A Simple Genetic Thrombosis Score Of Five Single Nucleotide Polymorphisms Is Associated With Risk Of First Venous Thrombosis In Pregnant Women

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3617-3617
Author(s):  
Lance A. Bare ◽  
Hugoline G. de Haan ◽  
Andre R. Arellano ◽  
Carmen H. Tong ◽  
James J. Devlin ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Venous Thrombosis ◽  
Pregnant Women ◽  
Odds Ratio ◽  
Factor V Leiden ◽  
Postpartum Women ◽  
Factor V ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Unit Increase

Abstract Background Venous thrombosis (VT), a major cause of maternal morbidity and mortality, is increased 4- to 5- fold during pregnancy. A thrombosis score comprising 5 single nucleotide polymorphisms (SNPs) [rs6025 (Factor V Leiden), rs1799963 (Prothrombin 20210 G>A), rs8176719 (ABO 261G>deletion), rs2066865 (FGG 10034 C>T) and rs2036914 (F11 10364T>C)] was previously shown to be associated with VT events in the general population. We asked whether this thrombosis score could predict VT in pregnant and postpartum women in a case-control study on the etiology of thrombosis. Methods We studied women during pregnancy and up to three months postpartum (55 controls, 144 cases) selected from over 5000 female cases and controls of the MEGA (the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis) study. The thrombosis score was calculated for each individual as a sum of risk alleles weighted by the log of the published odds ratio (de Haan et al, Blood 2012). The VT risk per unit of thrombosis score was calculated as a continuous variable in a logistic regression model that adjusted for age, smoking history and family history of VT. The thrombosis scores ranged from 0 to 1.8 in female participants in MEGA with genotypes for the 5 SNPs (n=3,464). Results In pregnant and postpartum women, the odds ratio per unit increase in thrombosis score was 10.7 (95%CI 3.2 to 36.2). When the thrombosis score was evaluated in a sub study of pregnant and postpartum women who do not carry factor V Leiden—an important contributant to the risk score— the remaining 4-SNP thrombosis score was also associated with VT: the odds ratio per unit increase in thrombosis score was 10.6 (95%CI 2.3-48.3).The American College of Obstetricians and Gynecologists recommends thromboprophylaxis during pregnancy and postpartum periods in women who are compound carriers of both factor V Leiden and prothrombin 20210 G>A; these compound carriers who do not carry other risk variants would have a thrombosis score of 1.02. Compared with women in the bottom quintile of thrombosis scores, women with thrombosis scores equal to or greater than 1.02 had an odds ratio for VT of 12.3 (95%CI 1.5 to 99.9). About 2% of female controls in MEGA had thrombosis scores equal to or greater than 1.02. Conclusions A 5-SNP thrombosis score that combines the VT risk of 5 genetic variants is associated with VT in pregnant women. Disclosures: Bare: Celera: Employment. Arellano:Celera: Employment. Tong:Celera: Employment. Devlin:Celera: Employment.

scholarly journals Clinical Applications of Whole-Blood PCR with Real-Time Instrumentation

2005 ◽  
Vol 51 (11) ◽  
pp. 2025-2030 ◽  
Author(s):  
Alison Castley ◽  
Melinda Higgins ◽  
John Ivey ◽  
Cyril Mamotte ◽  
David C Sayer ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Real Time ◽  
Whole Blood ◽  
Detection System ◽  
Melting Curve ◽  
Factor V Leiden ◽  
Melting Curve Analysis ◽  
Factor V ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Abstract Background: As the genetic basis of many human diseases is being discovered, there is increasing need for the detection of single-nucleotide polymorphisms/mutations in medical laboratories. We describe an innovative approach that combines PCR amplification directly on whole blood and real-time detection PCR technology (WB-RTD PCR). Methods: We compared WB-RTD PCR with the method for extracted DNA-RTD PCR for the detection of mutations in the prothrombin (n = 94), factor V Leiden (n = 49), and hemochromatosis (n = 22) genes. Mutation detection on the Roche LightCycler was based on use of fluorescence resonance energy transfer (FRET) probes and melting curve analysis. We also compared the WB-RTD PCR on the LightCycler and the ABI Prism™ 7700 sequence detection system with minor groove– binding nonfluorescent quencher probes. Results: We obtained complete concordance between both methods in assigning genotypes. We also demonstrated that the WB-RTD PCR method can be performed on real-time PCR instruments from Applied Biosystems and the LightCycler. Omission of the need for DNA extraction and gel electrophoresis allowed substantial labor and cost savings with this method. Conclusion: This approach has applications for testing other medically relevant single-nucleotide polymorphisms.

scholarly journals HMGB1 gene polymorphism is associated with coronary artery lesions and intravenous immunoglobulin resistance in Kawasaki disease

Rheumatology ◽  
2018 ◽  
Vol 58 (5) ◽  
pp. 770-775 ◽  
Author(s):  
Jong Gyun Ahn ◽  
Yoonsun Bae ◽  
Dongjik Shin ◽  
Jiho Nam ◽  
Kyu Yeun Kim ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Kawasaki Disease ◽  
Single Nucleotide Polymorphisms ◽  
Odds Ratio ◽  
Ivig Treatment ◽  
Nucleotide Polymorphisms ◽  
Coronary Artery Lesions ◽  
Hmgb1 Level ◽  
Single Nucleotide ◽  
Ivig Resistance

Abstract Objectives Kawasaki disease (KD) is an acute systemic vasculitis of unknown aetiology that affects infants and young children. Recent reports of elevated serum high mobility group box 1 (HMGB1) level during the acute phase of KD and its relationship to poor response to IVIG treatment suggest a possible association of HMGB1 polymorphisms with KD. We investigated the association between the polymorphisms of the HMGB1 gene, KD susceptibility, coronary artery lesions, and KD response to IVIG treatment. Methods Whole genome sequencing of the HMGB1 gene was performed to identify causative variants. Two tagging single nucleotide polymorphisms of the HMGB1 gene were selected using linkage disequilibrium analysis. The tagging single nucleotide polymorphisms were genotyped using the TaqMan Allelic Discrimination assay in a total of 468 subjects (265 KD patients and 203 controls). Results The HMGB1 single nucleotide polymorphisms were not associated with KD susceptibility. However, in KD patients, there was a significant association of rs1412125 with coronary artery lesions formation in the recessive model (GG vs AA + GA: odds ratio = 4.98, 95% CI = 1.69–14.66, P = 0.005). In addition, rs1412125 was associated with IVIG resistance in the recessive (GG vs AA + GA: odds ratio = 4.11, 95% CI = 1.38–12.23, P = 0.017) and allelic models (G vs A: odds ratio = 1.80, 95% CI = 1.06–3.06, P = 0.027). Conclusion The rs1412125 in HMGB1 might be a risk factor for the development of coronary artery lesions and IVIG resistance in KD patients.

scholarly journals Association of Single-Nucleotide Polymorphisms in DC-SIGN with Nasopharyngeal Carcinoma Susceptibility

2017 ◽  
Vol 2017 ◽  
pp. 1-6
Author(s):  
Sisi Li ◽  
Zhifang Lu ◽  
Mengwei Yao ◽  
Sisi Ning ◽  
Yuan Wu ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Nasopharyngeal Carcinoma ◽  
Single Nucleotide Polymorphisms ◽  
Odds Ratio ◽  
Chinese Population ◽  
Smoking History ◽  
Intercellular Adhesion Molecule ◽  
Nucleotide Polymorphisms ◽  
Gene Encoding ◽  
Single Nucleotide

The aim of this study was to explore potential relationships of four single-nucleotide polymorphisms (SNPs) in the gene encoding dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) with risk of nasopharyngeal carcinoma (NPC). The DC-SIGN SNPs rs7252229, rs4804803, rs2287886, and rs735240 were genotyped in 477 unrelated NPC patients and 561 cancer-free controls. At rs7252229, risk of NPC was significantly lower in individuals with GC (odds ratio [OR] 0.076, 95% confidence interval [CI] 0.008–0.690), GG (OR 0.056, 95%CI 0.006–0.487), or GC + GG (OR 0.059, 95%CI 0.007–0.515) than in individuals with the CC genotype, after adjusting for age, gender, smoking history, and EBV-VCA-IgA status. At rs4804803, risk of NPC was significantly higher in individuals with the genotype GG than in those with the genotype AA (adjusted OR 9.038, 95%CI 1.708–47.822). At rs735240, risk of NPC did not change significantly with genotypes AG, GG, or AG + GG after adjusting for age, gender, and smoking history. However, when data were also adjusted for EBV-VCA-IgA status, three genotypes emerged as associated with significantly higher risk of NPC than the AA genotype: AG (OR 2.976, 95%CI 1.123–7.888), GG (OR 3.314, 95%CI 1.274–8.622), or GG + AG (OR 3.191, 95%CI 1.237–8.230). Our results suggest that DC-SIGN SNPs rs7252229, rs4804803, and rs735240 may influence NPC risk in the Chinese population. The mechanisms mediating this risk require a further study.

Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24 000 years ago

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4666-4668 ◽  
Author(s):  
Ariella Zivelin ◽  
Ronit Mor-Cohen ◽  
Victoria Kovalsky ◽  
Nurit Kornbrot ◽  
Jacqueline Conard ◽  
...  
Keyword(s):  
Factor V Leiden ◽  
Wide Distribution ◽  
Factor V ◽  
Nucleotide Polymorphisms ◽  
Founder Effects ◽  
Single Nucleotide ◽  
Linkage Disequilibria ◽  
Last Glaciation ◽  
Prothrombin Gene ◽  
Credible Set

Abstract Prothrombin 20210G>A and factor V Leiden are common prothrombotic mutations in whites for which founder effects have been established. In this study, we analyzed the frequencies of 5 single nucleotide polymorphisms (SNPs) and 9 microsatellites flanking the prothrombin gene (F2) in 88 homozygotes for 20210A and 66 homozygotes for 20210G. For estimating the age of the prothrombin 20210G>A mutation, we used the DMLE+2.0 program, which analyzed linkage disequilibria between the mutation and the multiple markers that had been assessed. This analysis yielded an age estimate of 23 720 years (95% credible set, 19 080-31 340 years). A similar analysis by the DMLE+2.0 program was performed on 5 SNPs from previously studied homozygotes for factor V Leiden and controls that yielded an age estimate of 21 340 years (95% credible set, 16 880-29 480 years). The occurrence of the 2 mutations in whites toward the end of the last glaciation and their presently wide distribution in whites suggest selective evolutionary advantages for which some evidence was reported (diminished blood loss) or is controversial (protection against infections).

scholarly journals Association of Sex Determining Region Y-Box 17 Gene Polymorphisms and Intracranial Aneurysm: A Case-Control Study and Meta-analysis

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Museung Park ◽  
Yong-Jun Cho ◽  
Jin Sue Jeon
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Confidence Interval ◽  
Odds Ratio ◽  
Gene Polymorphisms ◽  
Meta Analysis ◽  
East Asian ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Unruptured Aneurysms ◽  
Asian Populations

Abstract INTRODUCTION Genome-wide association studies have revealed an association between SRY (Sex Determining Region Y)-box 17 (SOX17) gene and intracranial aneurysm (IA) formation. However, results were mainly derived from European and Japanese populations. We investigated the association between SOX17 gene polymorphisms and IA in a homogeneous Korean population. We performed a meta-analysis to assess these results in East-Asian populations. METHODS This cross-sectional study included 187 age- and sex-matched patients with IA and 372 control subjects. Genetic association analysis was performed in the generalized linear model to identify associations between 4 single nucleotide polymorphisms and IA, including 95 patients with ruptured aneurysms and 92 with unruptured aneurysms. The East-Asian meta-analysis of 5100 IA cases and 7930 control cases was conducted under an inverse variance model. RESULTS Among 4 single nucleotide polymorphisms that passed quality control tests, the minor C allele of rs1072737 was significantly associated with IA (odds ratio 0.69, 95% confidence interval 0.49-0.96, P = .03). None of the 4 single nucleotide polymorphisms showed a significant association between patients with ruptured and unruptured aneurysms. Meta-analysis revealed that G alleles of rs10958409 and rs9298506 were significantly associated with IA in the East-Asian population after removing study heterogeneity (odds ratio 1.11, 95% confidence interval 1.04-1.19, P = .0023 and odds ratio 1.19, 95% confidence interval 1.07-1.32, P = .0016). CONCLUSION Identification of genetic variants located near SOX17 is likely to be clinically significant for IA formation. rs10958409 and rs9298506 may increase risk of IA in East-Asian populations. Our findings may help in the identification of IA pathogenesis.

scholarly journals Coagulation Factors and the Risk of Ischemic Heart Disease

2018 ◽  
Vol 11 (1) ◽  
Author(s):  
Jie V. Zhao ◽  
C. Mary Schooling
Keyword(s):  
Heart Disease ◽  
Single Nucleotide Polymorphisms ◽  
Confidence Interval ◽  
Ischemic Heart Disease ◽  
Plasminogen Activator ◽  
Odds Ratio ◽  
Coagulation Factors ◽  
Ischemic Heart ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Background: Coagulation plays a role in ischemic heart disease (IHD). However, which coagulation factors are targets of intervention is unclear. We assessed how genetically predicted vWF (von Willebrand factor), ETP (endogenous thrombin potential), FVIII (factor VIII), d -dimer, tPA (tissue-type plasminogen activator), and PAI (plasminogen activator inhibitor)-1 affected IHD. We similarly estimated effects on lipids to determine whether any associations were independent of lipids. Methods and Results: Separate sample instrumental variable analysis with genetic instruments, that is, Mendelian randomization, was used to obtain unconfounded estimates of effects on IHD using extensively genotyped studies of coronary artery disease/myocardial infarction, CARDIoGRAMplusC4D Metabochip (64 374 cases, 130 681 controls) and CARDIoGRAMplusC4D 1000 Genomes (60 801 cases, 123 504 controls), and on lipids using the Global Lipids Genetics Consortium Results (n=196 475). Genetically predicted ETP was positively associated with IHD (odds ratio, 1.05 per log-transformed SD; 95% confidence interval, 1.03–1.07) based on 15 single-nucleotide polymorphisms, as were vWF (odds ratio, 1.05 per SD; 95% confidence interval, 1.02–1.08) and FVIII (odds ratio, 1.06 per SD; 95% confidence interval, 1.03–1.09) based on 16 and 6 single-nucleotide polymorphisms, respectively, but the latter associations were null after considering pleiotropy. vWF and FVIII were associated with higher LDL (low-density lipoprotein) cholesterol, but not after considering pleiotropy. Genetically predicted d -dimer, tPA, and PAI-1 were not clearly associated with IHD or lipids based on 3, 3, and 5 single-nucleotide polymorphisms, respectively. Conclusions: ETP may affect IHD. Assessing the role of its drivers in more precisely phenotyped studies of IHD could be worthwhile.

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