Novel Associations of Multiple Genetic Loci With Plasma Levels of Factor VII, Factor VIII, and von Willebrand Factor

Smith, Nicholas L.; Chen, Ming-Huei; Dehghan, Abbas; Strachan, David P.; Basu, Saonli; Soranzo, Nicole; Hayward, Caroline; Rudan, Igor; Sabater‐Lleal, Maria; Bis, Joshua C.; Maat, Moniek P.M. de; Rumley, Ann; Kong, Xiaoxiao; Yang, Qiong; Williams, Frances; Vitart, Véronique; Campbell, Harry; Mälarstig, Anders; Wiggins, Kerri L.; Duijn, Cornelia M. van; McArdle, Wendy L.; Pankow, James S.; Johnson, Andrew D.; Silveira, Angela; McKnight, Barbara; Uitterlinden, André G.; Aleksic, Nena; Meigs, James B.; Peters, Annette; Köenig, Wolfgang; Cushman, Mary; Kathiresan, Sekar; Rotter, Jerome I.; Bovill, Edwin G.; Hofman, Albert; Boerwinkle, Eric; Tofler, Geoffrey H.; Peden, John F.; Psaty, Bruce M.; Leebeek, Frank W.G.; Folsom, Aaron R.; Larson, Martin G.; Spector, Timothy D.; Wright, Alan F.; Wilson, James F.; Hamsten, Anders; Lumley, Thomas; Witteman, Jacqueline C. M.; Tang, Weihong; O’Donnell, Christopher J.

doi:10.1161/circulationaha.109.869156

Cited by 328 publications

(392 citation statements)

References 65 publications

(51 reference statements)

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“…Interestingly, according to the HapMap database, the rs10133762-G allele found to be associated with increased VWF levels [1] corresponds to the rs1884841-T allele associated with increased risk of VT, this observation being consistent with the well-known association between VWF levels and VT risk. It is worth noting that the rs10133762-G allele was associated with increased VWF plasma levels but no association was reported with FVIII [1]. In the TC2N gene where these two SNPs map has three different isoforms, one of them has an additional exon in its 5¢ sequence.…”

supporting

confidence: 74%

“…This SNP was studied because it is in nearly complete association with the rs10133762 found modulating plasma levels of VWF in the CHARGE consortium [1]. Interestingly, according to the HapMap database, the rs10133762-G allele found to be associated with increased VWF levels [1] corresponds to the rs1884841-T allele associated with increased risk of VT, this observation being consistent with the well-known association between VWF levels and VT risk. It is worth noting that the rs10133762-G allele was associated with increased VWF plasma levels but no association was reported with FVIII [1].…”

supporting

confidence: 55%

“…Impact on venous thrombosis risk of newly discovered gene variants associated with FVIII and VWF plasma levels. J Thromb Haemost 2011; 9: 229-31.Through a genome-wide association study (GWAS), seven new single nucleotide polymorphisms (SNPs) were recently found to be associated with plasma levels of factor (F) VIII and von Willebrand Factor (VWF) by the CHARGE consortium [1]. These SNPs were located in five genes that have not previously been suspected to be associated with these protein levels.…”

mentioning

confidence: 99%

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Impact on venous thrombosis risk of newly discovered gene variants associated with FVIII and VWF plasma levels

Morange

Antoni

Emmerich

et al. 2011

Journal of Thrombosis and Haemostasis

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To cite this article: Morange P-E, Saut N, Antoni G, Emmerich J, Tré gouë t D-A. Impact on venous thrombosis risk of newly discovered gene variants associated with FVIII and VWF plasma levels. J Thromb Haemost 2011; 9: 229-31.Through a genome-wide association study (GWAS), seven new single nucleotide polymorphisms (SNPs) were recently found to be associated with plasma levels of factor (F) VIII and von Willebrand Factor (VWF) by the CHARGE consortium [1]. These SNPs were located in five genes that have not previously been suspected to be associated with these protein levels. More specifically, VWF plasma levels were found to be influenced by SNPs located in TC2N (rs10133762), CLEC4M (rs868875), SCARA5 (rs2726953), STAB 2 (rs4981022) and STXBP5 (rs9390459). The last three genes were also found to be associated with FVIII plasma levels, either through the same SNP (rs9390459 for STXBP5) or via different SNPs (rs9644133 for SCARA5 and rs12229292 for STAB 2). Because high plasma levels of these two proteins are considered risk factors for venous thrombosis (VT) [2-4], we investigated the influence of these SNPs on VT risk using the results of our previously published GWAS on VT (in silico GWAS) and two candidate gene case-control studies, MARTHA and FARIVE, all three based on independent French populations [5].Two of these seven SNPs, rs9390459 and rs9644133, were available in the DNA chip array used in our previous GWAS, but none of them showed any trend of an association with VT risk (Table 1). The five other SNPs identified in CHARGE were not typed in our GWAS but according to the HapMap database, three of them, rs12229292, rs2726953 and rs10133762, were in strong linkage disequilibrium with SNPs available in our GWAS. Their best proxies were rs4981021 (pairwise r 2 = 0.879), rs4276643 (r 2 = 0.884) and rs1884841 (r 2 = 0.961), respectively (Table 1). Among those, only the rs1884841 showed a promising significant association with VT (Table 1) as the rs1884841-T allele was more frequent in cases than in controls (0.498 vs. 0.432, P = 6.45 · 10 )4). The latest two hit SNPs identified in CHARGE, rs4981022 and rs868875, were not in strong LD with any of the GWAS typed SNPs, with best proxies being rs608773 (r 2 = 0.124) and rs4964629 (r 2 = 0.266), respectively. As a consequence, we decided to genotype the rs1884841 in the MARTHA study composed of 1150 VT patients and 801 healthy individuals [5] for further support of association with VT as well as both SNPs that did not have good proxies in our GWAS, rs4981022 and rs868875. While the rs4981022 did not show any evidence of an association with VT risk in MARTHA, the rs868875-G allele was found to be less frequent in cases than in controls (0.292 vs. 0.338, P = 0.0025) and the rs1884841-T more frequent in cases than in controls (0.487 vs. 0.437, P = 0.0024) (Table 1). Consequently, these last two SNPs were further examined for support of an association with VT in a sample of 594 VT patients and 588 controls part of the FARIVE study [5]. We were not able to confirm th...

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supporting

confidence: 74%

supporting

confidence: 55%

mentioning

confidence: 99%

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Impact on venous thrombosis risk of newly discovered gene variants associated with FVIII and VWF plasma levels

Morange

Antoni

Emmerich

et al. 2011

Journal of Thrombosis and Haemostasis

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“…Although we do not discuss the results in this review, GWAS for coagulation and fibrinolysis have also been reported. [81][82][83][84][85] Associations at 12q24 Given the close biological relationship between PLT and CAD, 3 Soranzo et al 28 evaluated the risks of CAD in the loci associated with PLT and found an overlap between these two traits at 12q24. The variants identified at 12q24 were encompassed by a long-range haplotype that extended 41.5 Mbps on which significant pressure of natural selection was observed.…”

Section: Genetic Factors For Pltmentioning

confidence: 99%

Common genetic factors for hematological traits in Humans

Okada

Kamatani

2012

J Hum Genet

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“…Chosen based on data from Atherosclerosis Risk in Communities (ARIC) study (European ancestry) (Campos et al 2011, Smith et al 2010 and data on expression in cardiovascular disease (van Schie et al 2011). …”

Section: Polymorphisms Of Interestmentioning

confidence: 99%

Association between cognition and gene polymorphisms involved in thrombosis and haemostasis

Quinn

Alghamdi

Padmanabhan

et al. 2015

AGE

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An association between blood markers of thrombosis and haemostasis and cognitive decline has been described. These results may be confounded by lifestyle and environmental factors. We used a Mendelian randomisation approach to describe the association between thrombosis/haemostasis genotypes and cognition. We studied the genetic variants (single nucleotide polymorphisms) of circulating markers of thrombosis and haemostasis. Our chosen blood factors and associated polymorphisms were D-dimer [rs12029080], fibrinogen [rs1800789], plasminogen activator inhibitor [rs2227631], and von Willebrand factor [rs1063857]. We described association with multidomain cognitive test scores using data from the Scottish Family Health Study. Cognitive data were analysed for individual tests and combined to give a general cognitive factor. In 20,288 subjects, we found no evidence of association between cognitive function (individual tests and combined scores) and any of the above-mentioned single nucleotide polymorphisms. Lower scores on cognitive measures were associated with increasing age, socioeconomic deprivation, blood pressure, waist-hip ratio, smoking, and vascular comorbidity (all p < 0.001). In a post hoc sensitivity analysis restricted to those aged over 50 years, there was still no signal of association. Our data add to our understanding of determinants of cognition but are not definitive; the variation in blood levels explained by SNPs was modest and our sample size may have been insufficient to detect a modest association.

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Novel Associations of Multiple Genetic Loci With Plasma Levels of Factor VII, Factor VIII, and von Willebrand Factor

Cited by 328 publications

References 65 publications

Impact on venous thrombosis risk of newly discovered gene variants associated with FVIII and VWF plasma levels

Impact on venous thrombosis risk of newly discovered gene variants associated with FVIII and VWF plasma levels

Common genetic factors for hematological traits in Humans

Association between cognition and gene polymorphisms involved in thrombosis and haemostasis

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