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Human Molecular Genetics, 2002, Vol. 11, No. 23 2969-2977
© 2002 Oxford University Press

Angiotensin-1-converting enzyme (ACE) plasma concentration is influenced by multiple ACE-linked quantitative trait nucleotides

Roger Cox1, Nourdine Bouzekri2, Sabrina Martin3, Lorraine Southam1, Alison Hugill1, Mahamadee Golamaully4, Richard Cooper5, Adebowale Adeyemo6, Florent Soubrier3, Ryk Ward2, G. Mark Lathrop4, Fumihiko Matsuda4 and Martin Farrall7,*

1Medical Research Council, Mammalian Genetics Unit, Harwell, Didcot OX11 0RD, UK, 2Department of Biological Anthropology, University of Oxford, Oxford, UK, 3INSERM U 525, Faculté de Médecine Pitié-Salpêtrière, Université Paris VI, Paris, France, 4Centre National de Génotypage, Evry, France, 5Department of Preventive Medicine and Epidemiology, Loyola University Medical Center, Maywood, Illinois, USA, 6Department of Pediatrics/Institute for Child Health, College of Medicine, University of Ibadan, Ibadan, Nigeria and 7Department of Cardiovascular Medicine, University of Oxford, The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK

Received July 26, 2002; Accepted September 9, 2002

Circulating angiotensin-1-converting enzyme (ACE) is a highly heritable trait, and a major component of the genetic variance maps to the region of the ACE gene. The strong effect of the locus, and the interest in ACE as a candidate gene for cardiovascular disorders, has led to extensive investigation of its relationship to the ACE phenotype, providing one of the most complete examples of quantitative trait locus (QTL) analysis in humans. Resequencing of ACE followed by haplotype analysis in families of British and French origin has shown that the genetic variants that are primarily associated with the ACE trait map to an 18 kb interval flanked by two intragenic, ancestral recombination breakpoints. This critical interval contains dozens of ACE-associated variants in Caucasians, but identification of which of these directly influence ACE concentration is ambiguous because of the almost complete linkage disequilibrium in European populations. In a complementary sequencing and genotyping study of individuals from West African families, we show that this population has much greater haplotype diversity across the gene. Through analysis of the contrasting relationships of the trait phenotype with haplotypes that carry different allelic combinations from those observed in Caucasians, we demonstrate that (at least) two major intragenic sites within the critical interval and (at least) one minor promoter site are associated with the ACE quantitative trait through additive effects. These results point to the importance of analysing diverse populations with different gene genealogies in gene-association studies.

* To whom correspondence should be addressed: Tel: +44 1865287601; Fax: +44 1865287501; Email: martin.farrall{at}well.ox.ac.uk


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