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.


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.
Viiri
Leena E
LE
Department of Forensic Medicine, University of Tampere Medical School and Centre for Laboratory Medicine, Tampere University Hospital, Tampere, Finland. Leena.Viiri@uta.fi
Viiri
Keijo M
KM
Ilveskoski
Erkki
E
Huhtala
Heini
H
Mäki
Markku
M
Tienari
Pentti J
PJ
Perola
Markus
M
Lehtimäki
Terho
T
Karhunen
Pekka J
PJ
D000328:Adult; D000368:Aged; D000483:Alleles; D001018:Aortic Diseases / Q000235:genetics*; D053329:Apolipoprotein E2 / Q000235:genetics; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012907:Smoking
D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E