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Apolipoprotein A4 (apoA4) plays a role in intestinal lipid absorption. Several experimental interventions have shown that common variations at residues 347 (ThrVSer) and 360 (GlnVHis) on apoA4 are associated with differences in plasma lipid response to dietary fat; however, association studies between these variants and plasma lipid concentrations in populations reveal mixed results. We examined the effects of these polymorphisms in 758 randomly selected subjects (mean age 36.7 9.5 years) from 2 Spanish regions differing in latitude and fat intake: Arago´n and Comunidad Valenciana. Subjects were matched one to one by sex and age. Frequencies for the less common alleles were similar in both regions: 0.096 (95% CI: 0.111– 0.081) for codon 360 and 0.196 (95% CI: 0.216–0.176) for codon 347. In men and women there was no association between the codon 360 polymorphism and total cholesterol or triglyceride levels. However, subjects carrying the 360His allele had low-density lipoprotein (LDL) cholesterol concentrations statistically lower than homozygotes for the 360Gln allele, even after further adjustment for sex, age, region, body mass index, and APOE polymorphism ( p = 0.043). The less common allele at codon 347 (the 347Ser allele) was associated with increased LDL-cholesterol concentrations with a clear genedosage effect after multivariate adjustment ( p = 0.029). Although these polymorphisms showed no heterogeneity by geographic region, the magnitude of the effect was higher in subjects from Aragon compared with the Comunidad Valenciana, suggesting a possible influence of the higher fat intake in Aragon. In the combined association analysis subjects with the 360Gln/347Ser pseudohaplotype had the highest LDL-cholesterol concentrations, supporting the antagonistic effect between the 360His and the 347Ser alleles on this trait.