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

Abstract

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

The pleiotropic role of the fibrinogen γ′ chain in hemostasis

“…93 A recent German study showed that the same H2 was significantly more prevalent in VT patients and significantly associated with thromboembolic stroke. 91 No association of this SNP was found with risk of MI. 94 SNP 9340T3C was associated with increased ␥A/␥Ј fibrinogen levels, again confirmed in other studies, 84,87,91 and a slight decrease in DVT risk.…”

“…91 No association of this SNP was found with risk of MI. 94 SNP 9340T3C was associated with increased ␥A/␥Ј fibrinogen levels, again confirmed in other studies, 84,87,91 and a slight decrease in DVT risk. 81 In addition, 9340T3C was associated with a reduced risk in a Swedish MI study, 94 a Dutch study on ischemic stroke, 87 but not in a Dutch study on MI.…”

“…95 In addition, this SNP was recently shown to be less prevalent in German VT patients. 91 As with most common polymorphisms in the hemostatic system, however, the relationship between SNPs and disease is not always consistent, even if the SNPs have biologic plausibility as a disease modifier. 96,97 The 3 fibrinogen chains are clustered on the same chromosome, and there is a very high degree of linkage disequilibrium within and between the fibrinogen genes.…”

“…SNP 10034C3T was associated with reduced ␥A/␥Ј fibrinogen levels, which was later confirmed in other studies. 82,87,91 This SNP associated with an increased DVT risk in a Dutch population, 81 in an Austrian population, 92 and in a white population in the United States. 93 A recent German study showed that the same H2 was significantly more prevalent in VT patients and significantly associated with thromboembolic stroke.…”

Response: Elevated fibrinogen γ′ ratios and clinical outcomes

“…In addition, we examined the association between genetic variation in FGG and FGA genes and plasma levels of ␥A/␥Ј fibrinogen in the group of VT children. 1 We found in an independent study sample that For personal use only. on May 10, 2018. by guest www.bloodjournal.org From risk of VT and TS in children, and (2) the observed negative correlation of genetic VT risk with the plasma levels of the fibrinogen ␥Ј variant suggests that FGG-H2 and -H3 haplotypes modify thrombosis risk by controlling the level of this FGG splice isoform.…”