Studies in animal models and humans implicate cell adhesion molecules in atherogenesis but their role in mediating the risk of myocardial infarction is unclear. Adhesion of circulating leucocytes to the endothelial lining is an early event in the atherosclerotic process. A variety of cell adhesion molecules is involved in a cascade of events which result in the infiltration of leucocytes and monocytes into the evolving plaque. While the expression of some of these adhesion molecules may only be transitory, studies in transgenic mice deficient in one or other of the relevant genes confirm their contributory role in the extent and content of plaques. In 1996, Wenzel and colleagues ascertained the frequency of specific polymorphism of E-selectin, LExchanges in the E-selectin gene from serine to arginine, from leucine to phenylalanine, and from guanine to thymine (position 98) were more frequent in cases than in controls. Because of the small numbers of cases involved, the authors were unable to report on or adjust for any potential associations with intermediate traits such as hypercholesterolaemia, body mass index (BMI), or hypertension. Subsequently, the larger ECTIM study investigated 13 polymorphism of the P-selectin gene in 647 male cases with myocardial infarction and 758 controls from four regions of France and Northern Ireland. These findings have not yet been corroborated in other studies
The sampling frames for both countries were based upon the catchment areas for the local MONICA project registers. Male cases between the ages of 25–64 years were recruited between three and nine months after the index infarction. Recruitment procedures for female cases in Glasgow were exactly the same as for men but because of the much smaller population base and lower incidence, female subjects in Belfast aged 25–69 years were enrolled up to two years after their infarction.
Controls of comparable age (± one year) were recruited from random samples generated from the lists of general practitioners in the same area. This questionnaire closely reflected that used in the original ECTIM study but had an additional section for women to identify the subject’s menopausal status.
Genotype odds ratios for myocardial infarction were estimated by logistic regression adjusted for population, age, and sex. Associations with conventional risk factors were tested by analysis of variance, adjusted for age, sex, and menopausal status in women. Non-normally distributed variables were first log transformed. Informed consent was given by all subjects for DNA extraction.
In total, 201 female cases and 194 female controls were newly recruited in Belfast. An additional 100 male cases and 82 controls were also enrolled. In Glasgow, 291 male and 104 female cases were recruited, along with 274 and 97 controls. As approximately six years elapsed between the original study and recruitment of the additional subjects, some comparison of their characteristics is warranted. The male and female controls in the extension are significantly older than the controls (males) in the original ECTIM sample, by roughly four and seven years respectively.
In a large population based study in two regions of the UK, we have been able to corroborate the earlier ECTIM findings of a lower frequency of the less common allele (Pro715) of the Thr/Pro715 polymorphism in subjects with myocardial infarction. If able to combine the present findings with those from the first study, the combined odds ratio would be 0.73 overall, and 0.73 (95% CI 0.56 to 0.96) and 0.71 in men and women, respectively. We recruited women up to two years after their myocardial infarction and up to nine months for men. We do not believe that this biases the findings materially from selective mortality, as nearly 90% of the mortality from myocardial infarction occurs in the first 28 days after the attack.
There has been growing interest in the role of cellular adhesion molecules in atherogenesis. P-selectin is an integral membrane glycoprotein of platelet á granules and the membrane component of the Weibel-Palade bodies of endothelial cells, the organelle which stores von Willebrand factor. It is known that in vitro it is important for maintaining the non-adhesiveness of neutrophils in the circulation and for inhibiting superoxide generation. However, the biological significance of soluble P-selectin in vivo is unclear. Most previous studies have either dealt with animal models7 or with variations in the expressed proteins in different human conditions, including coronary artery spasm and postangioplasty restenosis
Within a couple of years the human genome will have been sequenced. While it may then be possible to distinguish functional from nonfunctional variants, the problems of accurately defining risk in populations, taking account of the many possible gene–gene and gene– environment interactions, will have reached a new level of complexity.