Correspondence

Polymorphisms in the Factor VII Gene and the Risk of Myocardial Infarction

N Engl J Med 2001; 344:458-459February 8, 2001

Article

To the Editor:

Girelli et al. (Sept. 14 issue)1 found that polymorphic alleles of the factor VII gene that are associated with low plasma levels of the coagulation factor confer protection against myocardial infarction in patients with coronary atherosclerosis. The authors discuss why their results differ from those of other investigators. They postulate that differences between the positive studies, all of which were carried out in Italian patients, and the negative ones, which were carried out in populations in France, Northern Ireland, and the Netherlands, might be related to the higher prevalence of the “protective” alleles in southern Europe (prevalence of the Q allele at position 353 associated with low factor VII levels, 14.5 percent in Spain and 15.1 percent in Italy)2 than in northern Europe (prevalence, 8.5 percent in Norway and 11.7 percent in the Netherlands).2 I think that two lines of evidence argue against this explanation. The most direct one is that the Q allele was not found to protect against myocardial infarction in an Italian study carried out in 200 patients and 200 healthy controls who were 45 years of age or younger (odds ratio, 0.95; 95 percent confidence interval, 0.64 to 1.40),3 in spite of the fact that the prevalence of the allele among controls was practically identical (16.5 percent)3 to that found by Girelli et al. in their control population (16.2 percent).

Another, less direct piece of evidence stems from the study by de Maat et al., who found a very high prevalence of the Q allele (26 percent) among Indians from the state of Gujarat, a population known to have a particularly high incidence of premature coronary artery disease.4 Therefore, it is unlikely that polymorphic alleles associated with low plasma levels of factor VII are protective only when they are more frequent in the population. I suggest that the explanation for the different results is that all the studies cited by Girelli et al. are not only heterogeneous in terms of the selection of patients and controls but also, and most important, of insufficient size. The negative results of the recent large-scale (4629 patients and 5934 controls) reevaluation5 of the hypothesized association between myocardial infarction and the insertion–deletion polymorphism of the gene encoding the angiotensin-converting enzyme illustrate the need for much larger studies to determine the role of genetic factors in complex diseases.

Pier Mannuccio Mannucci, M.D.
Istituto di Ricovero e Cura a Carattere Scientifico, Maggiore Hospital, 20122 Milan, Italy

5 References

1. 1

   Girelli D, Russo C, Ferraresi P, et al. Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease. N Engl J Med 2000;343:774-780
   Full Text | Web of Science | Medline

2. 2

   Bernardi F, Arcieri P, Bertina RM, et al. Contribution of factor VII genotype to activated FVII levels: differences in genotype frequencies between northern and southern European populations. Arterioscler Thromb Vasc Biol 1997;17:2548-2553
   CrossRef | Web of Science | Medline

3. 3

   Ardissino D, Mannucci PM, Merlini PA, et al. Prothrombotic genetic risk factors in young survivors of myocardial infarction. Blood 1999;94:46-51
   Web of Science | Medline

4. 4

   de Maat MPM, Green F, de Knijff P, Jespersen J, Kluft C. Factor VII polymorphisms in populations with different risks of cardiovascular disease. Arterioscler Thromb Vasc Biol 1997;17:1918-1923
   CrossRef | Web of Science | Medline

5. 5

   Keavney B, McKenzie C, Parish S, et al. Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. Lancet 2000;355:434-442
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Our study focused on a specific question that is not uncommon in clinical practice: why does myocardial infarction not occur in some patients despite the presence of angiographically documented severe coronary atherosclerotic disease? Remarkably, our patients with coronary artery disease had a substantial burden of conventional risk factors and a mean age of 61.3±8.8 years. Thus, they could be considered representative of the general population of such patients who are usually seen in practice. The only distinction, if any, was the severity of the disease, since most of our patients had stenosis of three vessels. Ardissino et al. report data on patients who had a myocardial infarction at a very young age (mean, 40.7±4.1 years).1 In addition, among the 171 patients for whom they reported angiographic data, 13 percent had normal coronary arteries and 46 percent had only single-vessel disease. Thus, we were not surprised by the fact that the results differed in such a highly selected population, since their patients represent the opposite end of the spectrum of patients with coronary artery disease (those who are younger and who do not have extensive coronary atherosclerosis) and in such a population, other interactions between genes or between genes and environmental factors may contribute to premature myocardial infarction. Similar reasoning could apply to the interpretation of the relatively high prevalence of the Q allele among Gujarati Indians, a population with distinctive ethnic and socioeconomic backgrounds. Moreover, de Maat et al.2 examined only 93 subjects from the “general population”; they had no information about the health status of the subjects, nor did they compare their findings with those in patients with established coronary artery disease. Thus, the two lines of evidence cited by Dr. Mannucci only seemingly contradict our results, since they were derived from studies that differed completely in terms of both selection criteria and design.

Domenico Girelli, M.D., Ph.D.
University of Verona, 37134 Verona, Italy

Francesco Bernardi, M.S.
University of Ferrara, 44100 Ferrara, Italy

Roberto Corrocher, M.D.
University of Verona, 37134 Verona, Italy

2 References

1. 1

   Ardissino D, Mannucci PM, Merlini PA, et al. Prothrombotic genetic risk factors in young survivors of myocardial infarction. Blood 1999;94:46-51
   Web of Science | Medline

2. 2

   de Maat MPM, Green F, de Knijff P, Jespersen J, Kluft C. Factor VII polymorphisms in populations with different risks of cardiovascular disease. Arterioscler Thromb Vasc Biol 1997;17:1918-1923
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Asim K. Duttaroy. (2005) Postprandial activation of hemostatic factors: Role of dietary fatty acids. Prostaglandins, Leukotrienes and Essential Fatty Acids 72:6, 381-391
   CrossRef

2. 2

   P. J. Grant. (2003) The genetics of atherothrombotic disorders: a clinician's view. Journal of Thrombosis and Haemostasis 1:7, 1381-1390
   CrossRef