Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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 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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Genomic structure, repeat elements and nucleotide variations in DCP1.
Figure 2: DCP1 genotypes and haplotypes.
Figure 3: Consensus parsimony gene tree for DCP1 haplotypes.

Accession codes




  1. Rigat, B. et al. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J. Clin. Invest. 86, 1343–1346 (1990).

    Article  CAS  Google Scholar 

  2. Schunkert, H. Polymorphism of the angiotensin-converting enzyme gene and cardiovascular disease. J. Mol. Med. 75, 867– 875 (1997).

    Article  CAS  Google Scholar 

  3. Soubrier, F., Nadaud, S. & Williams, T.A. Angiotensin I converting enzyme gene: regulation, polymorphism and implications in cardiovascular diseases. Eur. Heart J. 15, 24–29 ( 1994).

    Article  CAS  Google Scholar 

  4. Evans, A.E. et al. Polymorphisms of the angiotensin-converting-enzyme gene in subjects who die from coronary heart disease. Q. J. Med. 87, 211–214 (1994).

    CAS  PubMed  Google Scholar 

  5. O'Malley, J.P., Maslen, C.L. & Illingworth, D.R. Angiotensin-converting enzyme DD genotype and cardiovascular disease in heterozygous familial hypercholesterolemia. Circulation 97, 1780–1783 ( 1998).

    Article  CAS  Google Scholar 

  6. O'Donnell, C.J. et al. Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study. Circulation 97, 1766–1772 (1998).

    Article  CAS  Google Scholar 

  7. Schächter, F. et al. Genetic associations with human longevity at the APOE and ACE loci. Nature Genet. 6, 29– 32 (1994).

    Article  Google Scholar 

  8. Harding, R. et al. Archaic African and Asian lineages in the genetic ancestry of modern humans. Am. J. Hum. Genet. 60, 772–789 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang, D.G. et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 280, 1077–1082 (1998).

    Article  CAS  Google Scholar 

  10. Collins, F.S., Guyer, M.S. & Charkravarti, A. Variations on a theme: cataloging human DNA sequence variation. Science 278, 1580– 1581 (1997).

    Article  CAS  Google Scholar 

  11. Nachman, M.W., Bauer, V.L., Crowell, S.L. & Aquadro, C.F. DNA variability and recombination rates at X-linked loci in humans. Genetics 150,1133–1141 ( 1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hubert, C., Houot, A., Corvol, P. & Soubrier, P. Structure of the angiotensin I-converting enzyme gene. Two alternate promoters correspond to evolutionary steps of a duplicated gene. J. Biol. Chem. 266, 15377–15383 (1991).

    CAS  PubMed  Google Scholar 

  13. Clark, A.G. Inference of haplotypes from PCR-amplified samples of diploid populations. Mol. Biol. Evol. 7, 111– 122 (1990).

    CAS  PubMed  Google Scholar 

  14. Batzer, M.A. et al. African origin of human-specific polymorphic Alu insertions. Proc. Natl Acad. Sci. USA 91, 12288– 12292 (1994).

    Article  CAS  Google Scholar 

  15. Hey, J. Mitochondrial and nuclear genes present conflicting portraits of human origins. Mol. Biol. Evol. 14, 166–172 (1997).

    Article  CAS  Google Scholar 

  16. Clark, A.G. et al. Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase. Am. J. Hum. Genet. 63, 595–612 (1998).

    Article  CAS  Google Scholar 

  17. Zielenski, J. & Tsui, L.C. Cystic fibrosis: genotypic and phenotypic variations. Annu. Rev. Genet. 29, 777– 807 (1995).

    Article  CAS  Google Scholar 

  18. Scrivner, C.R., Byck, S., Prevost, L. & Hoang, L. in Variation in the Human Genome (ed. Weiss, K.M.) 73–90 (John Wiley & Sons, Chichester, 1996).

    Google Scholar 

  19. Long, A.D., Lyman, R.F., Langley, C.H. & Mackay, T.F. Two sites in the Delta gene region contribute to naturally occurring variation in bristle number in Drosophila melanogaster. Genetics 149, 999–1017 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Montgomery, H.E. et al. Human gene for physical performance. Nature 393, 221–222 (1998).

    Article  CAS  Google Scholar 

  21. Sing, C.F., Haviland, M.B., Zerba, K.E. & Templeton, A.R. Application of cladistics to the analysis of genotype-phenotype relationships. Eur. J. Epidemiol. 8 (suppl. 1), 3– 9 (1992).

    Article  Google Scholar 

  22. Keavney, B. et al. Measured haplotype analysis of the angiotensin-I converting enzyme gene. Hum. Mol. Genet. 7, 1745– 1751 (1998).

    Article  CAS  Google Scholar 

  23. Nickerson, D.A. et al. DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nature Genet. 19, 233– 240 (1998).

    Article  CAS  Google Scholar 

  24. Nickerson, D.A., Tobe, V.O. & Taylor, S.L. PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res. 25, 2745– 2751 (1997).

    Article  CAS  Google Scholar 

  25. Ewing, B., Hillier, L., Wendl, M.C. & Green, P. Base-calling of automated sequencer traces using phred. I. Accuracy assessment. Genome Res. 8,175–185 ( 1998).

    Article  CAS  Google Scholar 

  26. Tajima, F. Evolutionary relationship of DNA sequences in finite populations. Genetics 105, 437–460 ( 1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Tajima, F. Statistical method for testing the neutral mutation hypothesis by DNA polymorphisms. Genetics 123, 585–595 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Griffiths, R.C. & Tavaré, S. Ancestral inference in population genetics. Stat. Sci. 9, 307–319 (1994).

    Article  Google Scholar 

  29. Tavaré, S., Griffiths, R.C. & Donnelly, P. Inferring coalescence times from DNA sequence data. Genetics 145, 505–518 (1997).

    PubMed  PubMed Central  Google Scholar 

  30. Hudson, R.R. & Kaplan, N.L. Statistical properties of the number of recombination events in the history of a sample of DNA sequences. Genetics 111, 147–164 ( 1985).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


We thank P. Green, K. Weiss and U. Petralia for helpful comments. This work was supported in part by HG01436 and HL58238 (D.A.N.), HL58240 (A.G.C.) and NRSA Fellowship 1 F32 HG00187-01 (M.J.R.).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Mark J. Rieder.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rieder, M., Taylor, S., Clark, A. et al. Sequence variation in the human angiotensin converting enzyme. Nat Genet 22, 59–62 (1999).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing