Human Molecular Genetics Advance Access originally published online on September 14, 2004
Human Molecular Genetics 2004 13(21):2647-2657; doi:10.1093/hmg/ddh286
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Human Molecular Genetics, Vol. 13, No. 21 © Oxford University Press 2004; all rights reserved
A cladistic model of ACE sequence variation with implications for myocardial infarction, Alzheimer disease and obesity
1Center for Genomics and Bioinformatics, 2Division of Cardiovascular Epidemiology, Institute of Environmental Medicine and 3Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden, 4Department of Clinical Sciences, Care of the Elderly, University of Bristol, The John James Building, Frenchay Hospital, Bristol, UK, 5Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden, 6Department of Psychology, University of Southern California, Los Angeles, CA, USA and 7Department of Clinical Neuroscience and Transfusion Medicine, University of Göteborg, Sahlgren's University Hospital, Sweden
Received June 22, 2004; Revised August 25, 2004; Accepted September 4, 2004
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 8.4x10–6). 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.
* To whom correspondence should be addressed at: Center for Genomics and Bioinformatics, Karolinska Institute, Berzelius väg 35 171 77, Stockholm, Sweden. Tel: +46 852486274; Fax: +46 8324826; Email: jonathan.prince{at}cgb.ki.se
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