Glycoprotein Polymorphisms Research Articles

Comparison of DNA extraction methods for genotyping equine histidine-rich glycoprotein insertion/deletion polymorphisms using oral mucosa swabs and feces

Previously, we demonstrated unique insertion/deletion polymorphisms of equine histidine-rich glycoprotein (eHRG) with five genotypes composed of 45-bp or 90-bp deletions in the histidine-rich region of eHRG in Thoroughbred horses. Although leukocytes are typically used to collect DNA for genotyping, blood sampling from animals is sometimes difficult and invasive. Moreover, the method for extracting DNA from blood leukocytes involves complicated steps and must be performed soon after blood sampling for sensitive gene analysis. In the present study, we performed eHRG genotyping using DNA, isolated from oral mucosa swabs collected by rubbing the mucosa on the underside of the upper lip of horses and 100 mg of freshly excreted feces obtained by scraping their surface. In the present study, we performed eHRG genotyping using DNA isolated from oral mucosa swabs and feces of horses (18 Thoroughbreds, 17 mixed breeds, 2 warm bloods), and compared the accuracy of this method with that of the method using DNA from leukocytes. The DNA derived from oral mucosa swabs was sufficient in quantity and quality for eHRG genotyping. However, DNA derived from fecal samples requires a more sensitive detection system because of contamination with non-horse DNA, and the test quality is low. Collection of oral mucosa swabs is less invasive than blood sampling; further, oral swabs can be stored for a longer period in a specified high-quality solution. Therefore, collecting DNA samples from oral mucosa swabs is recommended for the genetic analysis of not only horses but also other animals that are not accustomed to humans.

Genetic Analysis of the Complete S1 Gene in Japanese Infectious Bronchitis Virus Strains.

The complete nucleotide sequence of the S1 glycoprotein gene of the Japanese infectious bronchitis virus (IBV) strains was determined and genetically analyzed. A total of 61 Japanese IBV strains were classified into seven genotypes, namely GI-1, 3, 7, 13, 18, 19, and GVI-1 using the classification scheme that was proposed by Valastro et al, with three exceptions. These genotypes practically corresponded to those defined in Japan, namely Mass, Gray, JP-II, 4/91, JP-I, JP-III, and JP-IV, which have been identified through their partial nucleotide sequences containing hypervariable regions 1 and 2. In addition, three exceptive strains were considered to be derived from recombination within the S1 gene of IBV strains G1-13 and GI-19. By analyzing the amino acid polymorphism of the S1 glycoprotein among Japanese genotypes, a diversity was observed based on the genotype-specific amino acid residue, the proteolytic cleavage motif at the S1/S2 cleavage site, and the position of the potential N-glycosylation sites.

ОЛЬ ПОЛИМОРФИЗМА ГЕНА MDR1 ДЛЯ НАЗНАЧЕНИЯ НЕСТЕРОИДНЫХ ПРОТИВОВОСПАЛИТЕЛЬНЫХ ПРЕПАРАТОВ ПРИ БОЛЕВОМ СИНДРОМЕ

Introduction. One of the key roles in the excretion of a number of drugs, in particular nonsteroidal anti- inflammatory drugs, has a transport protein glycoprotein P, encoded by the MDR1 gene. In this connection, the influence of genetic polymorphism of glycoprotein P on the pharmacokinetics of these drugs contributes to the prediction of clinical consequences. Aim. The aim of the current study was to study the associations of polymorphic markers C1236T and C3435T of the MDR1 gene encoding glycoprotein P with the development of undesirable drug reactions in patients with pain syndrome. Material and methods. The study included 69 patients with pain syndrome and were divided into 2 groups depending on the presence of adverse drug reactions: NLR+ - 20 patients and NLR - - 49 patients with pain syndrome. The association of the polymorphic marker C3435T of the MDR1 gene was also studied among 22 patients with adverse drug reactions (ADR+) and 47 patients with pain syndrome without the presence of adverse drug reactions (ADR-). Molecular genetic studies were carried out on the basis of the Laboratory of medical genetics of NIIG and the PC of the Ministry of Health of the Republic of Uzbekistan. Results and discussion. During the genotyping, it was found that the occurrence of alleles and genotypes of the polymorphic marker C3435T of the MDR1 gene had significantly significant differences among the patients of the examined groups, depending on adverse drug reactions. Conclusion. The association of the polymorphic marker C3435T of the MDR1 gene with the development of undesirable drug reactions in pain syndrome, the TT genotype and the T allele may be genetic risk factors (OR=4.0 and 8.25; 95% CI 1.78-9.09 and 2.56-26.57, respectively) predisposing to the development of undesirable drug reactions in patients with pain syndrome. Therefore, further study is necessary in order to carry out genotyping of the polymorphic marker C3435T of the MDR1 gene to increase the effectiveness and safety of therapy of nonsteroidal anti-inflammatory drugs.

Detection and isolation of QX-like infectious bronchitis virus in Japan.

The antigenic variant QX-like infectious bronchitis virus (IBV) is endemic in several countries. In Japan, the QX-like genotype is classified as the JP-III genotype based on the partial S1 gene and as the GI-19 genotype based on the complete S1 gene. This study showed that QX-like IBVs and JP-III IBVs can be identified based on the amino acid polymorphism of the S1 glycoprotein. Furthermore, genetic analysis of several IBV field strains detected in commercial broiler farms across the Kyushu area in 2020 revealed Japanese QX-like IBVs, which are highly homologous to the QX-like IBVs recently detected in China and South Korea. Herein, QX-like IBV field strains were isolated for evaluating commercial vaccine efficacy in our future studies.

Association of Fetuin-A with Thr256Ser exon polymorphism of α2-Heremans Schmid Glycoprotein (AHSG) gene in type 2 diabetic patients with overt nephropathy

BackgroundCirculatory Fetuin-A has been well reported to elevate the risk for Diabetic Nephropathy (DN) and is associated with many vascular complications. Compelling reports have well documented that the circulatory levels of Fetuin-A directly have an impact on its AHSG (α2- Heremans- Schmid Glycoprotein) gene single nucleotide polymorphisms (SNP). Thus, in this study among the South Indian T2DM population, we aim to explore the association of AHSG Thr256Ser (rs4918) SNP in subjects with DN and correlate with the circulatory levels of Fetuin-A at various stages of DN patients. MethodsA total of 975 subjects were recruited, such as Group-I, consisting of Controls (n = 300), Group-II, with normoalbuminuria (n = 300), Group-IIIa, with incipient microalbuminuria (n = 195), Group-IIIb, with persistent macroalbuminuria (n = 180)] and were subjected for genotyping using PCR-Restriction Fragment Length Polymorphism (RFLP). Circulatory Fetuin-A was measured using sandwich enzyme-linked immunosorbent assay (ELISA). ResultsThe ‘G’ allele of AHSG exon-7 (C/G) SNP is significantly concomitant and conferred significant risk for normoalbuminuria subjects. In the DN subjects, the ‘G' allele showed the risk for persistent macroalbuminuria. A noticeable stepwise decrease was evidenced in the circulatory Fetuin-A among persistent macroalbuminuria over incipient microalbuminuria from normoalbuminuria. Further, the circulatory Fetuin-A was lowered in DN subjects with mutant GG genotype than the wild CC. ConclusionAHSG Thr256Ser (rs4918) SNP was associated with renal complications among South Indian T2DM subjects.

PlA2 Polymorphism of Platelet Glycoprotein IIb/IIIa and C677T Polymorphism of Methylenetetrahydrofolate Reductase (MTHFR), but Not Factor V Leiden and Prothrombin G20210A Polymorphisms, Are Associated with More Severe Forms of Legg-Calvé-Perthes Disease.

The possible association of common polymorphic variants related to thrombophilia (the rs6025(A) allele encoding the Leiden mutation, rs1799963(A), i.e., the G20210A mutation of the prothrombin F2 gene, the rs1801133(T) variant of the methylenetetrahydrofolate reductase (MTHFR) gene that encodes an enzyme involved in folate metabolism, and rs5918(C), i.e., the ‘A2’ allele of the platelet-specific alloantigen system that increases platelet aggregation induced by agonists), with the risk of Legg–Calvé–Perthes disease (LCPD) and the degree of hip involvement (Catterall stages I to IV) was analyzed in a cohort study, including 41 children of ages 2 to 10.9 (mean 5.4, SD 2.2), on the basis of clinical and radiological criteria of LCPD. In 10 of the cases, hip involvement was bilateral; thus, a total of 51 hips were followed-up for a mean of 75.5 months. The distribution of genotypes among patients and 118 controls showed no significant differences, with a slightly increased risk for LCPD in rs6025(A) carriers (OR: 2.9, CI: 0.2–47.8). Regarding the severity of LCPD based on Catterall classification, the rs1801133(T) variant of the MTHFR gene and the rs5918(C) variant of the platelet glycoprotein IIb/IIIa were associated with more severe forms of Perthes disease (Catterall III–IV) (p < 0.05). The four children homozygous for mutated MTHFR had a severe form of the disease (Stage IV of Catterall) and a higher risk of non-favorable outcome (Stulberg IV–V).

Cytomegalovirus Glycoprotein Polymorphisms and Increasing Viral Load in Non-Transplant Patients with Hematological Malignancies Undergoing Chemotherapy: A Prospective Observational Study.

IntroductionCytomegalovirus (CMV) predisposes to several clinical complications and is a major cause of morbidity and mortality in immunocompromised patients, including patients with hematological malignancies (HM). The present study was carried out to determine the distribution of CMV glycoprotein B, N, and O (gB, gN, and gO) genotypes and their potential effect on its viral load and on clinical outcomes in a cohort of Tunisian non-hematopoietic stem cell transplant (HSCT) patients with HM undergoing chemotherapy.MethodsCMV viral load was evaluated by real-time quantitative PCR. The gB, gN, and gO genotypes of the CMV strains were analyzed by multiplex nested PCR and sequencing.ResultsThis prospective study involved 60 clinical isolates obtained from 60 non-HSCT patients with HM undergoing chemotherapy. Mixed CMV gB, gN, and gO genotypes were the predominant glycoprotein genotypes in 31%, 41.4%, and 46.4% of patients, respectively. Mixed gB genotypes were associated with higher initial levels of CMV load (p = 0.001), increased rate of fever (0.025), and co-infection with other herpesviruses (HHVs) (p = 0.024) more frequently than in single gB genotype. Mixed gN genotypes were more associated with severe lymphopenia (ALC < 500/µL) (p = 0.01) and increased risk of death (p = 0.042) than single gN genotype. Single gO2b genotype had also a more unfavorable outcome (p = 0.009) than the other single gO genotype. Mixed gO genotypes were associated with female gender (p = 0.015), acute leukemia disease (p = 0.036), initial high level of CMV viral load (at least 1000 copies/mL) (p = 0.029), skin rash (p = 0.01) more frequently than in single gO genotype. The gO1a/gN3b linkage was associated with an increased initial viral load (p = 0.012).ConclusionInfection with mixed CMV genotypes was common and multiple gB, gN, and gO genotypes were associated with clinical manifestation and higher viral load.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00457-z.

Polymorphisms of the cytomegalovirus glycoprotein B genotype in patients with Posner-Schlossman syndrome

AimsThe aim of this observational study was to report the distribution of glycoprotein B (gB) genotypes in the eyes of cytomegalovirus (CMV) positive patients with Posner-Schlossman syndrome (PSS), and to...

Impact of Platelet Glycoprotein Ia/IIa C807T Gene Polymorphisms on Coronary Artery Aneurysms of KD Patients

Background Kawasaki disease (KD) is a systemic vasculitis of unknown etiology in children. Coronary artery abnormalities are the most common complications of KD. Recent evidence showed that genetic polymorphisms may lead to susceptibility to KD. Genetic variants in platelet glycoprotein have been reported to be associated with coronary artery disease. The aim of the present study is to investigate the correlation between the role of platelet glycoprotein and coronary artery aneurysms in KD patients. Methods We did a case-control study that enrolled 818 KD patients and 1401 healthy children with the same age and sex from January 2013 to December 2016. Analysis of single-nucleotide polymorphism (rs1126643) of the platelet glycoprotein Ia/IIa C807T was performed by multiplex polymerase chain reactions in this study. Results A significant difference in the genotype distribution between KD cases and controls was observed for the glycoprotein Ia/IIa C807T (rs1126643) polymorphism (p=0.026). Compared with the healthy children, the rs1126643T allele carriers had odds ratio (OR) of 0.63 for developing KD (TT vs. CC: adjusted OR = 0.62, 95% confidence interval (CI) = 0.43–0.88,p=0.0078; TT vs. CT/CC: adjusted OR = 0.63, 95% CI = 0.44–0.889,p=0.0093). Furthermore, we also found that children less than 60 months of age and female patients with rs1126643 T allele carriers had an adjusted OR of 0.66 (95% CI = 0.46–0.95) for noncoronary artery aneurysm patients (p=0.0242). Single-nucleotide polymorphism rs1126643 TT seems to represent a protective factor against KD in coronary artery aneurysm formation in multivariate analysis. Conclusions The platelet glycoprotein Ia/IIa T allele carriers may have a protective effect on the risk of coronary artery aneurysms of KD patients, especially in females and children aged less than 60 months. These results may provide evidence for platelet glycoprotein Ia/IIa gene polymorphisms in the pathogenesis of KD patients.

DENV-3 precursor membrane (prM) glycoprotein enhances E protein immunogenicity and confers protection against DENV-2 infections in a murine model

ABSTRACT To improve a DNA vaccine containing the truncated dengue virus serotype 2 (DENV-2) envelope (E) protein and evaluate the influence of precursor membrane (prM) glycoprotein polymorphism on E protein immunogenicity, two vaccine candidates have been constructed by upstream insertion of the DENV-2 and DENV-3 prM genes into the DENV-2 E gene, named pCID2EtD2prM and pCID2EtD3prM, respectively. Both constructs were able to induce antibody production, which were neutralizing against DENV-2 in a murine model. Splenocytes of immunized groups, when challenged with virus, demonstrated Th1 cytokine pattern and proliferation, in addition to the increase of specific T cells. Vaccine candidates pCID2EtD2prM and pCID2EtD3prM confer 70% and 90% protection against DENV-2, respectively. The pCID2EtD3prM plasmid conferred only 40% protection in the lethal challenge with DENV-2. The results demonstrate that DENV-3 prM has a greater influence on the immunogenicity of the E protein and, probably due to its role as a chaperone, these results may be related to the correct folding and, consequently, an increase in the presentation efficiency of produced transcripts.

Bioengineered iPSC-derived megakaryocytes for the detection of platelet-specific patient alloantibodies

AbstractHuman platelet membrane glycoprotein polymorphisms can be immunogenic in man and are frequently the cause of clinically important immune reactions responsible for disorders such as neonatal alloimmune thrombocytopenia. Platelets from individuals carrying rare polymorphisms are often difficult to obtain, making diagnostic testing and transfusion of matched platelets challenging. In addition, class I HLA antibodies frequently present in maternal sera interfere with the detection of platelet-reactive alloantibodies. Detection of alloantibodies to human platelet antigen 3 (HPA-3) and HPA-9 is especially challenging, in part because of the presence of cell type–specific glycans situated near the polymorphic amino acid that together form the alloepitope. To overcome these limitations, we generated a series of HLA class I–negative blood group O induced pluripotent stem cell (iPSC) lines that were gene edited to sequentially convert their endogenous HPA-3a alloantigenic epitope to HPA-3b, and HPA-9a to HPA-9b. Subjecting these cell lines, upon differentiation into CD41+/CD42b+ human megakaryocytes (MKs), to flow cytometric detection of suspected anti-HPA-3 and HPA-9 alloantisera revealed that the HPA-3a–positive MKs specifically reacted with HPA-3a patient sera, whereas the HPA-3b MKs lost reactivity with HPA-3a patient sera while acquiring reactivity to HPA-3b patient sera. Importantly, HPA-9b–expressing MKs specifically reacted with anti-HPA-9b–suspected patient samples that had been undetectable using conventional techniques. The provision of specialized iPSC-derived human MKs expressing intact homozygous glycoprotein alloantigens on the cell surface that carry the appropriate endogenous carbohydrate moieties should greatly enhance detection of clinically important and rare HPA-specific alloantibodies that, to date, have resisted detection using current methods.

PB2436 PLATELET GLYCOPROTEIN (GP IIB/IIIA) GENE POLYMORPHISM AS A RISK FACTOR FOR ISCHEMIC CEREBRO VASCULAR STROKE

Background:Recent data which indicate considerable variability in platelet phenotype which accounts for differences in platelet surface receptor function, count and reactivity with subsequent thrombotic events. The identification of a contribution by platelet glycoproteins polymorphism to Ischemic cerebrovascular stroke which is a multifactorial, polygenic pathological process is challenging.Aims:Assessment of the genetic platelet glycoprotein (GPIIb/IIIa) polymorphism, as a genetic risk factor in ischemic cerebrovascular stroke patients in Ismailia, Egypt.Methods:Study population included: Fifty adult ischemic cerebrovascular stroke patients (acute, recent or old) and fifty‐healthy control group matching the patients group. Hematological and biochemical; Molecular assessment included DNA extraction and purification using micro‐centrifugation technique were done. DNA amplification was carried out by PCR‐RFLP technique. Genotypic determination of the platelet GPIIb/IIIa genotypes was carried out using agarose gel electrophoresis of the PCR products after endonuclease restriction with enzyme Msp‐I.Results:Platelet glycoprotein GP IIIa (PlA2/A2) genotypic distribution showed a statistically significant difference in ischemic cerebrovascular stroke patients in comparison with the healthy matched controls (the control group: GPIIIa (PlA1/PlA1: homozygous) 82%, GPIIIa (PlA1/PlA2 heterozygous) 16%, GPIIIa (PlA1/PlA1), and GPIIIa (PlA2/PlA2 homozygous) 2%.While the patients group: GPIIIa (PlA1/PlA1: homozygous) 58%, GPIIIa (PlA1/PlA2 heterozygous) 32%, GPIIIa (PlA1/PlA1), and GPIIIa (PlA2/PlA2 homozygous) 10%. There were statistically significant differences in between study groups regarding Platelet GP IIIa (PlA2/A2)genotypes, smoking, hypertension, diabetes, and dyslipidaemia; dyslipidaemia showed the highest odds ratio of all the risk factors.Summary/Conclusion:Conclusions: In this population, the genetic platelet glycoprotein GPIIIa (PlA1/PlA2) polymorphism is a reliable and significant predictor biomarker in the prediction of ischemic cerebrovascular stroke and the platelet glycoprotein GPIIIa (PlA2/PlA2) mutant allele was identified as a risk factor ischemic cerebrovascular stroke.image

Glycoprotein 96 polymorphisms are associated with the risk of systemic lupus erythematosus: A case-control study.

To investigate the clinical implications of a genetic polymorphism in glycoprotein 96 (GP96), by analyzing the association between the genotype and haplotype of GP96 with systemic lupus erythematosus (SLE). We analyzed cell-surface expression of GP96 in peripheral blood mononuclear cells (PBMCs) and serum titer of anti-GP96 antibody of SLE patients. Single nucleotide polymorphisms and deletion mutants of GP96 were detected by two-dimensional gene scanning (TDGS). Odds ratios with 95% confidence intervals (CI) were determined for each genotype and haplotype through the chi-square test. In total, 216 Korean SLE patients and 215 age- and sex-matched healthy controls were enrolled. In SLE patients, as opposed to healthy controls, cell-surface expression of GP96 among human leukocyte antigen-DR+ PBMCs (76.4% vs 45.5%, respectively, P<0.001) and serum anti-GP96 antibody titers (0.98 vs 0.50, respectively, P=0.012) increased. TDGS revealed six polymorphic sites in GP96, two of which were significantly associated with SLE (exon 1, g.-7C>G, odds ratio [OR] 1.78, 95% CI 1.16-2.75, P=0.009; exon 17, g.17009_17011del, OR 1.76, 95% CI 1.18-2.64, P=0.006). Two haplotypes (121111, 211212) were strongly associated with SLE (OR 8.92, 95% CI 1.10-72.6, P=0.041; OR 3.03, 95% CI 1.22-7.50, P=0.017, respectively) and specific clinical manifestations (discoid rash, arthritis, renal disorder, neurologic disorder, and hematologic disorder). Haplotype-based analysis revealed a stronger association between GP96 and SLE than did genotype-based analysis. The two polymorphisms, each in exons 1 and 17 of GP96 are potential genetic risk factors of SLE. Two haplotypes 121111 and 211212 are related to not only SLE but also specific clinical manifestations.

Identification of Single Nucleotide Polymorphism and Association Analysis of Alpha 2-Heremans Schmid Glycoprotein (AHSG) Gene Related to Fatty Acid Traits in Sheep

Fatty acid (FA) composition of meat is regulated by many genes. The aim of this study was to identify Single Nucleotide Polymorphism (SNP) of Alpha 2-Heremans Schmid Glycoprotein (AHSG) gene and analyze its association with fatty acid (FA) traits in lambs. The study used a total of 67 rams of 12 months with average body size of 25-30 kg, consisted of 20 heads of Javanese Fat-Tailed (JFT) sheep, 17 heads of Javanese Thin-Tailed (JTT) sheep, 10 heads of Composite Garut (CG) sheep, 10 heads of Compass Agrinak (CA) sheep and 10 heads of Barbados Black Belly Cross (BC) sheep. Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) were used to identify the single nucleotide polymorphisms (SNP) of AHSG gene. Association of AHSG genotypes with fatty acid traits was performed using General Linear Model by SAS 9.4 program. The SNP of AHSG gene was polymorphic with three genotypes (GG, GA and AA). In combined population, the genotype frequency of GG, GA and AA were 0.25, 0.13 and 0.62, respectively. The Chi-square test revealed that the locus of AHSG (g. 198655287 (G&gt;A) was in Hardy-Weinberg equilibrium, except in Composite Garut (CG), Compass Agrinak (CA) and Barbados Black Belly Cross (BC) sheep breeds. The g.198655287 (G&gt;A) SNP of AHSG gene was significantly associated (P&lt;0.05) with saturated fatty acid, including &lt;a href="https://en.wikipedia.org/wiki/Capric_acid"&gt;capric acid (C10:0)&lt;/a&gt;, palmitic acid (C16:0), heptadecanoic acid (17:0), &lt;a href="https://en.wikipedia.org/wiki/Arachidic_acid"&gt;arachidic acid (C20:0)&lt;/a&gt;, heneicosylic acid (C21:0), &lt;a href="https://en.wikipedia.org/wiki/Behenic_acid"&gt;behenic acid (C22:0)&lt;/a&gt;, &lt;a href="https://en.wikipedia.org/wiki/Tricosylic_acid"&gt;tricosylic acid (C23:0)&lt;/a&gt;, &lt;a href="https://en.wikipedia.org/wiki/Lignoceric_acid"&gt;lignoceric acid (C24:0)&lt;/a&gt;; with monounsaturated fatty acids, including &lt;a href="https://en.wikipedia.org/wiki/Palmitoleic_acid"&gt;palmitoleic acid (C16:1)&lt;/a&gt;; oleic acid (C18:1n9c); eicosenoic acid (C20:1); nervonic acid (C24:1) and with polyunsaturated fatty acids, including linoleic acid (C18:2n6c); γ-Linolenic acid; α-Linolenic acid; &lt;a href="https://en.wikipedia.org/w/index.php?title=Eicosadienoic_acid&amp;action=edit&amp;redlink=1"&gt;eicosadienoic acid (C20:2)&lt;/a&gt;; dihomo-gamma-linolenic acid; arachidonic acid; &lt;a href="https://en.wikipedia.org/w/index.php?title=Docosadienoic_acid&amp;action=edit&amp;redlink=1"&gt;docosadienoic acid(C22:2)&lt;/a&gt;; eicosapentanoic and docosahexaenoic acid. The SNP g. 198655287 (G&gt;A) of AHSG gene may be a useful marker for selecting and producing sheep meat having desirable fatty acids.

GP6 rs2304166 polymorphism is associated with response to natalizumab in multiple sclerosis patients

BackgroundCurrently, there are few established pharmacogenetic predictors of response to treatment in multiple sclerosis (MS) patients. Commonly used second line treatments include natalizumab that has proven to be successful in slowing MS progression in a subset of patients. Our aim was to identify pharmacogenetic factor(s) associated with MS patients’ response to natalizumab.MethodsTen MS patients not responding to natalizumab and 23 MS patients responsive to natalizumab were selected for exome sequencing. Exome sequences were analyzed and resultant variant was assessed in an additional cohort of 86 MS patients.ResultsExome analysis revealed a missense polymorphism (rs2304166) in glycoprotein VI (GP6) gene (19q13.42, c.940C > G, p.P314A) associated in homozygosity with MS poor response to natalizumab (p = 0.0012). An additional cohort of 86 MS patients of which 19 were natalizumab unresponsive and 67 responsive confirmed rs2304166 CC significant association with poor response to natalizumab (p = 0.0000027). In addition, rs2304166 CC MS patients had increased MS disability despite taking natalizumab (Odds ratio 22.18, 95% CI: 5.758–95.88, p = 0.00000001).ConclusionNatalizumab is a commonly used second line treatment for MS, and poor response to natalizumab appears to be associated with rs2304166 CC genotype in MS patients. Our findings suggest the need to investigate GP6’s rs2304166 role as a potential pharmacogenetic predictor for MS patients’ response to natalizumab.

Analysis of Human Platelet Antigen (HPA) in Thrombocytopenia Patients

Human Platelet Antigen (HPA) is a form of immunogenic polymorphism of platelet membrane glycoproteins. Human Platelet Antigen can cause platelet alloimmunization response will be clinical manifestations of immune thrombocytopenia, such as Fetal Neonatal Allo-immune Thrombocytopenia (FNAIT), Post Transfusion Purpura (PTP), and Platelet Transfusion Refractory (PTR), Idiopathic Thrombocytopenic Purpura (ITP). The aim of this study to research on seroprevalence (genotype and frequency) of Human Platelet Antigen (HPA) in Patients with Non-Immune and immune Thrombocytopenic.

Neonatal alloimmune thrombocytopenia due to a new alloantigen Bl(a) defined by an Asp458Gly substitution in GPIIIa.

Neonatal alloimmune thrombocytopenia (NAIT) commonly arises due to antibodies against a small number of well-defined human platelet antigens (HPAs). A minority of NAIT cases occur due to maternal immunization against low-frequency polymorphisms in platelet glycoprotein that result in new immunogenic epitopes. Antibodies to these novel epitopes can be detected by the incubation of maternal serum with paternal platelets and is usually performed after initial investigation using HPA-typed panel platelets has failed to provide evidence of NAIT. The propositus and the parents from a case of suspected neonatal alloimmune thrombocytopenia (NAIT) were investigated using serologic and molecular techniques to detect and identify relevant platelet-specific antibodies and for HPA typing. Calculations of molecular dynamics were undertaken to explore potential variations in the molecular structure. Maternal antibodies were detected that were reactive only in crossmatch with paternal platelets using the platelet immunofluorescence test (PIFT) and a GPIIb/IIIa monoclonal antibody immobilization of platelet antigen (MAIPA) assay. In the propositus and father, a novel mutation c.1373 A > G was found in exon 10 of ITGB3 resulting in the substitution of an aspartic acid for a glycine (p.Asp458Gly). Recombinant GPIIIa glycoprotein mutated to contain the novel mutation and expressed in HEK293 cells with GPIIb was also specifically recognized by maternal antibodies. Calculations of molecular dynamics identified that the mutation was in a structurally constrained site. This case describes a low-frequency platelet antigen (Asp458Gly) that defines a further alloantigenic target in NAIT. The case emphasizes the role of the platelet crossmatch as the single most useful tool to establish evidence of immunization of low-frequency platelet glycoprotein polymorphisms. A crossmatch should always be performed where there is strong clinical evidence of NAIT but initial laboratory investigations are not confirmatory.

Genetic Variability of SRC Family Kinases and Its Association with Platelet Hyperreactivity and Clinical Outcomes: A Systematic Review.

Platelet hyperactivity has been implicated in many cardiovascular (CV) events such as ischemic stroke, myocardial infarction and CV death. Genetic variability of platelet receptors has been shown to impact Src family kinases (SFKs) activation and in turn influence platelet activation. SFKs are important signal transmitters in platelets, interacting with several receptors as GPIIB/IIIa, GPIb, PEAR 1, GPIa, GPVI, PECAM and CD148. In this review, we focused on genetic variants of platelet receptors whose signals are transmitted mainly by SFKs and may be associated with clinical manifestations of platelet hyperactivation like MI or IS. The genetic variants of platelet receptors, the signals of which are transmitted by SFKs, and the associated clinical manifestations in platelet hyperactivation, have been examined. The most extensively studied receptors were glycoprotein polymorphisms. The greatest numbers of genetic variants were analyzed in GPIb. GPIIb/IIIa receptor polymorphisms were also well analyzed and many studies highlighted their associations with ischemic stroke (IS) and myocardial infarction (MI). However, there are a number of conflicting studies finding that GPIIb/IIIa receptor polymorphisms may not influence platelet hyperactivity. Moreover, variability within some other receptors like GPVI, PECAM, PEAR1, and CD148 was analyzed only in single studies. Src family kinases are one of the most important signal transmitters in platelets. Some receptors have well documented interactions with SFKs, while other have not been examined in humans or data about its association originated from single studies. Further studies are necessary to confirm the findings and reduce falsepositive associations.

HRG C633T polymorphism and risk of gestational hypertensive disorders: a pilot study

BackgroundPreeclampsia and gestational hypertensive disorders are thought to occur due to endothelial cell dysfunction and abnormal placentation, triggered by angiogenesis-related factors yet undetermined. The aim of this study was to investigate whether a genetic polymorphism (SNP) of Histidine-rich glycoprotein (HRG), HRG C633T SNP, is associated with gestational hypertensive disorders.MethodsIt was performed a nested case-control study from the BASIC Cohort of Uppsala University Hospital comprising 92 women diagnosed with gestational hypertensive disorders without other comorbidities and 200 women with full term uncomplicated pregnancies, all genotyped regarding HRG C633T SNP.ResultsThe genetic analysis of the study sample showed that C/C genotype was more prevalent among controls. The presence of the T-allele showed a tendency towards an increased risk of gestational hypertensive disorders. After clustering the study participants based on their genotype, it was observed that the odds for gestational hypertensive disorders among heterozygous C/T or homozygous T/T carriers were higher compared to homozygous C/C carriers [OR 1.72, 95% CI (1.04–2.84)]. The association remained significant even after adjustment for maternal age, BMI and parity.ConclusionsThe HRG C633T genotype seems to be associated with gestational hypertensive disorders, and as part of a greater algorithm, might contribute in the future to the prediction of the individual susceptibility to the condition.

Genetic Polymorphisms of coagulation factors and platelet glycoproteins in patients with chronic myeloproliferative neoplasms

Genetic Polymorphisms of coagulation factors and platelet glycoproteins in patients with chronic myeloproliferative neoplasms