Genetics of Hemostasis: Differential Effects of Heritability and Household Components Influencing Lipid Concentrations and Clotting Factor Levels in 282 Pediatric Stroke Families

Nowak‐Göttl, Ulrike; Langer, Claus; Bergs, Sandra; Thedieck, Sabine; Sträter, Ronald; Stoll, Monika

doi:10.1289/ehp.10754

Cited by 34 publications

(25 citation statements)

References 46 publications

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“…9 The estimates of h 2 in 2 other studies involving individuals with thrombosis or stroke were much lower, at 23.6% and 18.2%, respectively. 31,32 Our heritability estimate may have been higher than the later reports due to the healthy and young nature of our subjects, which could have decreased A1, allele 1 (minor allele and tested allele); A2, allele 2 (major allele); Dir, direction of effect for the tested allele; SE, standard error. *Position uses NCBI Build 36 coordinates (UCSC hg18), which is used throughout the study.…”

Section: Discussionmentioning

confidence: 79%

Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels

Ma¹,

Ozel²,

Ramdas³

et al. 2014

Blood

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• Genome-wide association analyses revealed common DNA variants in PLG, LPA, and near SIGLEC14 that contribute to plasma plasminogen level variation.• Tobacco smoking and female sex were associated with higher levels of plasminogen.Plasminogen is the precursor of the serine protease plasmin, a central enzyme of the fibrinolytic system. Plasma levels of plasminogen vary by almost 2-fold among healthy individuals, yet little is known about its heritability or genetic determinants in the general population. In order to identify genetic factors affecting the natural variation of plasminogen levels, we performed a genome-wide association study and linkage analysis in a sample of 3456 young healthy individuals who participated in the Genes and Blood Clotting Study (GABC) or the Trinity Student Study (TSS). Heritability of plasminogen levels was 48.1% to 60.0%. Tobacco smoking and female sex were associated with higher levels of plasminogen. In the meta-analysis, 11 single-nucleotide polymorphisms (SNPs) in 2 regions reached genome-wide significance (P < 5.0E-8). Of these, 9 SNPs were near the PLG or LPA genes on Chr6q26, whereas 2 were on Chr19q13 and 59 upstream of SIGLEC14. These 11 SNPs represented 4 independent signals and collectively explained 6.8% of plasminogen level variation in the study populations. The strongest association was observed for a nonsynonymous SNP in the PLG gene (R523W). Individuals bearing an additional copy of this allele had an average decrease of 13.4% in plasma plasminogen level. (Blood. 2014;124(20):3155-3164)

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Section: Discussionmentioning

confidence: 79%

Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels

Ma¹,

Ozel²,

Ramdas³

et al. 2014

Blood

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“…The replication study sample with pediatric TS and criteria for group assignment to vascular stroke were described in detail elsewhere. 11,12 Blood sample collection Blood sample collection from patients was done in the morning after a 12-hour fasting period (infants fasted 4-6 hours); samples were drawn by peripheral venipuncture into plastic tubes containing one-tenth by volume of 3.8% trisodium citrate (Sarstedt) and were immediately placed on melting ice. The blood samples from patients were collected 6 to 12 months after the acute thrombotic event and at least 6 weeks apart from anticoagulation.…”

Section: Methodsmentioning

confidence: 99%

Fibrinogen α and γ genes and factor VLeiden in children with thromboembolism: results from 2 family-based association studies

Nowak‐Göttl

Weiler

Hernández

et al. 2009

Blood

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Previous case-control studies showed that genetic variation in the fibrinogen ␥ gene (FGG) increased the risk for deep vein thrombosis (VT) in adults. We investigated the association between the fibrinogen ␣ (FGA) and FGG haplotypes, the factor V Leiden -mutation, and pediatric VT and thromboembolic stroke (TS) in 2 independent study samples. Association analysis revealed that the FGA-H1 and FGG-H2 haplotypes were significantly overtransmitted to VT patients (FGA-H1, P ‫؍‬ .05; FGG: H2, P ‫؍‬ .032). In contrast, the FGG-H3 haplotype was undertransmitted (P ‫؍‬ .022). In an independent study sample, FGA-H1 (P ‫؍‬ .008) and FGG-H2 (P ‫؍‬ .05) were significantly associated with TS. The association of FGA and FGG haplotypes with VT was more pronounced in FV Leiden

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“…4 Over the past 3 years, research in pediatric stroke has emphasized not only single gene associations but also heritability of coagulation factors, 57 candidate gene polymorphisms, and haplotype associations. 58 -60 The results of these individual studies on the risk of stroke onset associated with thrombophilia have been contradictory or inconclusive, mainly because of a lack of statistical power.…”

Section: Editorial See P 1795 Clinical Perspective On P 1847mentioning

confidence: 99%

Impact of Thrombophilia on Risk of Arterial Ischemic Stroke or Cerebral Sinovenous Thrombosis in Neonates and Children

et al. 2010

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Background-The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies. Methods and Results-A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web ofScience, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95% CI, 2.44 to 22.42); protein C deficiency, 8.76 (95% CI, 4.53 to 16.96); protein S deficiency, 3.20 (95% CI, 1.22 to 8.40), factor V G1691A, 3.26 (95% CI, 2.59 to 4.10); factor II G20210A, 2.43 (95% CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95% CI, 1.20 to 2.08); antiphospholipid antibodies (AIS) [CSVT]) is estimated to be between 2.6 and 6.4 per 100 000 per year, reflecting a trend toward a higher frequency in more current literature. 1-3 Underlying conditions in children with symptomatic cerebrovascular accidents include congenital heart malformations, hemolytic anemias, and collagen vascular diseases, as well as some rare inborn metabolic disorders. 4 In addition, risk factors include trauma and infectious diseases. Apart from acquired thrombophilic risk factors such as the presence of antiphospholipid antibodies, 5,6 inherited thrombophilia, particularly antithrombin, protein C, and protein S deficiency, variants of coagulation factor V (G1691A) and factor II (G20210A), and elevated lipoprotein(a), have been found in small case series and case-control studies to be associated with AIS or CSVT in infants and children. Furthermore, an association of the thermolabile MTHFR C677T genotype with stroke is controversial in both adults and children. 5353 In fact, the increased likelihood of having a blood clot in the vasculature is related to elevated homocysteine levels, and mutations in the MTHFR gene only exploit their effect by contributing to the elevated homocysteine plasma level. Because adequate folate levels essentially cancel out the impaired regulation of homocysteine induced by MTHFR mutations, not all people will develop high homocysteine levels. [53][54][55][56] , Editori...

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Genetics of Hemostasis: Differential Effects of Heritability and Household Components Influencing Lipid Concentrations and Clotting Factor Levels in 282 Pediatric Stroke Families

Cited by 34 publications

References 46 publications

Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels

Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels

Fibrinogen α and γ genes and factor VLeiden in children with thromboembolism: results from 2 family-based association studies

Impact of Thrombophilia on Risk of Arterial Ischemic Stroke or Cerebral Sinovenous Thrombosis in Neonates and Children

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