Katzov Hagit, Bennet Anna M, Kehoe Patrick, Wiman Björn, Gatz Margaret, Blennow Kaj, Lenhard Boris, Pedersen Nancy L, de Faire Ulf, Prince Jonathan A
Center for Genomics and Bioinformatics, Karolinska Institute, Berzelius väg 35 171 77, Stockholm, Sweden.
Hum Mol Genet. 2004 Nov 1;13(21):2647-57. doi: 10.1093/hmg/ddh286. Epub 2004 Sep 14.
Sequence variation in ACE, which encodes angiotensin I converting enzyme, contributes to a large proportion of variability in plasma ACE levels, but the extent to which this impacts upon human disease is unresolved. Most efforts to associate ACE with other heritable traits have involved a single Alu insertion/deletion polymorphism, despite the probable existence of other functional sequence variants with effects that may not be consistently detectable by solely typing the Alu indel. Here, utilizing single nucleotide polymorphisms (SNPs) that differentiate major ACE clades in European populations, we demonstrate a number of significant phenotype associations across more than 4000 Swedish individuals. In a systematic analysis of metabolic phenotypes, effects were detected upon several traits, including fasting plasma glucose levels, insulin levels and measures of obesity (P-values ranging from 0.046 to 8.4 x 10(-6)). Extending cladistic models to the study of myocardial infarction and Alzheimer disease, significant associations were observed with greater effect sizes than those typically obtained in large-scale meta-analyses based on the Alu indel. Population frequencies of ACE genotypes were also found to change with age, congruent with previous data suggesting effects upon longevity. Clade models consistently outperformed those based upon single markers, reinforcing the importance of taking into consideration the possible confounding effects of allelic heterogeneity in this genomic region. Utilizing computational tools, potential functional variants are highlighted that may underlie phenotypic variability, which is discussed along with the broader implications these results may have for studies attempting to link variation in ACE to human disease.
编码血管紧张素I转换酶的ACE基因序列变异在很大程度上导致了血浆ACE水平的差异，但这种差异对人类疾病的影响程度尚未明确。尽管可能存在其他功能序列变异，其影响可能无法通过仅检测Alu插入/缺失多态性来一致地检测到，但大多数将ACE与其他遗传性状关联的研究都涉及单一的Alu插入/缺失多态性。在这里，利用区分欧洲人群主要ACE进化枝的单核苷酸多态性（SNP），我们在4000多名瑞典个体中证明了许多显著的表型关联。在对代谢表型的系统分析中，检测到对几种性状的影响，包括空腹血糖水平、胰岛素水平和肥胖指标（P值范围从0.046到8.4×10⁻⁶）。将进化枝模型扩展到心肌梗死和阿尔茨海默病的研究中，观察到的显著关联的效应大小比基于Alu插入/缺失的大规模荟萃分析中通常获得的效应大小更大。还发现ACE基因型的群体频率随年龄变化，这与之前表明对寿命有影响的数据一致。进化枝模型始终优于基于单一标记的模型，这强化了考虑该基因组区域等位基因异质性可能的混杂效应的重要性。利用计算工具，突出了可能是表型变异基础的潜在功能变异，并与这些结果对试图将ACE变异与人类疾病联系起来的研究可能产生的更广泛影响一起进行了讨论。
