title: Angiotensin-1-converting enzyme (ACE) plasma concentration is influenced by multiple ACE-linked quantitative trait nucleotides.
abstract: 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.
authors.affiliation: Medical Research Council, Mammalian Genetics Unit, Harwell, Didcot OX11 0RD, UK.
authors.forename: Roger
authors.initials: R
authors.lastname: Cox
authors.forename: Nourdine
authors.initials: N
authors.lastname: Bouzekri
authors.forename: Sabrina
authors.initials: S
authors.lastname: Martin
authors.forename: Lorraine
authors.initials: L
authors.lastname: Southam
authors.forename: Alison
authors.initials: A
authors.lastname: Hugill
authors.forename: Mahamadee
authors.initials: M
authors.lastname: Golamaully
authors.forename: Richard
authors.initials: R
authors.lastname: Cooper
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adeyemo
authors.forename: Florent
authors.initials: F
authors.lastname: Soubrier
authors.forename: Ryk
authors.initials: R
authors.lastname: Ward
authors.forename: G Mark
authors.initials: GM
authors.lastname: Lathrop
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
mesh_terms: D044383:Black People; D004247:DNA / Q000235:genetics; D005602:France; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D007703:Peptidyl-Dipeptidase A / Q000097:blood* / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D040641:Quantitative Trait Loci; D006113:United Kingdom; D044465:White People
chemical_list: D004247:DNA; D007703:Peptidyl-Dipeptidase A