Combinations Of Genetic Variants Research Articles

Ассоциации нарушений ядерной ДНК с индивидуальными вариантами генов системы репарации ДНК APEX1, ERCC2, ERCC5, PARP1 и hOGG1 у работников угольных теплоэлектростанций

Combinations of genetic variants and environmental factors are responsible for the development of many human diseases. Information on individual capacity to accumulate DNA damages is essential to advance the development of personalized disease prevention in environmentally exposed populations. Coal-fired thermal power plants burn huge amounts of coal per year and emit corresponding amounts of toxic gases, ash, and volatile organic compounds. The elements that make up coal are a large group of diverse pollutants associated with threats to human health and the environment. The current work is based on identifying the risks associated with the health of workers at coal-fired thermal power plants. The study is devoted to the assessement of the DNA damage degree in connection with individual sensitivity in 455 workers of coal-fired thermal power plants in the city of Kemerovo and 533 residents of the same region not associated with production. The research materials are represented by 988 samples of peripheral venous blood from residents of the Kemerovo region. Control donors were selected according to the gender, age, and smoking status of coal-fired power plant workers. Micronucleus testing with a cytokinetic block on peripheral blood lymphocytes was used to register DNA disorders. Determination of the influence of genetic factors on the degree of DNA damage was carried out using allele-specific polymerase chain reaction of polymorphic variants of the DNA repair system genes APEX1 rs1130409, ERCC2 rs13181, PARP1 rs1136410, hOGG1 rs1052133 and ERCC5 rs17655. Increased frequencies of DNA disorders were detected in carriers of the heterozygous genotype of the APEX1 gene and minor variants of APEX1, ERCC2, hOGG1 and ERCC5.

Analysis of NOS Gene Polymorphisms in Relation to Cluster Headache and Predisposing Factors in Sweden.

Cluster headache is characterized by activation of the autonomic-trigeminal reflex. Nitric oxide can trigger headaches in patients, and nitric oxide signaling is known to be affected in cluster headache. Based on the hypothesis of nitric oxide being involved in cluster headache pathophysiology we investigated nitric oxide synthases as potential candidate genes for cluster headache. We analyzed eight variants in the three forms of nitric oxide synthase (NOS) genes, inducible NOS (iNOS), endothelial NOS (eNOS) and neuronal NOS (nNOS), and tested for association with cluster headache. Swedish cluster headache patients (n = 542) and controls (n = 581) were genotyped using TaqMan® assays on an Applied Biosystems 7500 qPCR cycler. This is the largest performed genetic study on NOS involvement in cluster headache so far. We found an association between cluster headache and one iNOS haplotype consisting of the minor alleles of rs2297518 and rs2779249 (p = 0.022). In addition, one of the analyzed nNOS variants, rs2682826, was associated with reported triptan use (p = 0.039). Our data suggest that genetic variants in NOS genes do not have a strong influence on cluster headache pathophysiology, but that certain combinations of genetic variants in NOS genes may influence the risk of developing the disorder or triptan use.

1548 The Combination of Candidate Genes in the Formation of Endometriosis in Women of Russia's Central Region

Study Objective Study of role of the combination genetic polymorphisms rs7759938, rs7766109 and rs13111134 in formation of endometriosis. Design Prospective cohort study. Setting Perinatal center St. Joasaph Belgorod Regional Clinic Hospital. Patients or Participants The research group consisted of 688 women between 2010 and 2013, of which 252 endometriosis patients and 436 persons of the control group. Main group and control group included Russian women who were native of Central Region of Russia and who were not relatives to each other. Patients with endometriosis were provided with clinical and gynecological examination, ultrasound investigation if pelvic floor, laparoscopic inspection with histologic confirmation after biopsy. Interventions Typing of single nucleotide polymorphism of the following genes was performed for patients with endometriosis women from control group: rs7759938, rs7766109 and rs13111134. Analysis of roles of combinations of genetic variants in occurrence of endometriosis was performed with the help of APSampler software. Measurements and Main Results It has been discovered that combination of genetic variants C rs7759938 with A rs7766109 and A rs13111134 occur in 10.89% of sick women, respectively, which is 1.86 times lower than that occur in control group (20.23%, pbonf=0.03). When there are these combination of polymorphic markers, pathology risk of endometriosis is significantly lower (OR=0.48, CI 0.35-0.66). Conclusion Protective meaning at formation of endometriosis belongs to combination of genetic variants C rs7759938 with A rs7766109 and A rs13111134 (OR=0.48).

Short communication: Application of proteomics for characterization of caseinomacropeptide isoforms before and after desialidation

Caseinomacropeptide (CMP) is an important polypeptide found in cheese whey that has various biological activities and functional properties. Because sialylations play an important role in the functional properties of CMP, the aim of the present work was to characterize CMP isoform heterogeneity in a commercial glycosylated CMP (gCMP) isolate using liquid chromatography- and gel-based proteomics before and after desialidation. Using 2-dimensional gel electrophoresis (2-DGE), we observed a shift in isoelectric point (pI) after enzymatic desialidation, indicating that sialylated gCMP were located at pI 3.0 to 3.1, but desialylated gCMP had repositioned to pI 3.7 to 3.9. We used liquid chromatography/mass spectroscopy (LC-ESI/MS) for further analysis of the glycan chains of gCMP. In total, we identified 19 CMP isoforms, of which 13 were glycosylated and 6 were nonglycosylated. We also detected 3 genetic variants (A, B, and E), with up to 3 glycosylations attached per gCMP. Further, we identified up to 4 isomers, reflecting different sites of glycosylation in the peptide backbone of these isoforms. The dominating gCMP isoform of genetic variant E appeared to contain 4 N-acetyl-neuraminic acid (NeuAc) residues, whereas the dominating gCMP isoforms of variants A and B appeared to contain 2 NeuAc. The identification revealed conversions of isoforms containing different combinations of genetic variants and degrees of glycosylation, sialylation, and phosphorylation to various desialylated counter-isoforms. The content of sialylated gCMP relative to the total CMP content was 37% (wt/wt), which decreased to 1.5% after sialidase treatment, indicating 96% effectivity of the desialidation. This approach can be valuable for future functionality studies specifically addressing the importance of NeuAc.

GEMPROT: visualization of the impact on the protein of the genetic variants found on each haplotype.

When analyzing sequence data, genetic variants are considered one by one, taking no account of whether or not they are found in the same individual. However, variant combinations might be key players in some diseases as variants that are neutral on their own can become deleterious when associated together. GEMPROT is a new analysis tool that allows, from a phased vcf file, to visualize the consequences of the genetic variants on the protein. At the level of an individual, the program shows the variants on each of the two protein sequences and the Pfam functional protein domains. When data on several individuals are available, GEMPROT lists the haplotypes found in the sample and can compare the haplotype distributions between different sub-groups of individuals. By offering a global visualization of the gene with the genetic variants present, GEMPROT makes it possible to better understand the impact of combinations of genetic variants on the protein sequence. GEMPROT is freely available at https://github.com/TaniaCuppens/GEMPROT. An on-line version is also available at http://med-laennec.univ-brest.fr/GEMPROT/. Supplementary data are available at Bioinformatics online.

A Bayesian approach to Mendelian randomisation with dependent instruments.

Mendelian randomisation (MR) is a method for establishing causality between a risk factor and an outcome by using genetic variants as instrumental variables. In practice, the association between individual genetic variants and the risk factor is often weak, which may lead to a lack of precision in the MR and even biased MR estimates. Usually, the most significant variant within a genetic region is selected to represent the association with the risk factor, but there is no guarantee that this variant will be causal or that it will capture all of the genetic association within the region. It may be advantageous to use extra variants selected from the same region in the MR. The problem is to decide which variants to select. Rather than selecting a specific set of variants, we investigate the use of Bayesian model averaging (BMA) to average the MR over all possible combinations of genetic variants. Our simulations demonstrate that the BMA version of MR outperforms classical estimation with many dependent variants and performs much better than an MR based on variants selected by penalised regression. In further simulations, we investigate robustness to violations in the model assumptions and demonstrate sensitivity to the inclusion of invalid instruments. The method is illustrated by applying it to an MR of the effect of body mass index on blood pressure using SNPs in the FTO gene.

Human Genetic Variability Contributes to Postoperative Morphine Consumption.

High interindividual variability in postoperative opioid consumption is related to genetic and environmental factors. We tested the association between morphine consumption, postoperative pain, and single nucleotide polymorphisms (SNPs) within opioid receptor μ 1 (OPRM1), catechol-O-methyltransferase (COMT), uridine diphosphate glucose-glucuronosyltransferase-2B7, and estrogen receptor (ESR1) gene loci to elucidate genetic prediction of opioid consumption. We analyzed 20 SNPs in 201 unrelated Caucasian patients who underwent abdominal surgery and who were receiving postoperative patient-controlled analgesia-administered morphine. Morphine consumption and pain intensity were dependent variables; age and sex were covariates. A haplotype of 7 SNPs in OPRM1 showed significant additive effects on opioid consumption (P=.007); a linear regression model including age and 9 SNPs in ESR1, OPRM1, and COMT explained the highest proportion of variance of morphine consumption (10.7%; P=.001). The minimal model including 3 SNPs in ESR1, OPRM1, and COMT explained 5% of variance (P=.007). We found a significant interaction between rs4680 in COMT and rs4986936 in ESR1 (P=.007) on opioid consumption. SNPs rs677830 and rs540825 of OPRM1 and rs9340799 of ESR1 were nominally associated with pain Numeric Rating Scale scores. Combinations of genetic variants within OPRM1, COMT, and ESR1 better explain variability in morphine consumption than single genetic variants. Our results contribute to the development of genetic markers and statistical models for future diagnostic tools for opioid consumption/efficacy. This article presents the efforts dedicated to detect correlations between the genetic polymorphisms and the clinical morphine effect self-administered by patients using a patient-controlled analgesia pump after major surgery. The clinical effect is expressed in terms of morphine consumption and pain scores. REGISTERED ON CLINICALTRIALS.GOV: NCT01233752.

Combinations of Genetic Data Present in Bipolar Patients, but Absent in Control Persons.

The main objective of the study was to find combinations of genetic variants significantly associated with bipolar disorder. In a previous study of bipolar disorder, combinations of three single nucleotide polymorphism (SNP) genotypes taken from 803 SNPs were analyzed, and four clusters of combinations were found to be significantly associated with bipolar disorder. In the present study, combinations of four SNP genotypes taken from the same 803 SNPs were analyzed, and one cluster of combinations was found to be significantly associated with bipolar disorder. Combinations from the new cluster and from the four previous clusters were identified in the genomes of 209 of the 607 patients in the study whereas none of the 1355 control participants had any of these combinations in their genome.

Pentraxin 3 in Systemic Lupus Erithematosus: Questions to be Resolved

Systemic lupus erythematosus (SLE) is a autoimmune disorder with unpredictable course that involves polyclonal autoimmunity against multiple autoantigens and presents a broad spectrum of clinical manifestations (fever, skin rashes, arthralgia, inflammation of kidney, lungs, or brain). The pathogenesis of SLE is based on a combinations of genetic variants and environmental factor that promote loss-of-tolerance or tissue inflammation. In fact there is growing evidence to suggest that inflammation and related molecules plays a key role in the pathogenesis of SLE. The pentraxin superfamily (PTXs), divided into long and short PTXs, can induce by and a variety of inflammation-associated stimuli. Alongside the classical short pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP), pentraxin 3 ( PTX3) is a prototypic of long pentraxin family, a multifunctional protein characterized by a cyclic multimeric structure and a conserved domain

Responsiveness to metformin in girls with androgen excess: collective influence of genetic polymorphisms

To study the relationship between the responsiveness to metformin in girls with androgen excess and combinations of genetic variants-as reflected in a polymorphism score-in single nucleotide polymorphisms (OCT1, STK11, and FTO genes) and in the repeat numbers within the AR and SHBG genes. Longitudinal (1-year) follow-up. University hospital. Hyperandrogenic adolescent girls receiving metformin. Single nucleotide polymorphisms and repeat numbers were assessed in 104 adolescent girls with androgen excess. The polymorphism score was the sum of subscores given for response alleles in OCT1, STK11, and FTO and for high repeat numbers in SHBG and AR alleles. The response to metformin (850 mg/d) was judged by changes over 1 year in endocrine-metabolic state and body composition. Changes in fasting insulin levels, triacylglycerol levels, LDL-HDL ratio, and body composition differed strikingly by polymorphism score. Collectively, genetic polymorphisms had a major influence on the responsiveness to metformin in adolescent girls with androgen excess.

Gallbladder Cancer Predisposition: A Multigenic Approach to DNA-Repair, Apoptotic and Inflammatory Pathway Genes

Gallbladder cancer (GBC) is a multifactorial disease with complex interplay between multiple genetic variants. We performed Classification and Regression Tree Analysis (CART) and Grade of Membership (GoM) analysis to identify combinations of alleles among the DNA repair, inflammatory and apoptotic pathway genetic variants in modifying the risk for GBC. We analyzed 16 polymorphisms in 8 genes involved in DNA repair, apoptotic and inflammatory pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were XRCC1, OGG1, ERCC2, MSH2, CASP8, TLR2, TLR4 and PTGS2. Single locus analysis by logistic regression showed association of MSH2 IVS1+9G>C (rs2303426), ERCC2 Asp312Asn (rs1799793), OGG1 Ser326Cys (rs1052133), OGG1 IVS4-15C>G (rs2072668), CASP8 -652 6N ins/del (rs3834129), PTGS2 -1195G>A (rs689466), PTGS2 -765G>C (rs20417), TLR4 Ex4+936C>T (rs4986791) and TLR2 –196 to –174del polymorphisms with GBC risk. The CART analysis revealed OGG1 Ser326Cys, and OGG1 IVS4-15C>G polymorphisms as the best polymorphic signature for discriminating between cases and controls. In the GoM analysis, the data was categorized into six sets representing risk for GBC with respect to the investigated polymorphisms. Sets I, II and III described low intrinsic risk (controls) characterized by multiple protective alleles while sets IV, V and VI represented high intrinsic risk groups (GBC cases) characterized by the presence of multiple risk alleles. The CART and GoM analyses also showed the importance of PTGS2 -1195G>A polymorphism in susceptibility to GBC risk. In conclusion, the present multigenic approach can be used to define individual risk profiles for gallbladder cancer in North Indian population.

The impact of genetic variation in the region of the GPIIIa gene, on PlA2 expression bias and GPIIb/IIIa receptor density in platelets

Some studies have suggested that genetic variability in the glycoprotein (GP) IIIa gene modulates expression of platelet GPIIb/IIIa (alpha(2b)beta(3)). We sought to determine as to whether combinations of genetic variants within the GPIIIa gene (haplotypes) influenced the expression of GPIIIa RNA and protein levels in human platelets. Three promoter polymorphisms, Pl(A1/A2) genotype and platelet receptor densities were determined in 207 acute coronary syndrome (ACS) patients. Allele-specific quantitative reverse transcription-polymerase chain reaction of platelet RNA from Pl(A1/A2) heterozygotes identified a greater expression of Pl(A2) bearing transcripts among heterozygotes. Among the patients studied, the ratio of Pl(A1)/Pl(A2) RNA expression was significantly influenced by promoter haplotype (P < 0.01). However, this effect reflected carriership of rare not common haplotypes (P = 0.2). There was a threefold variation between subjects in the number of GPIIb/IIIa receptors expressed per platelet, although no association between receptor density and the Pl(A2) (P = 0.93) or promoter polymorphisms was demonstrated (-468A, P = 0.52; -425C, P = 0.59; -400A, P = 0.52). Among common haplotypes, Pl(A1)/Pl(A2) RNA expression was negatively correlated with adjusted GPIIb/IIIa receptor density (P = 0.04). The overall trend towards higher expression of Pl(A2) bearing message in Pl(A1/A2) heterozygotes, and the existence of rare haplotypes with more pronounced changes indicate the existence of cis-acting genetic factors that remain to be identified.