Failure to replicate thrombomodulin genetic variant predictors of venous thromboembolism in African Americans.
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ABSTRACT:
SUBMITTER: Folsom AR
PROVIDER: S-EPMC5542854 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Venous thromboembolism (VTE) is the third most common life-threatening cardiovascular condition in the United States, with African Americans (AAs) having a 30% to 60% higher incidence compared with other ethnicities. The mechanisms underlying population differences in the risk of VTE are poorly understood. We conducted the first genome-wide association study in AAs, comprising 578 subjects, followed by replication of highly significant findings in an independent cohort of 159 AA subjects. Logistic regression was used to estimate the association between genetic variants and VTE risk. Through bioinformatics analysis of the top signals, we identified expression quantitative trait loci (eQTLs) in whole blood and investigated the messenger RNA expression differences in VTE cases and controls. We identified and replicated single-nucleotide polymorphisms on chromosome 20 (rs2144940, rs2567617, and rs1998081) that increased risk of VTE by 2.3-fold (P< 6 × 10(-7)). These risk variants were found in higher frequency among populations of African descent (>20%) compared with other ethnic groups (<10%). We demonstrate that SNPs on chromosome 20 are cis-eQTLs for thrombomodulin (THBD), and the expression of THBD is lower among VTE cases compared with controls (P= 9.87 × 10(-6)). We have identified novel polymorphisms associated with increased risk of VTE in AAs. These polymorphisms are predominantly found among populations of African descent and are associated with THBD gene expression. Our findings provide new molecular insight into a mechanism regulating VTE susceptibility and identify common genetic variants that increase the risk of VTE in AAs, a population disproportionately affected by this disease.
| S-EPMC4832509 | biostudies-literature
Project description:To identify novel single nucleotide polymorphisms (SNPs) associated with venous thromboembolism (VTE) in African-Americans (AAs), we performed a genome-wide association study (GWAS) of VTE in AAs using the Electronic Medical Records and Genomics (eMERGE) Network, comprised of seven sites each with DNA biobanks (total ~39,200 unique DNA samples) with genome-wide SNP data (imputed to 1000 Genomes Project cosmopolitan reference panel) and linked to electronic health records (EHRs). Using a validated EHR-driven phenotype extraction algorithm, we identified VTE cases and controls and tested for an association between each SNP and VTE using unconditional logistic regression, adjusted for age, sex, stroke, site-platform combination and sickle cell risk genotype. Among 393 AA VTE cases and 4,941 AA controls, three intragenic SNPs reached genome-wide significance: LEMD3 rs138916004 (OR=3.2; p=1.3E-08), LY86 rs3804476 (OR=1.8; p=2E-08) and LOC100130298 rs142143628 (OR=4.5; p=4.4E-08); all three SNPs validated using internal cross-validation, parametric bootstrap and meta-analysis methods. LEMD3 rs138916004 and LOC100130298 rs142143628 are only present in Africans (1000G data). LEMD3 showed a significant differential expression in both NCBI Gene Expression Omnibus (GEO) and the Mayo Clinic gene expression data, LOC100130298 showed a significant differential expression only in the GEO expression data, and LY86 showed a significant differential expression only in the Mayo expression data. LEMD3 encodes for an antagonist of TGF-?-induced cell proliferation arrest. LY86 encodes for MD-1 which down-regulates the pro-inflammatory response to lipopolysaccharide; LY86 variation was previously associated with VTE in white women; LOC100130298 is a non-coding RNA gene with unknown regulatory activity in gene expression and epigenetics.
| S-EPMC5831339 | biostudies-literature
Project description:ESSENTIALS: There is little prospective information on genetic risk scores to predict venous thromboembolism (VT). Community based cohort followed a median of 22.6 years for VT occurrence. A 5-SNP risk score identified whites at risk of VT, but not African Americans. The utility of genetic risk scores for VT is yet to be established.Case-control studies have created genetic risk scores of single nucleotide polymorphisms (SNPs) associated with venous thromboembolism (VTE) and documented their ability to predict VTE, but prospective data are lacking.To test the ability of a genetic risk score to predict VTE incidence in a prospective study, particularly in African Americans.We computed a previously proposed genetic risk score, based on five established VTE SNPs in the F5, F2, ABO, FGG, and F11 genes, in 9520 whites and 3049 African Americans initially free of VTE. We followed them a median of 22.6 years for VTE occurrence (n = 380 events in whites and n = 187 in African Americans).In whites, the five-SNP weighted genetic risk score ranged from 0 to 5.8, and VTE risk increased 1.41-fold (95% confidence interval [CI] 1.27-fold to 1.56-fold) per allele increment. In African Americans, the weighted genetic risk score ranged from 0 to 4.6 and the hazard ratio per risk allele was 1.14 (95% CI 0.94-1.38), with adjustment for 10 principal components of ancestry. The area under the receiver operating characteristic curve for 20-year prediction of VTE from the weighted genetic risk score was 0.59 (95% CI 0.56-0.63) in whites and 0.56 (95% CI 0.51-0.61) in African Americans. Adding non-genetic factors increased the area under the curve to 0.67 in whites and to 0.66 in African Americans.Higher values for a five-SNP genetic risk score helped identify white adults at risk of VTE. The genetic risk score did not identify future VTE occurrence in African Americans.
| S-EPMC4715510 | biostudies-literature
Project description:IntroductionAfrican Americans have a higher incidence of venous thromboembolism (VTE) than European descent individuals. However, the typical genetic risk factors in populations of European descent are nearly absent in African Americans, and population-specific genetic factors influencing the higher VTE rate are not well characterized.MethodsWe performed a candidate gene analysis on an exome-sequenced African American family with recurrent VTE and identified a variant in Protein S (PROS1) V510M (rs138925964). We assessed the population impact of PROS1 V510M using a multicenter African American cohort of 306 cases with VTE compared to 370 controls. Additionally, we compared our case cohort to a background population cohort of 2203 African Americans in the NHLBI GO Exome Sequencing Project (ESP).ResultsIn the African American family with recurrent VTE, we found prior laboratories for our cases indicating low free Protein S levels, providing functional support for PROS1 V510M as the causative mutation. Additionally, this variant was significantly enriched in the VTE cases of our multicenter case-control study (Fisher's Exact Test, P = 0.0041, OR = 4.62, 95% CI: 1.51-15.20; allele frequencies - cases: 2.45%, controls: 0.54%). Similarly, PROS1 V510M was also enriched in our VTE case cohort compared to African Americans in the ESP cohort (Fisher's Exact Test, P = 0.010, OR = 2.28, 95% CI: 1.26-4.10).ConclusionsWe found a variant, PROS1 V510M, in an African American family with VTE and clinical laboratory abnormalities in Protein S. Additionally, we found that this variant conferred increased risk of VTE in a case-control study of African Americans. In the ESP cohort, the variant is nearly absent in ESP European descent subjects (n = 3, allele frequency: 0.03%). Additionally, in 1000 Genomes Phase 3 data, the variant only appears in African descent populations. Thus, PROS1 V510M is a population-specific genetic risk factor for VTE in African Americans.
| S-EPMC5023936 | biostudies-literature
Project description:BackgroundVenous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.MethodsWe present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.ResultsIn our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.ConclusionsOur cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.
| S-EPMC10152894 | biostudies-literature
Project description:Variants in the CYP2C9 (i.e. *2 and *3) and VKORC1 (i.e. 1173C/T or -1639G/A) genes have been shown to influence warfarin dose requirements. However, these factors seem to explain less of the dose variability in African Americans who have a lower prevalence of the CYP2C9*2 and *3 and VKORC1 1173T alleles.In African Americans, the VKORC1 rs17886199 variant was statistically significantly associated with log-transformed warfarin maintenance dose, independent of the influence of VKORC1 1173C>T and CYP2C9*2 and *3. However, replication of our finding is needed to confirm the association of rs1786199 SNP in African Americans, since Limdi et al.[3] did not examine the effect of this SNP because the prevalence of the rs1786199 A-allele was too low.To raise hypotheses with regards to whether genetic variants in the VKORC1, CYP2C9, EPHX1, GGCX and ALB genes might influence warfarin dose in African Americans and Caucasians, independent of the effects of the VKORC1 1173C>T and CYP2C9*2 and *3 variants.From a prospective cohort study, we obtained additional DNA on 36 Caucasian and 22 African American warfarin users who reached maintenance dose and genotyped them for tagSNPs (r2<0.8) in VKORC1, EPHX1, GGCX and ALB genes, and one exonic CYP2C9 SNP. Linear regression models were fitted to estimate the relationship (P value) between log-transformed maintenance dose and each SNP and the amount of the warfarin dose variability accounted for by each SNP (partial R2).In African Americans, the VKORC1 rs17886199 A-allele was associated with a lower dose (GG=46.3 mg and GA=25.6 mg; P=0.002), independent of the VKORC1 1173C>T and CYP2C9*2 and *3 variants. Even after applying Bonferroni correction, the P value would still be considered statistically significant. The VKORC1 rs17886199 variant was not found in Caucasians. In Caucasians, the EPHX1 rs1051741 T-allele was associated with a lower dose (CC=41.3 mg and CT=30.0 mg; P=0.04). The latter was no longer statistically significant after applying Bonferroni correction.Our pilot study suggests that the VKORC1 rs17886199 variant could influence warfarin maintenance dose among African Americans, even after accounting for the influence of the VKORC1 1173C>T variant. Future studies with a larger sample size will be needed to confirm our findings.
| S-EPMC2949912 | biostudies-literature
Project description:Circulating lipid concentrations are among the strongest modifiable risk factors for coronary artery disease (CAD). Most genetic studies have focused on Caucasian populations with little information available for populations of African ancestry. Using a cohort of ~2800 African-Americans (AAs) from a biobank at Vanderbilt University (BioVU), we sought to trans-ethnically replicate genetic variants reported by the Global Lipids Genetics Consortium to be associated with lipid traits in Caucasians, followed by fine-mapping those loci using all available variants on the MetaboChip. In AAs, we replicated one of 56 SNPs for total cholesterol (TC) (rs6511720 in LDLR, P=2.15 × 10-8), one of 63 SNPs for high-density lipoprotein cholesterol (HDL-C) (rs3764261 in CETP, P=1.13 × 10-5), two of 46 SNPs for low-density lipoprotein cholesterol (LDL-C) (rs629301 in CELSR2/SORT1, P=1.11 × 10-5 and rs6511720 in LDLR, P=2.47 × 10-5) and one of 34 SNPs for TG (rs645040 in MSL2L1, P=4.29 × 10-4). Using all available variants on MetaboChip for fine mapping, we identified additional variants associated with TC (APOE), HDL-C (LPL and CETP) and LDL-C (APOE). Furthermore, we identified two loci significantly associated with non-HDL-C: APOE/APOC1/TOMM40 and PCSK9. In conclusion, the genetic architecture of lipid traits in AAs differs substantially from that in Caucasians and it remains poorly characterized.
| S-EPMC5612856 | biostudies-literature
Project description:African Americans (AAs) and obese individuals have increased thrombotic risk. This study evaluated the effectiveness and safety of rivaroxaban versus warfarin in obese, AAs with nonvalvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). Optum® De-Identified Electronic Health Record (EHR) data was used to perform separate propensity-score matched analyses of adult, oral anticoagulant (OAC)-naïve AAs with NVAF or acute VTE, respectively; who had a body mass index≥30kg/m2 and ≥12-months EHR activity with ≥1-encounter before OAC initiation. Cox regression was performed and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). For the NVAF analysis, 1,969 rivaroxaban- and 1,969 warfarin-users were matched. Rivaroxaban was not associated with a difference in stroke/systemic embolism versus warfarin (HR = 0.88, 95%CI = 0.60-1.28), but less major bleeding (HR = 0.68, 95%CI = 0.50-0.94) was observed. Among 683 rivaroxaban-users with VTE, 1:1 matched to warfarin-users, rivaroxaban did not alter recurrent VTE (HR = 1.36, 95%CI = 0.79-2.34) or major bleeding (HR = 0.80, 95%CI = 0.37-1.71) risk versus warfarin at 6-months (similar findings observed at 3- and 12-months). Rivaroxaban appeared to be associated with similar thrombotic, and similar or lower major bleeding risk versus warfarin in these obese, AA cohorts.
| S-EPMC7588768 | biostudies-literature
Project description:New-onset heart failure (HF) is associated with cardiovascular morbidity and mortality. It is uncertain to what extent HF confers an increased risk of venous thromboembolism (VTE). Adults ?65 years old hospitalized with a new diagnosis of HF were identified from Medicare claims from 2007-2013. We identified the incidence, predictors and outcomes of VTE in HF. We compared VTE incidence during follow-up after HF hospitalization with a corresponding period 1-year prior to the HF diagnosis. Among 207,535 patients with a new HF diagnosis, the cumulative incidence of VTE was 1.4%, 2.5%, and 10.5% at 30 days, 1 year, and 5 years, respectively. The odds of VTE were greatest immediately after new-onset HF and steadily declined over time (OR 2.2 [95% CI 2.0-2.3], OR 1.5 [1.4-1.7], and OR 1.2 [1.2-1.3] at 0-30 days, 4-6 months, and 7-9 months, respectively). Over 26-month follow-up, patients with HF were at two-fold higher risk of VTE than patients without HF (adjusted HR 2.31 [2.18-2.45]). VTE during follow-up was associated with long-term mortality (adjusted HR 1.60, 95% CI 1.56-1.64). In conclusion, patients with HF are at increased risk of VTE early after a new HF diagnosis. VTE in patients with HF is associated with long-term mortality.
| S-EPMC6874686 | biostudies-literature
Project description:The anticoagulant warfarin has >30 million prescriptions per year in the United States. Doses can vary 20-fold between patients, and incorrect dosing can result in serious adverse events. Variation in warfarin pharmacokinetic and pharmacodynamic genes, such as CYP2C9 and VKORC1, do not fully explain the dose variability in African Americans. To identify additional genetic contributors to warfarin dose, we exome sequenced 103 African Americans on stable doses of warfarin at extremes (≤ 35 and ≥ 49 mg/week). We found an association between lower warfarin dose and a population-specific regulatory variant, rs7856096 (P = 1.82 × 10(-8), minor allele frequency = 20.4%), in the folate homeostasis gene folylpolyglutamate synthase (FPGS). We replicated this association in an independent cohort of 372 African American subjects whose stable warfarin doses represented the full dosing spectrum (P = .046). In a combined cohort, adding rs7856096 to the International Warfarin Pharmacogenetic Consortium pharmacogenetic dosing algorithm resulted in a 5.8 mg/week (P = 3.93 × 10(-5)) decrease in warfarin dose for each allele carried. The variant overlaps functional elements and was associated (P = .01) with FPGS gene expression in lymphoblastoid cell lines derived from combined HapMap African populations (N = 326). Our results provide the first evidence linking genetic variation in folate homeostasis to warfarin response.
| S-EPMC4183989 | biostudies-literature