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DOI: 10.1055/s-0038-1650323
Low Plasma Levels of Factor Vile and Antigen Are More Strongly Associated with the 10 Base Pair Promoter (-323) Insertion than the Glutamine 353 Variant
Publication History
Received 12 September 1995
Accepted after resubmission 05 January 1996
Publication Date:
10 July 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199604/lookinside/thumbnails/10-1055-s-0038-1650323-1.jpg)
Summary
In a group of 705 healthy middle-aged men, we have examined the relationship between plasma levels of Factor VII (FVII) c and Factor VII antigen (FVIIag) and two polymorphisms in the FVII gene. One polymorphism alters arginine at position 353 to glutamine (R/Q), and the other is the result of a 10 base pair (bp) insertion in the promoter region at position -323 from the start of translation (0/1 Obp). The frequency for the Q allele was 0.105 (95% Cl 0.09-0.12) and for the lObp allele was 0.117 (95% Cl 0.10-0.13). Men who were carriers of either of the rare alleles had levels of FVIIc and FVIIag that were approximately 20% lower than non-carriers, and both of these effects were highly statistically significant (p < 0.0001). Strong allelic association was observed between the two polymorphisms, with R and 0 bp being on the same chromosome in 96% of cases, and Q and 10 bp being on the same chromosome in 90% of cases where this could be determined unambiguously (Delta = 0.92, X2 = 1206, p < 0.0001). This strong allelic association created three major genotype groups which were found to have significantly different levels of FVIIc (p < 0.001). In the 547 men homozygous for both common alleles (R/R & 0/0), mean (SD) FVIIc was 101 (29) as compared with 85 (30) in the 20 men with the genotype R/R & 0/10 and 81(23) in the 126 men with the genotype R/Q & 0/10, suggesting a larger lowering effect associated with the 10 bp allele (16%) compared to the Q allele (an additional 4%). The lowering effect on FVII associated with the 10 bp allele remained statistically significant after adjusting for the effect of the Q allele (p = 0.004 for FVIIc and p = 0.06 for FVIIag), but the effect associated with the Q allele was no longer significant after adjusting for the 10 bp allele, suggesting that the strongest effect on levels of FVIIc was associated with the 0/10 bp genotype. In the sample overall, plasma FVIIc was associated positively with serum triglyceride concentration and the slope of this relationship was significantly greater in those with the genotype R/R compared to the other groups combined (0.12 versus 0.02, p = 0.008) with differences of similar size seen in the 0/0 compared to 0/10+10/10 groups. However, using the combined genotypes, the slope of this relationship in the R/R & 0/10 group was 0.38 and was significantly steeper (p = 0 .0 1 ) than in the other two groups who did not differ in this respect (slopes 0.11 and 0.08). This effect was seen on four subsequent annual examinations, and was also evident in the relationship between FVIIag and triglyceride concentration (p = 0.003 for difference between groups measured at baseline only). These data suggest that part of the previously described effects on FVIIc levels associated with the R/Q polymorphism may be explained by genetic variation in the promoter region of the FVII gene.
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References
- 1 Rapaport SI, Rao LVM. Initiation and regulation of tissue factor-dependent blood coagulation. Thrombosis Council Distinguished Lecture. Arterioscler Thromb 1992; 2: 111-121
- 2 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WRS, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 2: 533-537
- 3 Heinrich J, Balleisen L, Schulte H, Assmann G, van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk. Results from the PROCAM study in healthy men. Arterioscler Thromb 1994; 14: 54-59
- 4 Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-1079
- 5 Meade TW, Wilkes HC, Stirling Y, Brennan PJ, Kelleher C, Browne W. Randomized controlled trial of low dose warfarin in the primary prevention of ischaemic heart disease in men at high risk: design and pilot study. Eur Heart J 1988; 9: 836-843
- 6 Simpson HCR, Meade TW, Stirling Y, Mann JI, Chakrabarti RR, Woolf L. Hypertriglyceridaemia and hypercoagulability. Lancet 1983; 2: 786-790
- 7 Miller GJ, Martin JC, Mitropoulos KA, Reeves BEA, Thompson RL, Meade TW, Cooper JA, Cruickshank JK. Plasma factor VII is activated by postprandial triglyceridaemia, irrespective of dietary fat composition. Atherosclerosis 1991; 86: 163-171
- 8 Mitropoulos KA, Miller GJ, Watts GF, Durrington PN. Lipolysis of triglyceride-rich lipoproteins activates coagulant factor XII: a study in familial lipoprotein-lipase deficiency. Atherosclerosis 1992; 95: 119-125
- 9 Silveira A, Karpe F, Blombäck M, Steiner G, Walldius G, Hamsten A. Activation of coagulation factor VII during alimentary lipemia. Arterioscl Thromb 1994; 14: 60-69
- 10 Carvalho de Sousa J, Bruckert E, Giral P, Soria C, Chapman J, Truffert J, Dairou F, de Gennes JL, Caen JP. Coagulation factor VII and plasma triglycerides. Decreased catabolism as a possible mechanism of factor VII hyperactivity. Haemostasis 1989; 19: 125-130
- 11 Green F, Kelleher C, Wilkes H, Temple A, Meade T, Humphries S. A common genetic polymorphism associated with lower coagulation factor VII levels in healthy individuals. Arterioscler Thromb 1991; 11: 540-546
- 12 Lane A, Cruickshank JK, Stewart J, Henderson A, Humphries S, Green F. Genetic and environmental determinants of factor VII coagulant activity in different ethnic groups at differing risk of coronary heart disease. Atherosclerosis 1992; 94: 43-50
- 13 Humphries SE, Lane A, Green FR, Cooper J, Miller GJ. Factor VII coagulant activity and antigen levels in healthy men are determined by interaction between factor VII genotype and plasma triglyceride concentration. Arterioscl Thromb 1994; 14: 193-198
- 14 Silveria A, Green F, Karpe F, Blombäck M, Humphries S, Hamsten A. Plasma factor VII antigen and activity levels are determined by factor VII genotype and postprandial triglyceride-rich lipoprotein levels. Arterioscl Thromb 1994; 72 (05) 734-739
- 15 Lane A, Green F, Humphries S, Ruddock V, Meade T. Effect of factor VII genotype on response to warfarin treatment. Thromb Haemost 1995; 73: 325
- 16 Meilahn E, Humphries S, Ferrell R, Kiss J, Green F, Temple A, Kuller L. Genetic determination of coagulation factor VIIc levels among healthy middle-aged women. Thromb Haemost 1995; 73: 623-625
- 17 Lane A, Green F, Scarabin PY, Nicaud V, Bara L, Humphries S, Evans A, Luc G, Cambou JP, Arveiler D, Cambien F. The factor VII Arg/Gln353 polymorphism determines factor VII coagulant activity in patients with myocardial infarction (MI) and control subjects in Belfast and in France but is not a strong indicator of MI risk in the ECTIM study. Atherosclerosis 1996; 119: 119-127
- 18 Marchetti G, Patracchini P, Papacchini M, Ferrati M, Bemardi F. A polymorphism in the 5’ region of coagulation factor VII gene (F7) caused by an inserted decanucleotide. Hum Genet 1993; 90: 575-576
- 19 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215-1216
- 20 O’Hara PJ, Grant FJ, Haldeman BA, Gray CL, Insley MY, Hagen FS, Murray MJ. Nucleotide sequence of the gene coding for human factor VII, a vitamin K-dependent protein participating in blood coagulation. Proc Natl AcadSci USA 1987; 84: 5158-5162
- 21 Chakravati A, Buetow KH, Antonarakis SE, Waber PG, Boehm CD, Kazazian HH. Non-uniform recombination within the human beta-globin gene cluster. Am J Hum Genet 1984; 36: 1239-1258
- 22 Cooper DN, Krawczak M. The mutational spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions. Hum Genet 1990; 85: 55-74
- 23 Krawczak M, Cooper DM. Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment. Hum Genet 1991; 86: 425-441
- 24 Marchetti G, Patracchini P, Gemmati D, De Rosa V, Pinotti M, Rodorigo G, Casonato A, Girolami A, Bemardi F. Detection of two missense mutations and characterization of a repeat polymorphism in the Factor VII gene (F7). Hum Genet 1992; 89: 497-502