Sequence variation in the human angiotensin converting enzyme

Angiotensin converting enzyme (encoded by the gene DCP1, also known as ACE) catalyses the conversion of angiotensin I to the physiologically active pe ptide angiotensin II, which controls fluid-electrolyte balance and systemic blood pressure. Because of its key function in the renin-angiotensin syste m, many association studies have been performed with DCP1. Nearly all studi es 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 enz yme or cardiovascular pathophysiologies(1-3). Many epidemiological studies suggest that the DCP1*D allele confers increased susceptibility to cardiova scular disease; however, other reports have found no such association or ev en a beneficial effect (refs 4-7), We present here the complete genomic seq uence of DCP1 from 11 individuals, representing the longest contiguous scan (24 kb) for sequence variation in human DNA, We identified 78 varying site s in 22 chromosomes that resolved into 13 distinct haplotypes, Of the varia nt sites, 17 were in absolute linkage disequilibrium with the commonly type d Alu insertion/deletion polymorphism, producing two distinct and distantly related clades, We also identified a major subdivision in the Alo deletion clade that enables further analysis of the traits associated with this gen e. The diversity uncovered in DCP1 is comparable to that described for othe r regions in the human genomes-(8-11), The highly correlated structure in D CP1 raises important issues for the determination of functional DNA variant s within genes and genetic studies in humans based on marker association.