A direct assessment of genetic contribution to the incidence of coronary infarct in the general population Greek EPIC cohort

Authors: YIANNAKOURIS, N - HAROKOPIO UNIV OF ATHENS; TRICHOPOULOU, A - UNIVERSITY OF ATHENS; BENETOU, V - UNIVERSITY OF ATHENS; PSALTOPOULOU, T - UNIVERSITY OF ATHENS; Ordovas, Jose; TRICHOOULOS, D - HARVARD SCHOOL PUB HEALTH

Submitted to: European Journal of Epidemiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/29/2006
Publication Date: 11/22/2006
Citation: Yiannakouris, N., Trichopoulou, A., Benetou, V., Psaltopoulou, T., Ordovas, J.M., Trichooulos, D. 2006. A direct assessment of genetic contribution to the incidence of coronary infarct in the general population Greek EPIC cohort. European Journal of Epidemiology. 21(12):859-867.

Interpretive Summary: Genetic linkage studies in families have led to the elucidation of the etiology of major gene disorders and have also succeeded in identifying genes involved in the etiology of some complex diseases. Genetic association studies, however, that had originally been heralded as very promising had, with few exceptions, led to disappointments. For coronary heart disease (CHD) which is characterized by complex underlying pathogenesis, multiple genes with weak or modest individual effects, interaction with environmental factors and study design limitations, particularly low statistical power, have hindered the identification of genes with etiologic importance. Nevertheless, a number of candidate gene polymorphisms have been identified, on the basis of their presumed physiologic or pathophysiologic role and limited, but growing, empirical evidence. In nutritional epidemiology, where individual food or food groups also have weak, interactive and frequently undetectable effects on the occurrence of complex chronic diseases, several a priori nutritional scores that integrate the effects of the individual nutritional variables have been used with considerable success. Similarly, in the field of genetic epidemiology, several investigators have suggested that genetic association studies should move away from analysis of genes one at a time and focus instead simultaneously on several genes. We have thus developed a simple a priori score (the genetic predisposition scale and corresponding score, GPS) relying on a total of 11 polymorphisms in 9 genes and assigning a value of 1 to homozygotes of the high-risk allele, a value of 0 to homozygotes of the low-risk allele and 0.5 to heterozygotes and then summing over the 11 polymorphisms. The resulting score was then studied in relation to the incidence of coronary infarct using data from a Greek prospective investigation.

Technical Abstract: To estimate the fraction of the incidence of coronary infarct attributable to the combined action of common genetic polymorphisms likely to be related to this condition, we conducted a case-control study nested within the Greek component of the European Prospective Investigation into Cancer and Nutrition. A total of 202 cases with a new, medically confirmed coronary infarct and 197 controls who had not developed an infarct by the time the corresponding case was diagnosed,were identified. A simple a priori score, relying on a total of 11 genetic polymorphisms was developed. Each polymorphism contributed 1 unit if the subject was homozygous for the high-risk allele, 0.5 units if the subject was heterozygous and 0 units if the subject was homozygous for the low-risk allele. Cases were over-represented in the presumed high genetic risk score values (chi square for trend = 10.18; p = 0.0014). The odds ratio to develop coronary infarct was 1.55 (95% confidence interval: 1.02-2.37) for score >/=3.0, and 2.02 (1.31-3.11) for score >/=3.5. In both instances the population fraction of the disease attributable to genetic predisposition exceeded 22%. Assuming a prior probability of at least 0.10 for the score to be predictive of coronary infarct risk, our findings are more likely than not to be truly positive. Our results, based on a simple score integrating the additive impact of 11 genetic polymorphisms, indicate that genetic predisposition accounts for a considerable fraction of the incidence of coronary infarct in the community.