic variants in proteins that participate in complex signaling pathways has led to an enhanced understanding of host response to infection, and mechanisms of autoimmunity and autoinflammation. Identifying genetic mechanisms of PIDs not only furthers immunological knowledge but also benefits patients by dictating targeted therapies or hematopoietic stem cell transplantation. Here, we highlight several of these areas in the field of primary immunodeficiency, with a focus on the most recent advances.

Beyond Survival in Solid Organ Transplantation: A Summary of Expert Presentations from the Sandoz 6th Standalone Transplantation Meeting, 2018.

Beyond Survival in Solid Organ Transplantation: A Summary of Expert Presentations from the Sandoz 6th Standalone Transplantation Meeting, 2018.

Comment: β-Amyloid pathology and Parkinson disease.

Recent evidence from histopathologic, CSF, and amyloid PET studies show that β-amyloid (Aβ) pathology is also involved in the pathophysiology of Parkinson disease (PD), correlating with a more rapid cognitive decline and predicting progression in levodopa-resistant gait impairment.1 The pathophysiology as well as the neural networks involved, however, are not fully understood, especially the intriguing interaction between α-synuclein and Aβ pathology. Decreased clearance rates, in contrast to increased production rates, for both Aβ1-42 and Aβ1-40 may be the main trigger in Alzheimer disease.2 Whether this is also true in patients with PD awaits future research. Thus, Brockmann and colleagues3 investigated genetic variants in proteins (loss of function alleles) involved in the clearance of Aβ ( APOE , membrane metalloproteinase, and cystatin C [ CST ]). They identified a large group of patients with PD (n=456) with a subgroup of 103 patients with dementia and evaluated single nucleotide polymorphisms (SNP) in the respective genes in relation to a number of clinical variables and CSF Aβ1-42 levels.

Pharmacogenetics and personalized treatment of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is one of the most prevalent diseases in the world. An important difference in effectiveness and toxicity of hypoglycemic agents has been associated with the presence of genetic variants in people with T2DM. We conducted a literature review up November 2015 by combining keywords type 2 diabetes mellitus, hypoglycemic agents and pharmacogenetics (PKG). Metformin, sulfonylureas, and meglitinide drugs are widely used for the T2DM treatment, although new drugs in combination with metformin are administered. Genetic variants in proteins that function as carriers, channels, or metabolizing enzymes affect both the pharmacokinetics and pharmacodynamics of these agents. Significant progress in T2DM’s pharmacogenetics has been made; however, more studies involving a larger number of patients from different ethnic groups must be done. Furthermore, patients with T2DM generally are complex patients receiving hypolipidemic and hypotensive medications. Drug-drug interaction studies between these drugs must be done to really know the contribution of each polymorphism in drug effectiveness and/or toxicity.

New Challenges and Promises in Solid Organ Transplantation Pharmacogenetics: the Genetic Variability of Proteins Involved in the Pharmacodynamics of Immunosuppressive Drugs

Interindividual variability in immunosuppressive drug responses might be partly explained by genetic variants in proteins involved in the immune response or associated with IS pharmacodynamics. On a general basis, the pharmacogenetics of drug target proteins is less known and understood than that of proteins involved in drug disposition pathways. The aim of this review is to facilitate research related to the pharmacodynamics of the main immunosuppressive drugs used in solid organ transplantation. We elaborated a quality of evidence grading system based on a literature review and identified 'highly recommended', 'recommended' or 'potential' candidates for further research. It is likely that a number of additional rare variants might further explain drug response phenotypes in transplantation, and particularly the most severe ones. The advent of next-generation sequencing will help to identify those variants.

THU0242 Effect of Genetic Variants in Proteins of the Folic Acid Metabolic Pathways in the Toxicity of Methotrexate

BackgroundThe study of genetic variants of enzymes in the metabolic pathways of folic acid has provided conflicting results regarding toxicity or clinical response to methotrexate (MTX). There are several reasons...

Human Genetic Variation Influences Vitamin C Homeostasis by Altering Vitamin C Transport and Antioxidant Enzyme Function

New evidence for the regulation of vitamin C homeostasis has emerged from several studies of human genetic variation. Polymorphisms in the genes encoding sodium-dependent vitamin C transport proteins are strongly associated with plasma ascorbate levels and likely impact tissue cellular vitamin C status. Furthermore, genetic variants of proteins that suppress oxidative stress or detoxify oxidatively damaged biomolecules, i.e., haptoglobin, glutathione-S-transferases, and possibly manganese superoxide dismutase, affect ascorbate levels in the human body. There also is limited evidence for a role of glucose transport proteins. In this review, we examine the extent of the variation in these genes, their impact on vitamin C status, and their potential role in altering chronic disease risk. We conclude that future epidemiological studies should take into account genetic variation in order to successfully determine the role of vitamin C nutriture or supplementation in human vitamin C status and chronic disease risk.

Genetic variants implicated in airway remodelling are risk factors for asthma severity in children and young adults

<h3>Introduction</h3> Exacerbations affect quality-of-life, health care costs and represent a major cause of morbidity in children with asthma. To control the severity of asthma, physicians prescribe increasingly powerful regimes of medications in a tiered process according to BTS/SIGN guidelines. This process is often hit-and-miss with each patient responding uniquely, causing undue suffering and healthcare expenditure. We aim to identify predictive markers of asthma severity. <h3>Methods</h3> Participants were recruited into the BREATHE study, a UK wide cross sectional study of gene environment interactions in children and young adults with asthma. 1539 children and young adults with physician-diagnosed asthma (age 3-22 years) from Sussex, England and Tayside and Dumfries, Scotland agreed to participate between 2004 and 2011. The dataset includes demographic, anthropometric and clinical details from 29 primary care practices and 8 secondary care asthma clinics. We have developed a global index of asthma severity through construction of a composite variable in the form of bronchodilator use adjusted asthma treatment class. <h3>Results</h3> The homozygous C allele of CHI3L1rs4950928 is a risk factor for asthma-related hospital admissions (OR=1.39; 95% CI 1.02–1.88; P=.035). The co-dominant A allele of MMP9rs17576 is a risk factor for asthma-related exacerbations (OR=1.47; 95% CI 1.07–2.03; P=0.018), and asthma-related absence (OR=1.59; 95% CI 1.14–2.23; P=0.007). The co-dominant A allele of MMP9rs6073983 is protective for asthma-related exacerbations (OR=1.88; 95% CI 1.14–3.10;P=.014), asthma-related absence (OR=2.50; 95% CI 1.42-4.42; P=0.002) and increased asthma severity (OR=2.05; 95% CI 1.22–3.42; P=0.006). The co-dominant G allele of MMP12rs652438 increases the risk of asthma-related exacerbations (OR=1.51; 95% CI 1.05–2.18; P.026 and increased asthma severity (OR=1.74; 95% CI 1.03–2.96; P=0.040). The merged <i>GSTM1</i> null/<i>GSTP1</i>rs1695/<i>GSTT1</i> null mutant variant increases the risk of asthma-related hospital admission (OR=1.51; 95% CI 1.04–2.26; P=0.046). <h3>Conclusion</h3> Here we present clinically relevant findings on the impact of genetic variants in proteins influencing airway remodelling, on asthma severity in children and young adults with asthma. The presented variants increase the risk of asthma exacerbations and medication requirements in children and young adults. The study increases our understanding of the role of these molecules in causing asthma exacerbations, and influencing medication related asthma severity. The work could define susceptible population groups among children with asthma and help develop novel, personalised approaches for asthma management, providing economic benefits for an over-stretched healthcare system.

Correlation between κ-casein variants and citrate content in milk quantified by capillary electrophoresis

Abstract The milks of cows with known genetic variants of proteins were quantified by capillary electrophoresis (CE) for citrate content. From seven test-bulls of the breed Swiss Brown×Brown Swiss (SB × BS) with the two casein haplotypes B-A-B-A and B-A-B-B for αs1-, αs2,-, β-, and κ-casein (CN), 137 daughters were selected. They were assigned into two groups according to the casein haplotype inherited from the father. During the first lactation, from each cow, two milk samples, i.e. between 30–80 and 170–215 days were analysed for citrate content. From the data obtained no correlation between the casein haplotype and the citrate content in milk was found. The same applies when the cows were grouped according to κ-CN genotypes AA, AB and BB. The citrate content in the second interval between 170 and 215 days was for all cows significantly lower than in the first interval (30–80 days) of the lactation.

GENETIC VARIANTS OF PROTEINS FROM THE RENIN ANGIOTENSIN SYSTEM ARE ASSOCIATED WITH PRESSURE LOAD CARDIAC HYPERTROPHY

1. The relationship between the angiotensinogen (AGT) T174M, angiotensin converting enzyme (ACE) insertion/deletion (I/D) and the angiotensin II type 1 receptor (AT1) genetic markers and left ventricular hypertrophy was examined in normal subjects and those with aortic stenosis. 2. Subjects with aortic stenosis had higher left ventricular systolic pressure and relative wall thickness (RWT) compared with normal. However, within aortic stenosis subjects, left ventricular RWT did not correlate with left ventricular systolic pressure or with aortic valve area. 3. In subjects with aortic stenosis, left ventricular RWT was higher in those with ACE DD (P < 0.05) or AGT T174M (P < 0.06) compared with those with the ACE II or ID genotype or AGT TT174 genotype. No relationship was observed with any of the AT1 alleles. The ACE and AGT genetic markers independently predicted left ventricular RWT in aortic stenosis. No association was observed between these genotypes and left ventricular RWT in normal subjects. 4. The data suggest that the AGT T174M and ACE I/D genotypes may act together to influence the degree of hypertrophy in subjects with aortic stenosis. 5. In patients with aortic stenosis, genetic variants of proteins from the renin angiotensin system may be at least as important as left ventricular systolic pressure in determining the degree of left ventricular hypertrophy and could therefore explain the clinical variation observed in the progression to cardiac dysfunction.