Abstract for presentation at 11th International Congress of Human Genetics

Coronary artery disease (CAD) is the most common cause of death in Western societies and develops as a result of complex interactions between genetic and environmental factors. In previous studies using mouse models, we provided evidence that 5-lipoxygenase (5-LO) deficiency confers dramatic resistance to aortic lesion development. By extending these findings to humans, we demonstrated that certain “deleted” alleles of a promoter repeat polymorphism were associated with carotid intima-media thickness, an accepted surrogate marker for atherosclerosis. To confirm these initial observations, we have now genotyped the same polymorphism in a large cohort of patients with myocardial infarction (MI) and matched controls from Costa Rica. Relative to the wildtype allele of 5 repeats, deleted alleles with 3 repeats conferred protection against MI (O.R. 0.47; 95% CI 0.23-0.96) whereas alleles with 4 repeats tended to increase risk (O.R. 1.21; 95% 0.67-2.2) in this population. To determine whether these associations were due to functional differences between these alleles, we measured mRNA levels in leukocytes from individuals in the control group with different genotypes. In agreement with the genetic associations, individuals homozygous for the 4 allele had increased 5-LO mRNA than individuals with other genotypes. Since samples from 33 individuals were not available for analysis, we measured allele specific mRNA levels in 35 and 45 heterozygous individuals. Relative to the 5 repeat allele, mRNA from the 3 allele was expressed approximately 20% less (P<0.0001) whereas the 4 allele had ~50% increased expression (P<0.0001). Thus, these data are consistent with the protective effect of the 3 allele and the risk promoting effect of the 4 allele that was observed on MI. Taken together, these results provide additional evidence for the role of the 5-LO gene in CAD, consistent with genetic associations reported with other genes of the pathway.