Genetic Determination of Coagulation Factor VIIc Levels among Healthy Middle-aged Women

Summary

A recent study (1) reported variation among men in clotting factor Vile levels is associated with a genetic polymorphism detected by the restriction enzyme Msp I. The present study determined the Msp I genotype (Arg₃₅₃, Gln₃₅₃ alleles) for 189 women (mean age 53) who were subjects in the Healthy Women Study, a population study of CHD risk factor change at menopause. Women with the Arg/Arg genotype (n = 147) had an 16% higher (geometric) mean FVIIc level than those with the Arg/Gln (n = 41) genotype (1.21 vs 1.04 U/ml, p<0.01), while the one subject with the Gln/Gln genotype had an FVIIc level of 1.00 U/ml. These results are consistent with those previously found in healthy men (1). In addition, women carrying the Gin allele did not exhibit the elevation in FVIIc with menopause and use of hormone therapy found among those with the Arg allele, suggesting that genotype may modify the observed rise in factor Vile at menopause. Possibly because of the small sample size this interaction did not reach conventional levels of statistical significance. Results of multiple linear regression analyses controlling for age, hormone use, obesity, (In) triglyceride levels, and family history of CHD found FVIIc levels to be significantly (p<0.001) related to genotype. Thus, genotype appears to be a major determinant of FVIIc levels among women.

• References

• 1 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
• 2 Rapaport SI, Rao LV M. Thrombosis Council Distinguished Lecture: initiation and regulation of tissue factor-dependent blood coagulation. Arterioscler Thromb 1992; 12: 1111-1121
• 3 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. Arterioscler Thromb 1994; 14: 193-198
• 4 Pfeiffer RA, Ott R, Taben KD. Clotting factors VII and X as useful markers of terminal deletion of chromosome 13. Hum Gen 1985; 69: 192
• 5 Meade TW, Brozovic M, Chakrabarti RR. et al Haemostatic function and ischaemic heart disease: Principal results of the Northwick Park Heart Study. Lancet 06.09.1986; 220: 533-537
• 6 Scarabin PY, van DredenP, Bonithon-Kop C, Orssaud G. et al Age-related changes in factor VII activation in healthy women. Clin Sci 1988; 75: 341-343
• 7 Meade TW, Haines AP, Imeson JD, Stirling Y, Thompson SG. Menopausal status and haemostatic variables. Lancet 1983; 1: 22-24
• 8 Dalaker K, Prydz H. The coagulation factor VII in pregnancy. Br J Haematol 1984; 56: 233-241
• 9 Scarabin PY, Bonithon-Kopp C, Bara L, Malmejac A, Guize L, Samkama M. Factor VII activation and menopausal status. Thromb Res 1990; 57: 227-234
• 10 Meilahn EN, Kuller LH, Matthews KA, Kiss JE. 1 Hemostatic factors according to menopausal status and use of hormone replacement therapy. Ann Epidemiol 1992; 2: 445-455
• 11 Meade TW. The epidemiology of haemostatic and other variables in coronary artery disease. In Thrombosis and Haemostasis. Verstraete M, Vermylen J, Lijnen HR, Arnout J. (Eds) Leuven Univ Press; Leuven: 1987. pp 37-60
• 12 Matthews KA, Kelsey SF, Meilahn EN, Kuller LH, Wing RR. Educational attainment and behavioral and biologic risk factors for coronary heart disease in middle-aged women. Am J Epid 1989; a 129: 1132-1144
• 13 Lenahan JG, Smith K. Hemostasis. 18th ed Organon-Teknika Press; 1986
• 14 Matthews KA, Meilahn EN, Kuller LH, Kelsey SF, Caggiula AW, Wing RR. Menopause and risk factors for coronary heart disease. N Engl J Med 1989; b 321: 641-646
• 15 Lowe GD O, Wood DA, Douglas JT, Riemersma RA, Macintyre CC A, Takase T, Tuddenham EG, Forbes CD, Elton RA, Oliver MF. Relationships of plasma viscosity, coagulation and fibrinolysis to coronary risk factors and angina. Thromb Haemost 1991; 65: 339-343
• 16 Miller GJ, Walter SJ, Stirling Y, Thompson SG, Esnouf MP, Meade TW. Assay of factor VII activity by two techniques: evidence for increased conversion of VII to aVIIa in hyperlipidaemia, with possible implications for ischaemic heart disease. Br J Haematol 1985; 59: 249-258
• 17 Hoffman CJ, Miller RH, Hultin MB. Correlation of factor VII activity and antigen with cholesterol and triglycerides in healthy young adults. Arterioscler Thromb 1992; 12: 267-270