Measured haplotype analysis of the angiotensin-I converting enzyme gene |
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Authors: | Keavney B; McKenzie CA; Connell JM; Julier C; Ratcliffe PJ; Sobel E; Lathrop M; Farrall M |
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Institution: | The Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Windmill Road, Oxford OX3 7BN, UK. |
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Abstract: | Linkage and segregation analysis have shown that circulating angiotensin-I
converting enzyme (ACE) levels are influenced by a major quantitative trait
locus that maps within or close to the ACE gene. The D variant of a 287 bp
insertion/deletion (I/D) polymorphism in intron 16 of the gene is
associated with high ACE levels and may also be related to increased risk
of cardiovascular disease. Multiple variants that are in linkage
disequilibrium with the I/D polymorphism have been described, but it is
unknown if any of these are directly implicated, alone or in combination
with as yet undiscovered variants, in the determination of ACE levels. An
analysis of 10 polymorphisms spanning 26 kb of the ACE gene revealed a
limited number of haplotypes in Caucasian British families due to strong
linkage disequilibrium operating over this small chromosomal region. A
haplotype tree (cladogram) was constructed with three main branches (clades
A-C) which account for 90% of the observed haplotypes. Clade C is most
likely derived from clades A and B following an ancestral recombination
event. This evolutionary information was then used to direct a series of
nested, measured haplotype analyses that excluded upstream sequences,
including the ACE promoter, from harbouring the major ACE-linked variant
that explains 36% of the total trait variability. Residual familial
correlations were highly significant, suggesting the influence of
additional unlinked genes. Our results demonstrate that a combined
cladistic/measured haplotype analysis of polymorphisms within a gene
provides a powerful means to localize variants that directly influence a
quantitative trait.
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