Interactions of functional apolipoprotein E gene promoter polymorphisms with smoking on aortic atherosclerosis.

BACKGROUND Apolipoprotein E gene (APOE) interacts with environmental factors in defining risk for atherosclerosis. We studied whether the APOE epsilon2/epsilon3/epsilon4 genotype or APOE promoter polymorphisms -219G/T and +113G/C might interact with smoking on the development of fatty streaks. We also studied the previously unknown effects of +113G/C on transcriptional activity. METHODS AND RESULTS The fatty streak areas of aorta were measured morphometrically in subjects of the Helsinki Sudden Death Study. Within APOE epsilon3/epsilon3 subjects, there was a strong interaction between smoking and both -219G/T (P=0.009) and +113G/C (P=0.003) promoter polymorphisms on abdominal aorta fatty streak area: the -219T- and +113C-allele carriers had larger lesion areas compared with G/G (12.7% versus 5.9%, P=0.007; 12.9% versus 6.3%, P=0.010, respectively) within nonsmokers. Within smokers, the associations were inverse. Moreover, smoking increased the fatty streak area within -219G/G or +113G/G genotypes and -219G/+113G/epsilon3 haplotype carriers. Functional studies in reporter assay showed that in comparison with the +113G allele, the +113C allele had higher transcriptional activity and bound transcription factors from liver cell nuclear extract with significantly lower affinity. CONCLUSIONS In middle-aged Finnish men with APOE epsilon3/epsilon3 genotype, the APOE promoter polymorphisms -219G/T and +113G/C interact with smoking in modulating aortic atherosclerosis. The +113G/C polymorphism has an effect on transcriptional activity.