Xu C F, Angelico F, Del Ben M, Humphries S
Centre for the Genetics of Cardiovascular Disorders, University College and Middlesex School of Medicine, London, England.
Genet Epidemiol. 1993;10(2):113-22. doi: 10.1002/gepi.1370100204.
We have investigated the effect of the G/A substitution in the promoter region of the apolipoprotein (apo) AI gene (-75 bp) on plasma lipid, lipoprotein and apolipoprotein levels in a sample of 204 children from central Italy. The subjects included 111 boys and 93 girls, aged 8-11 years old. The frequency of the A allele was 0.19 in the total sample, and 0.21 and 0.17 in boys and girls, respectively. Using analysis of variance, we found the G/A substitution was significantly associated with plasma levels of total cholesterol, LDL cholesterol, apo B, and apo AI in boys, accounting for 7.0, 4.2, 5.3, and 4.3% of the sample variance, respectively. Individuals with an A allele had higher mean levels of these lipid traits than individuals homozygous for the G allele. A dietary intervention study had been carried out in a subset of these children, and the effect of the G/A substitution on plasma apo AI levels remained when boys changed to a low fat low cholesterol diet. However, no significant association was observed in girls between any of the lipid traits and the G/A genotypes. We have previously reported in this sample of children that the two polymorphisms detected with restriction enzyme PvuII, with variable sites in the first intron of the apo CIII gene (Pvu II-CIII) and the apo CIII-AIV intergenic region (Pvu II-AIV), were associated with significant differences on plasma apo AI levels. We found that the association reached statistical significance in boys only in this study. Taking these three polymorphisms together, the effects on plasma apo AI levels were additive in boys, accounting for 20.0% of the sample variance. Boys having the genotype GG/V-V+ of the G/A substitution and the PvuII-AIV RFLP had mean apo AI levels 36 mg/dl lower than boys with the genotype GA + AA/V-V-. In girls, however, there was evidence of significant interaction of effects between the PvuII-AIV RFLP and the G/A substitution (P < 0.04), with the A allele being associated with higher levels of plasma apo AI only in girls having the rare allele (V+) of the PvuII-AIV RFLP. We conclude that genetic variation at the apo AI-CIII-AIV gene cluster is having a major impact on the determination of plasma apo AI levels in this sample of young boys, with additive effects due to functional changes at several places in this gene cluster detected directly (G/A) or in allelic association with the PvuII-CIII and PvuII-AIV polymorphisms.(ABSTRACT TRUNCATED AT 400 WORDS)
我们研究了载脂蛋白（apo）AI基因启动子区域（-75 bp）的G/A替换对意大利中部204名儿童样本中血浆脂质、脂蛋白和载脂蛋白水平的影响。受试者包括111名男孩和93名女孩，年龄在8至11岁之间。A等位基因在总样本中的频率为0.19，在男孩和女孩中分别为0.21和0.17。通过方差分析，我们发现G/A替换与男孩的总胆固醇、低密度脂蛋白胆固醇、apo B和apo AI血浆水平显著相关，分别占样本方差的7.0%、4.2%、5.3%和4.3%。携带A等位基因的个体这些脂质特征的平均水平高于G等位基因纯合个体。对这些儿童中的一部分进行了饮食干预研究，当男孩改为低脂低胆固醇饮食时，G/A替换对血浆apo AI水平的影响仍然存在。然而，在女孩中，未观察到任何脂质特征与G/A基因型之间存在显著关联。我们之前在这个儿童样本中报告过，用限制性内切酶PvuII检测到的两个多态性，在apo CIII基因（Pvu II-CIII）的第一个内含子和apo CIII-AIV基因间区域（Pvu II-AIV）有可变位点，与血浆apo AI水平的显著差异相关。我们发现仅在本研究中这种关联在男孩中达到统计学显著水平。将这三个多态性综合起来，对男孩血浆apo AI水平的影响是累加的，占样本方差的20.0%。具有G/A替换和PvuII-AIV RFLP的GG/V-V+基因型的男孩，其平均apo AI水平比具有GA + AA/V-V-基因型的男孩低36 mg/dl。然而，在女孩中，有证据表明PvuII-AIV RFLP与G/A替换之间存在显著的效应相互作用（P < 0.04），仅在具有PvuII-AIV RFLP罕见等位基因（V+）的女孩中，A等位基因与较高的血浆apo AI水平相关。我们得出结论，在这个小男孩样本中，apo AI-CIII-AIV基因簇的遗传变异对血浆apo AI水平的决定有重大影响，由于在该基因簇中几个位置直接检测到的功能变化（G/A）或与PvuII-CIII和PvuII-AIV多态性的等位基因关联而产生累加效应。（摘要截选至400字）
