Quantitative Variation in Plasma Angiotensin-I Converting Enzyme Activity Shows Allelic Heterogeneity in the ABO Blood Group Locus

Authors

  • Chikashi Terao,

    1. The Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  • Nervana Bayoumi,

    1. Physiology Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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  • Colin A. McKenzie,

    1. Tropical Metabolism Research Unit, University of the West Indies, Mona, Jamaica
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  • Diana Zelenika,

    1. Commisariat à l’énergie Atomique (CEA), Institut Genomique, Centre National de Genotypage, Evry, France
    2. Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain, Paris, France
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  • Shigeo Muro,

    1. Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  • Michiaki Mishima,

    1. Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  • The Nagahama Cohort Research Group,

    1. The following investigators belonging to Kyoto University Graduate School of Medicine (Kyoto, Japan) were core members of the Nagahama Study Group: Takeo Nakayama (Department of Health Informatics); Shinji Kosugi (Department of Medical Ethics); Akihiro Sekine, Takahisa Kawaguchi, Ryo Yamada and Yasuharu Tabara (The Center for Genomic Medicine)
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  • John M C Connell,

    1. College of Medicine, Dentistry and Nursing, University of Dundee, UK
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  • Mark A. Vickers,

    1. School of Medicine, University of Aberdeen, UK
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  • G. Mark Lathrop,

    1. Commisariat à l’énergie Atomique (CEA), Institut Genomique, Centre National de Genotypage, Evry, France
    2. Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain, Paris, France
    3. McGill University and Genome Quebec Innovation Center, Montreal, Canada
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  • Martin Farrall,

    1. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
    2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
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  • Fumihiko Matsuda,

    1. The Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  • Bernard D. Keavney

    Corresponding author
    1. Institute of Genetic Medicine, Newcastle University, UK
    2. Institute of Cardiovascular Sciences, Manchester University, UK
    • The Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Corresponding author: Bernard D. Keavney, Institute of Genetic Medicine, Newcastle University, Central Parkway, NE1 3BZ, UK. Tel: +44 191 241 8615; Fax: +44 191 241 8666; E-mail: bernard.keavney@newcastle.ac.uk

Summary

Angiotensin-I converting enzyme (ACE) occupies a pivotal role in cardiovascular homeostasis. Major loci for plasma ACE have been identified at ACE on Chromosome 17 and at ABO on Chromosome 9. We sought to characterise the genetic architecture of plasma ACE at finer resolution in two populations. We carried out a GWAS in 1810 individuals of Japanese ethnicity; this identified signals at ACE and ABO that together accounted for nearly half of the population variability of the trait. We conducted measured haplotype analysis at the ABO locus in 1425 members of 248 British families using haplotypes of three SNPs, which together tagged the alleles responsible for the principal blood group antigens A1, A2, B and O. Type O alleles were associated with intermediate plasma ACE activity compared to Type A1 alleles (in whom plasma ACE activity was ∼36% lower) and Type B alleles (in whom plasma ACE activity was ∼36% higher). We demonstrated heterogeneity among A alleles: A2 alleles were associated with plasma ACE activity that was very similar to the O alleles. Variation at ACE accounted for 35% of the trait variance, and variation at ABO accounted for 15%. A further 10% could be ascribed to polygenic effects.

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