Novel genetic risk factors for venous thrombosis; a haplotype-
based candidate gene approach
Uitte de Willige, S.
Citation
Uitte de Willige, S. (2007, May 23). Novel genetic risk factors for venous
thrombosis; a haplotype-based candidate gene approach. Hemostasis and
Thrombosis Research Center, Department of Hematology, Faculty of Medicine,
Leiden University. Retrieved from https://hdl.handle.net/1887/11970
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis
in the Institutional Repository of the University of Leiden
Downloaded from: https://hdl.handle.net/1887/11970
Note: To cite this publication please use the final published version (if
applicable).
Chapter 3.3
Polymorphisms in the 3’-end of the fibrinogen
gamma gene and risk of venous thromboembolism
in the African-American and Caucasian population
Shirley Uitte de Willige, Meredith E. Pyle, Hans L. Vos, Marieke C.H. de Visser, Cathy Lally, Nicole F. Dowling,
W. Craig Hooper, Rogier M. Bertina, Harland Austin Submitted for publication
Summary
Background Genetic determinants of venous thromboembolism (VTE) in the African- American population are poorly characterized. Recently, a haplotype of the fibrinogen gamma gene (FGG-H2), tagged by polymorphism 10034C>T in the 3'- end of FGG, was found to be associated with the risk of venous thrombosis in a large study of Caucasian subjects. In contrast to the two most important genetic conditions predisposing to venous thrombosis in the Caucasian population, Factor V Leiden and prothrombin G20210A, this FGG polymorphism is common among African-Americans.
Objectives We evaluated whether FGG 3'-end single nucleotide polymorphisms (SNPs) are associated with the risk of VTE in the African-American population and aimed to replicate the association of SNP 10034C>T (FGG-H2) with the risk of VTE in the Caucasian population.
Patients/Methods We used 325 Caucasian cases and 350 Caucasian controls, and 304 African-American cases and 278 African-American controls from the Genetic Attributes and Thrombosis Epidemiology (GATE) study. SNPs 9340T>C and 10034C>T were genotyped by TaqMan analysis. Additionally, nucleotides 9257 to 10152 of FGG were re-sequenced in all subjects.
Results In the Caucasian population SNP 10034C>T was associated with a significant 2.1-fold increased risk in the idiopathic subgroup. The corresponding risk among African-Americans was increased (1.5), but this finding did not reach statistical significance. Additionally, a new variation in the 3'-end of FGG was found in position 9937, conferring a C>T change. This variation was mainly present in African-Americans.
Conclusions FGG SNP 10034C>T is a risk factor for VTE, with the strongest effect observed in the Caucasian population.
Introduction
Venous thromboembolism (VTE) is a common vascular disease affecting about 1-3 in 1000 individuals annually.1,2 The most frequent manifestations of VTE are thrombosis of the deep veins of the leg (DVT) and pulmonary embolism (PE). Major complications are a potentially disabling post-thrombotic syndrome and acute death from a PE.3 VTE is a multicausal disease, in which both genetic and environmental (e.g. advanced age, immobilization, surgery, hormone use, pregnancy, malignancy) risk factors are involved.3 The genetic determinants of VTE in the African-American population are poorly characterized. The two most important genetic conditions predisposing to venous thrombosis among the Caucasian population, Factor V Leiden4 and the prothrombin G20210A mutation,5 are rare in the African-American population.6-8 Despite the rarity of known genetic risk factors among African- Americans, it has been found that the incidence of idiopathic venous thrombosis and the prevalence of family history of VTE is equal for African-American and Caucasian
Chapter 3.3
80
cases, suggesting that also among African-Americans a strong genetic component contributes to the etiology of VTE.9,10
One of the unknown genetic risk factors for VTE in the African-American population may be a recently described genetic risk factor for DVT in the Caucasian population.11 Homozygosity for haplotype 2 (H2) tagging single nucleotide polymorphism (SNP) 10034C>T [rs2066865], located in the 3' UTR of the fibrinogen gamma gene (FGG), was found to be associated with a 2.4-fold increased risk of DVT in subjects of Dutch origin.11 In this study population another haplotype (FGG- H3), tagged by SNP 9340T>C [rs1049636], was found to be associated with a slight reduction in DVT risk. The two haplotypes did not influence total fibrinogen levels, but influenced fibrinogen γ' levels, a product of alternative splicing of FGG, and fibrinogen γ'/total fibrinogen ratios. In a functional study on SNPs 9615C>T and 10034C>T, which tag FGG-H2, it was shown that SNP 10034C>T is located in a functional CstF binding site and is involved in regulating the usage of the main polyadenylation signal of FGG (manuscript in preparation). We proposed that the 10034C>T change is the functional variation in the FGG-H2 haplotype, which acts on the risk of DVT by reducing the fibrinogen γ'/total fibrinogen ratio.
The minor allele frequencies (MAFs) of SNPs 9340T>C and 10034C>T are reported to be higher in healthy African-American subjects compared to healthy European- American subjects.12 In addition, HapMap data show that 10034T is more frequent among 60 African (Yoruba) subjects compared to 60 Caucasian subjects, while 9340C is less frequent among Africans.13
The aims of this study were to assess whether SNPs 9340T>C and 10034C>T, located in the 3'-end of FGG, are associated with VTE in African-American subjects and to replicate the association of these SNPs with VTE in Caucasian subjects. For this study, we used a large American case-control study on risk factors for VTE, the Genetic Attributes and Thrombosis Epidemiology (GATE) study, which includes subjects of both the African-American and the Caucasian population.
Materials and Methods Study Population
The design of the GATE study has been described in detail previously.10 In short, cases, aged 18-70 years, included hospitalized patients diagnosed between March 1998 and December 2002 with a recent first or recurrent episode of DVT and/or PE at two University hospitals in Atlanta, Georgia. Patients with severe illness or with cognitive deficits were excluded. Control subjects were selected from a list of patients who visited the office of one of ten physicians at a university-affiliated primary care clinic between January 1997 and December 2000 and were frequency matched to cases on age, sex and race. Racial assignment was self-reported. Clinic
patients with a history of VTE, using anticoagulant medication or with a mental or physical problem were not eligible as controls.
Genetic analyses
SNPs 9340T>C and 10034C>T were genotyped by 5' nuclease/TaqMan analyses.14 The polymerase chain reactions with fluorescent allele-specific oligonucleotide probes (Applied Biosystems) and fluorescence endpoint reading for allelic discrimination were done on an Mx3000P instrument (Stratagene). Additional SNPs specific to African-Americans are known to be present in the 3’-end of FGG.12,13 Therefore, we additionally re-sequenced nucleotides 9257 to 10152 (numbering according to SeattleSNPs;12 GenBank accession number AF350254). SeattleSNPs data show that there are 5 SNPs present in this part of FGG: 9340C>T [rs1049636], 9595T>C [rs2066879], 9615C>T [rs2066864], 9765T>A [rs2066880], and 10034C>T [rs2066865]. SNPs 9595T>C and 9765T>A are restricted to the African- American subjects and have not been reported in the Caucasian subjects, while SNP 9615C>T is completely linked to SNP 10034C>T in both Caucasians and African- Americans.12 For only one of 114 African-American subjects recombination between these two SNPs was reported by HapMap.13 Sequencing was performed on an ABI 3100 DNA analyzer (Applied Biosystems). Reactions were performed using the ABI PRISM® BigDye Terminator v1.1 Cycle Sequencing Kit (Applied Biosystems). Primer and probe sequences are available upon request.
Fibrinogen measurement
Total fibrinogen levels were measured on the STA/Compact (Diagnostica Stago) using STA Fibrinogen reagents and Nerl Ultrapure Reagent Grade Water (New England Reagent Laboratory) as reported previously.15
Statistical analyses
All analyses were performed separately for African-American subjects and Caucasian subjects. In the healthy control subjects, Hardy-Weinberg equilibrium for each SNP was tested by χ2 analysis. To investigate whether the SNPs were associated with the risk of VTE, ORs and 95%CIs were calculated. TaqMan genotyping analyses failed for 9 of 1304 samples. These samples were excluded from the analyses. To compare the analyses with previous findings in the Leiden Thrombophilia Study,11 separate analyses were performed for cases with first events of DVT with or without a PE (DVT (+PE)), excluding only malignancies. Since more than half of all patients had a provoked event, we additionally analyzed only idiopathic cases. An idiopathic event was defined as an initial thrombotic event not provoked by cancer, major surgery, placement of a central line or dialysis port, a prolonged stay in the intensive care unit, injury or prolonged immobilization, organ transplant, current use of a wheelchair, and events occurring during pregnancy. These categories are not mutually exclusive. To investigate the association between the SNPs and total
Chapter 3.3
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fibrinogen levels, mean fibrinogen levels in control subjects were tested by Student’s t-test.
Results
Patient population
Table 1 shows the baseline characteristics of the study participants by race. The age distributions were similar for patients and control subjects within racial groups.
However, there were also several important differences between the groups. Among patients, the prevalence of female gender is higher among African-Americans than it is among Caucasians. Caucasian subjects have a slightly higher frequency of a positive family history of VTE than African-American subjects. In both races family history of VTE and diabetes are more prevalent among patients than among control subjects, whereas among African-American control subjects the prevalence of diabetes is considerably higher compared to Caucasian control subjects (p<0.001).
Overall, African-American subjects have a higher BMI than Caucasian subjects. BMI of patients of both races are comparable, while among control subjects, BMI of African-Americans is higher than that of Caucasians. African-American patients have slightly more first events and idiopathic events, while malignancies have more frequently been reported in Caucasian patients.
Table 1 Baseline characteristics of study participants, by race
African-American Caucasian
Patients Controls Patients Controls Characteristic (N=304) (N=278 ) (N=325) (N=350 ) Age ± SD 46.7 ± 12.4 48.2 ± 13.0 50.6 ± 12.5 51.5 ± 12.5
Sex Male 41.4 % 38.8 % 57.5 % 58.6 %
Female 58.6 % 61.2 % 42.5 % 41.4 %
Family history of VTE 22.8 % 9.8 % 28.0 % 11.9 % BMI
<18.5 4.0 % 1.1 % 2.2 % 2.0 %
18.5-24.9 26.7 % 19.1 % 24.7 % 41.5 %
25.0-30.0 30.0 % 34.9 % 33.6 % 36.1 %
≥30.0 39.3 % 45.0 % 39.5 % 20.3 %
Diabetes 22.7 % 15.8 % 15.7 % 4.9 % Event
DVT (+PE) 81.3 % NA 82.2 % NA
PE 18.7 % NA 17.8 % NA
First event 78.3 % NA 72.0 % NA
Malignancies 21.4 % 6.8% 28.6 % 8.9%
Idiopathic 49.3 % NA 42.5 % NA
SD: standard deviation, NA: not applicable
Table 2 Minor allele frequencies of SNPs 9340T>C and 10034C>T in healthy subjects of different study populations, by race
9340C 10034T
Caucasians African- Caucasians African-
Study Americans Americans
SeattleSNPs 0.217 0.271 0.152 0.313
HapMap 0.283 0.192 0.258 0.316
GATE 0.288 0.238 0.244 0.296
LETS 0.307 - 0.270 - SeattleSNPs12: 23 Caucasians, 24 African-Americans; HapMap13: 60 Caucasians, 60 Africans; GATE: 347 Caucasians, 275 African-Americans; LETS11: 471 Caucasians
SNPs 9340T>C and 10034C>T and risk of VTE
In contrast to what was reported by SeattleSNPs,12 but similar to the data of HapMap,13 the minor allele frequency (MAF) of SNP 9340T>C in our study population of African-American control subjects was lower compared to the MAF in Caucasian control subjects (Table 2). The MAF of SNP 10034C>T was indeed higher in African-American control subjects compared to Caucasian control subjects, although the frequency in our Caucasian control population was considerably higher than that reported by SeattleSNPs and more like the frequency reported by HapMap and previously observed in LETS. An explanation for the discrepancies in allele frequencies may be the small sample size of the populations studied in Seattle. Of both SNPs, the MAFs of the Caucasian controls of the present study were slightly lower compared to the MAFs found previously in LETS.
Table 3 Minor allele frequencies of 3'-end FGG SNPs in GATE patients and control subjects, by race
Caucasians African-Americans SNP allele Patients Controls Patients Controls
9340C 0.254 0.288 0.235 0.238 9595T 0.003 0.001 0.038 0.041 9615T 0.275 0.239 0.321 0.299 9765A 0.003 0.003 0.061 0.089 9937T 0.000 0.002 0.015 0.019
10034T 0.266 0.244 0.315 0.296
In both races, the distribution of the genotypes among control subjects was in Hardy-Weinberg equilibrium for all SNPs. Minor allele frequencies in patients and control subjects are shown in Table 3. Initial analyses focused on SNPs 9340T>C and 10034C>T. ORs for SNPs 9340T>C and 10034C>T are shown in Table 4. First, we analyzed all patients and controls by race (panel A). In the African-American population, both SNPs did not clearly influence the risk of VTE. In the Caucasian population SNP 9340T>C was associated with a slight, non-significant decrease in
Chapter 3.3
84
risk, while homozygosity for SNP 10034C>T was associated with a non-significant 1.6-fold increase in risk.
We additionally analyzed the risk of patients with a first event of DVT (+PE), without having a malignancy (Table 4, panel B). By this selection, we could compare the GATE results with the LETS results.11 In African-American subjects, the risk associated with SNP 9340T>C increased, while SNP 10034C>T still showed no effect on risk. In Caucasian subjects, the influence of both SNPs did not change importantly, the risk for SNP 9340T>C still being slightly decreased and the risk for SNP 10034C>T still being non-significantly increased.
Table 4 Thrombosis risk for SNPs 9340T>C and 10034C>T, by race
African-American Caucasian
Patients Controls OR Patients Controls OR Genotype* n (%) n (%) (95% CI) n (%) n (%) (95% CI)
A. All
9340T>C
TT 175 (57.6) 155 (56.4) 1* 181 (55.7) 174 (50.1) 1*
TC 115 (37.8) 109 (39.6) 0.9 (0.7-1.3) 123 (37.8) 146 (42.1) 0.8 (0.6-1.1) CC 14 (4.6) 11 (4.0) 1.1 (0.5-2.6) 21 (6.5) 27 (7.8) 0.7 (0.4-1.4)
10034C>T CC 144 (47.7) 137 (49.8) 1* 179 (55.1) 198 (56.7) 1*
CT 126 (41.7) 113 (41.1) 1.1 (0.8-1.5) 119 (36.6) 132 (37.8) 1.0 (0.7-1.4) TT 32 (10.6) 25 (9.1) 1.2 (0.7-2.2) 27 (8.3) 19 (5.5) 1.6 (0.8-2.9)
B. First event DVT (+PE), malignancies excluded
9340T>C TT 65 (47.1) 155 (56.4) 1* 76 (55.1) 174 (50.1) 1*
TC 65 (47.1) 109 (39.6) 1.4 (0.9-2.2) 54 (39.1) 146 (42.1) 0.9 (0.6-1.3) CC 8 (5.8) 11 (4.0) 1.7 (0.7-4.5) 8 (5.8) 27 (7.8) 0.7 (0.3-1.6)
10034C>T CC 66 (47.8) 137 (49.8) 1* 68 (49.3) 198 (56.7) 1*
CT 60 (43.5) 113 (41.1) 1.1 (0.7-1.7) 59 (42.8) 132 (37.8) 1.3 (0.9-2.0) TT 12 (8.7) 25 (9.1) 1.0 (0.5-2.1) 11 (8.0) 19 (5.5) 1.7 (0.8-3.7)
C. Idiopathic
9340T>C TT 90 (60.0) 155 (56.4) 1* 78 (56.5) 174 (50.1) 1*
TC 55 (36.7) 109 (39.6) 0.9 (0.6-1.3) 53 (38.4) 146 (42.1) 0.8 (0.5-1.2) CC 5 (3.3) 11 (4.0) 0.8 (0.3-2.3) 7 (5.1) 27 (7.8) 0.6 (0.2-1.4)
10034C>T CC 71 (47.7) 137 (49.8) 1* 70 (50.7) 198 (56.7) 1*
CT 59 (36.9) 113 (41.1) 1.0 (0.7-1.5) 54 (39.1) 132 (37.8) 1.2 (0.8-1.8) TT 19 (12.8) 25 (9.1) 1.5 (0.8-2.8) 14 (10.1) 19 (5.5) 2.1 (1.0-4.4)
*Reference category
Finally, we analyzed the risk of VTE in idiopathic cases (Table 4, panel C). In both African-Americans and Caucasians SNP 9340T>C was associated with a slight reduction of VTE risk. Homozygosity for SNP 10034C>T was associated with a 1.5- fold increased risk of VTE in African-Americans, and with a 2.1-fold increase in Caucasians. This risk only reached significance in the Caucasian population.
Linkage disequilibrium
According to the data of SeattleSNPs the rare T-alleles of SNPs 9615C>T and 10034C>T are completely linked, both in the subjects of European descent and in the subjects of African-American descent.12 This was also seen in the Dutch population of the Leiden Thrombophilia Study (LETS) (S. Uitte de Willige and F.R.
Rosendaal, July 2006). For only one of 114 African-American subjects recombination between these two SNPs was reported by HapMap.13 However, in the present study we found some recombination between SNPs 9615C>T and 10034C>T. The rare allele of SNP 9615C>T was not linked to the rare allele of SNP 10034C>T in 4 Caucasian subjects (three cases and one control) and 12 African-American subjects (three cases and nine controls). Both combinations were present, 9615C with 10034T and 9615T with 10034C. For all risk analyses, similar results as for SNP 10034C>T were obtained for SNP 9615C>T. Unfortunately, the number of subjects with recombination between 9615C>T and 10034C>T was too low to find any significant differences between the two SNPs in their association with VTE.
Sequencing results
Sequencing of the 3'-end of the FGG gene resulted in the identification of six gene variants instead of the expected five (Table 3).12 We found an additional rare variation at position 9937, conferring a C>T change. This variation was mainly present in the African-American population (MAF in control subjects: 0.019, MAF in cases: 0.015). There was only one Caucasian control subject that was heterozygous for this new variation (MAF: 0.002). SNPs 9595C>T and 9765T>A did not exclusively exist in the African-American population, as reported by SeattleSNPs,12 but were very rare among Caucasian subjects (Table 3). Only two cases and one control subject were heterozygous for SNP 9595C>T, and only two cases and two control subjects were heterozygous for SNP 9765T>A. For SNPs 9595C>T, 9765T>A and 9937C>T there were no differences in allele frequencies between African- American cases and controls.
Plasma fibrinogen levels
We also analyzed the association of the SNPs of the 3'-end of FGG with total fibrinogen levels in control subjects. Total fibrinogen levels were higher in African- American control subjects (3.71±0.92 g/L vs. 3.37±0.79 g/L in Caucasian control subjects, p<0.001), but in both races none of the FGG 3’-end SNPs was associated with total fibrinogen levels (data not shown).
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Discussion
The two most important genetic conditions predisposing to venous thrombosis among the Caucasian population, Factor V Leiden and the prothrombin G20210A mutation, are rare in the African-American population, while the incidence of idiopathic venous thrombosis and the prevalence of a family history of VTE is equal for African-American and Caucasian cases. This suggests that also among African- Americans genetic components contribute to the etiology of VTE. These genetic components have not been elucidated yet. Other genetic risk factors for VTE in the Caucasian population do not or only mildly influence the risk of VTE in the African- American population.15-21
Recently, we found that a haplotype of the fibrinogen gamma gene (FGG-H2) was associated with decreased fibrinogen γ' levels and fibrinogen γ'/total fibrinogen ratios and with an increased risk of DVT in a large study of Caucasian subjects.11 We functionally showed that the H2 tagging SNP 10034C>T, which is located in a functional CstF site in the 3'-end of FGG, is responsible for these effects (manuscript in preparation). In the present study we investigated whether FGG 3'-end SNPs were associated with the risk of VTE in the African-American population and aimed to replicate the association of SNP 10034C>T with the risk of VTE in the Caucasian population in the Genetic Attributes and Thrombosis Epidemiology (GATE) study.
In the African-American population none of the SNPs in the 3'-end of FGG was significantly associated with the risk of VTE. In the group of African-American patients with a first event of DVT (+PE) without malignancies, we found a slight, although non-significant increase in risk associated with SNP 9340T>C. This is in contrast to the slight decrease in risk we found in the Caucasian population, in this study and in the Dutch Leiden Thrombophilia Study.11 In African-Americans with idiopathic VTE, homozygosity for SNP 10034C>T was associated with a non- significant 1.5-fold increase in risk. In the Caucasian population an increased risk was found for homozygous 10034T carriers in all conditions tested. However, only in Caucasians with idiopathic thrombosis was this risk significant, replicating our initial findings in LETS, in which the risk for idiopathic homozygous carriers of FGG-H2, tagged by SNP 10034C>T, was significantly increased 2.2-fold.11 Similar results were obtained for SNP 9615C>T which previously was found to be completely linked to the 10034C>T SNP in Caucasians. Nevertheless, in the GATE study population there was recombination between these SNPs among 4 Caucasian subjects and 12 African-American subjects, but these numbers were too low to find any significant differences between the two SNPs and the risk of VTE.
Since we only screened the 3'-end of FGG and not the whole gene, we did not cover all haplotypes known to exist in FGG. In the Caucasian population, the typed SNPs tagged the common haplotypes H2 and H3, but the African-American population has
much more variation in the FGG gene, as in their whole genome.22 At least four more SNPs had to be genotyped to be able to tag all African-American haplotypes reported by SeattleSNPs.12 Therefore we restricted our analyses to the SNP genotypes themselves.
So far, SNPs 9595T>C and 9765T>A were only found in the African-American population.12 However, in this study we found two Caucasian cases and one Caucasian control subject that were heterozygous for SNP 9595C>T, and two Caucasian cases and two Caucasian control subjects that were heterozygous for SNP 9765T>A. Self-reported blacks in the United States are largely of mixed race, while there are only few self-reported whites that have genetic African ancestry.23 It may be that the few Caucasian subjects that carried an allele of SNPs 9595T>C or 9765T>A have some genetic African ancestry. This may also be the case for the new variation we found, 9937C>T, which was mainly present in the African-American population, while we found only one heterozygous Caucasian control subject.
Among control subjects, none of the SNPs was associated with total fibrinogen levels as measured by Clauss assay, either in Caucasians or African-Americans. This is in agreement with previous findings in subjects of Dutch (Caucasian) origin in LETS,11 but is in contrast to a study by Reiner et al. who found that in European-Americans the rare allele of SNPs FGA Thr312Ala and FGG 10034C>T (which are strongly linked) were associated with decreased functional fibrinogen levels, although not with fibrinogen protein concentration.24
A limitation of the present study may be the use of outpatient controls. This will most likely not be a problem for gene comparisons, but their use might be less suitable for comparison of plasma total fibrinogen levels. Fibrinogen is a well-known acute phase reactant and clinic controls could have increased fibrinogen levels, because of the presence of inflammatory conditions. We found that African- American control subjects had higher total fibrinogen levels than Caucasian control subjects. This is in accordance with results of the CARDIA study,25,26 but in contrast to results of Cook et al. who found in a population based survey in South London, England, that total fibrinogen levels were lower in immigrants of African origin compared to the levels in the white population.27 These differences might be due to differences in life style between Europeans and Americans or differences in population characteristics, e.g. the prevalence of diabetes and obesity, or smoking habits.
We observed several important differences between the two ethnic populations.
Among patients, the sex ratio is different for African-Americans and Caucasians, since about 60% of African-American patients are female, whereas about 40% of Caucasian patients are female. Obesity is a risk factor for VTE among Caucasians,
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but it is not among African-Americans. Furthermore, African-American patients have slightly more first events and idiopathic events, while malignancies have more frequently been reported in Caucasian patients. Importantly, the risks of the FGG 10034T allele appear to be different in both populations. All this suggests that risk factors might be very different between populations. This is most likely not caused by different molecular mechanisms, but by different interactions between the risk factors, either genetic or environmental. The effect of the 10034T allele may be affected by variations in the quality and quantity of splicing and polyadenylation factors. These variations may be different between ethnical groups, but we assume that the effect of a reduced fibrinogen γ'/total fibrinogen ratio on the risk of VTE is not dependent on race, since in a study on the fibrinogen γ' content in the thrombotic microangiopathy syndrome it was shown that there were no significant differences between the mean values of the fibrinogen γ'/total fibrinogen ratio for African-American and Caucasian subjects, while in both ethnical groups, 10034T carriers had lower fibrinogen γ'/total fibrinogen ratios.28
In summary, the present study shows that none of the SNPs located in the 3'-end of the fibrinogen gamma gene is significantly associated with the risk of VTE in African- Americans. African-American patients with idiopathic VTE which are homozygous for SNP 10034C>T had a non-significant 1.5-fold increased risk of VTE, while the same Caucasian patients homozygous for SNP 10034C>T had a significant 2.1-fold increase in risk. These results generally support our previous finding that FGG-H2 homozygosity, tagged by SNP 10034C>T, is a risk factor for venous thrombosis, with the strongest effect observed in the Caucasian population. Larger studies on genetic risk factors for VTE in the African-American population are warranted to replicate these findings.
Acknowledgements
This study was financially supported by grant 912-02-036 from the Netherlands Organization for Scientific Research (NWO). The GATE study was supported by a grant from the CDC through the Associations of Schools of Public Health/CDC Cooperative Agreement mechanism.
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