Zerba K E, Ferrell R E, Sing C F
Bristol-Myers Squibb, Pharmaceutical Research Institute, Non-clinical Biostatistics, Princeton, NJ 08543-5400, USA.
Hum Genet. 2000 Nov;107(5):466-75. doi: 10.1007/s004390000394.
We analyzed the influence of age, apolipoprotein E (ApoE) genotype, and their interaction on the variation of each of all possible pairwise correlations among plasma levels of ApoE, ApoB, total cholesterol, triglyceride, and HDL cholesterol. Our cross-sectional study sample included 1,876 individuals (979 females and 897 males) from the Rochester, MN population, unselected for health, with a common ApoE genotype of epsilon32, epsilon33, or epsilon43, and ranging in age from 5 to 90 years. We conducted analyses on data from female and male subjects separately, using a hierarchical set of generalized additive models. The age changes in the correlations were estimated using a 30-year sliding window across the age range. There were qualitative differences between genders in the age at which the peaks in the correlations occurred. For female subjects, peaks in correlations were mostly in the middle and older age windows, whereas in males, peaks were mostly in the younger and middle age windows. We found for both genders that for each of the possible pairwise correlations, the influence of age was significantly dependent on ApoE genotype (all Pr<0.0001). We also found for female and male subjects that the epsilon32- and epsilon43- specific age changes in the correlations were each significantly different from those for the epsilon33 genotype (Pr<0.0001), with two exceptions for males (marginally significant differences, P<0.08). We conclude that the influence of ApoE genotypic variation extends far beyond the levels of the gene product, to the dynamics of the relational order among measures of lipid metabolism with age. Moreover, age and common ApoE genotype are not independent predictors of the gender-specific changes in relational order that we observed among these measures of lipid metabolism. These results have implications for the development and application of therapeutic approaches to treat human disease and our enhanced understanding of the role of genetic variation in the dynamic actions of complex adaptive systems with age that occur in response to environmental change. These dynamic actions emerge as the phenotypes that are measures of human health in the population at large.
我们分析了年龄、载脂蛋白E（ApoE）基因型及其相互作用对血浆中ApoE、ApoB、总胆固醇、甘油三酯和高密度脂蛋白胆固醇水平之间所有可能的两两相关性变化的影响。我们的横断面研究样本包括来自明尼苏达州罗切斯特市的1876名个体（979名女性和897名男性），这些个体未经过健康筛选，具有常见的ApoE基因型ε3/2、ε3/3或ε4/3，年龄范围为5至90岁。我们分别对女性和男性受试者的数据进行分析，使用了一组分层的广义相加模型。相关性的年龄变化是通过在整个年龄范围内使用30年的滑动窗口来估计的。相关性峰值出现的年龄在性别之间存在质的差异。对于女性受试者，相关性峰值大多出现在中年和老年窗口，而对于男性，峰值大多出现在年轻和中年窗口。我们发现，对于男女两性，在每一种可能的两两相关性中，年龄的影响都显著依赖于ApoE基因型（所有P<0.0001）。我们还发现，对于女性和男性受试者，ε3/2和ε4/3特异性的相关性年龄变化各自与ε3/3基因型的变化显著不同（P<0.0001），男性有两个例外（边缘显著差异，P<0.08）。我们得出结论，ApoE基因型变异的影响远远超出基因产物的水平，延伸到脂质代谢指标之间随年龄变化的关系秩序动态。此外，年龄和常见的ApoE基因型并不是我们在这些脂质代谢指标中观察到的性别特异性关系秩序变化的独立预测因素。这些结果对于治疗人类疾病的治疗方法的开发和应用以及我们对基因变异在随年龄变化的复杂适应系统动态作用中的作用的深入理解具有重要意义。这些动态作用表现为在总体人群中衡量人类健康的表型。
