Measured haplotype analysis of the ACE gene in Caucasian British families excluded upstream sequences from harboring the major ACE-linked variant that explains 36% of trait variability.
Observational
Combined cladistic and measured haplotype analysis provides a powerful method to localize genetic variants directly influencing quantitative traits like circulating ACE levels.
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.
Keavney et al. (Thu,) conducted a observational in Circulating angiotensin-I converting enzyme (ACE) levels. 10 polymorphisms spanning 26 kb of the ACE gene was evaluated on Localization of the major ACE-linked variant. Measured haplotype analysis of the ACE gene in Caucasian British families excluded upstream sequences from harboring the major ACE-linked variant that explains 36% of trait variability.