Angiotensin converting enzyme (encoded by the gene DCP1, also known
as ACE) catalyses the conversion of angiotensin I to the physiologically
active peptide angiotensin II, which controls fluid-electrolyte balance and
systemic blood pressure. Because of its key function in the renin-angiotensin
system, many association studies have been performed with DCP1. Nearly
all studies have associated the presence (insertion, I) or absence (deletion,
D) of a 287-bp Alu repeat element in intron 16 with the levels of circulating
enzyme or cardiovascular pathophysiologies1,
2,
3. Many epidemiological
studies suggest that the DCP1*D allele confers increased susceptibility
to cardiovascular disease; however, other reports have found no such association
or even a beneficial effect (refs 4, 5, 6, 7).
We present here the complete genomic sequence of DCP1 from 11 individuals,
representing the longest contiguous scan (24 kb) for sequence variation in
human DNA. We identified 78 varying sites in 22 chromosomes that resolved
into 13 distinct haplotypes. Of the variant sites, 17 were in absolute linkage
disequilibrium with the commonly typed Alu insertion/deletion polymorphism,
producing two distinct and distantly related clades. We also identified a
major subdivision in the Alu deletion clade that enables further analysis
of the traits associated with this gene. The diversity uncovered in DCP1
is comparable to that described for other regions in the human genome8,
9,
10,
11. The highly correlated structure in DCP1 raises
important issues for the determination of functional DNA variants within genes
and genetic studies in humans based on marker association.
