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Thromb Haemost 1996; 75(04): 567-572
DOI: 10.1055/s-0038-1650323
Original Article
Schattauer GmbH Stuttgart

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

Steve Humphries
1   The Centre for Genetics of Cardiovascular Disorders, University College London Medical School, London
,
Anne Temple
1   The Centre for Genetics of Cardiovascular Disorders, University College London Medical School, London
,
Anne Lane
1   The Centre for Genetics of Cardiovascular Disorders, University College London Medical School, London
*   Current address: A. Lane, Room 352, Warren Alpert Building, Harvard Medical School, 200, Longwood Avenue, Boston MA 02115, USA
,
Fiona Green
1   The Centre for Genetics of Cardiovascular Disorders, University College London Medical School, London
**   F. Green, Nuffield Dept Surgery, University of Oxford, John Radcliffe Hospital, Headington Oxford, OX3 9DM, UK
,
Jackie Cooper
2   The MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, The Medical College of St. Bartholomew’s Hospital, London, UK
,
George Miller
2   The MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, The Medical College of St. Bartholomew’s Hospital, London, UK
› Author Affiliations
Further Information

Publication History

Received 12 September 1995

Accepted after resubmission 05 January 1996

Publication Date:
10 July 2018 (online)

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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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