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A genome-wide search replicates evidence of a quantitative trait locus for circulating angiotensisn l-converting enzyme (ACE) unlinked to the ACE gene

By Coiln A. McKenzie, Xiaofeng Zhu, Terrence E. Forrester, Amy Luke, Adebowale A. Adeyemo, Nourdine Bouzekri and Richard S. Cooper


Background: angiotensin I-converting enzyme (ACE) plays an important role in cardiovascular homeostasis. There is evidence from different ethnic groups that circulating ACE levels are influenced by a quantitative trait locus (QTL) at the ACE gene on chromosome 17. The finding of significant residual familial correlations in different ethnic groups, after accounting for this QTL, and the finding of support for linkage to a locus on chromosome 4 in Mexican-American families strongly suggest that there may well be QTLs for ACE unlinked to the ACE gene.<br/>Methods: a genome-wide panel of microsatellite markers, and a panel of biallelic polymorphisms in the ACE gene were typed in Nigerian families. Single locus models with fixed parameters were used to test for linkage to circulating ACE with and without adjustment for the effects of the ACE gene polymorphisms.<br/>Results: strong evidence was found for D17S2193 (Zmax = 3.5); other nearby markers on chromosome 17 also showed modest support. After adjustment for the effects of the ACE gene locus, evidence of "suggestive linkage" to circulating ACE was found for D4S1629 (Zmax = 2.2); this marker is very close to a locus previously shown to be linked to circulating ACE levels in Mexican-American families.<br/>Conclusion: in this report we have provided further support for the notion that there are QTLs for ACE unlinked to the ACE gene; our findings for chromosome 4, which appear to replicate the findings of a previous independent study, should be considered strong grounds for a more detailed examination of this region in the search for genes/variants which influence ACE levels. The poor yields, thus far, in defining the genetic determinants of hypertension risk suggest a need to look beyond simple relationships between genotypes and the ultimate phenotype. In addition to incorporating information on important environmental exposures, a better understanding of the factors which influence the building blocks of the blood pressure homeostatic network is also required. Detailed studies of the genetic determinants of ACE, an important component of the renin-angiotensin system, have the potential to contribute to this strategic objectiv

Topics: R1, QH426
Year: 2008
OAI identifier: oai:eprints.soton.ac.uk:79360
Provided by: e-Prints Soton

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  1. (1993). AA: Faster sequential genetic linkage computations.
  2. (1996). Alhenc-Gelas F: Development of enzyme-linked immunoassays for human angiotensin I converting enzyme suitable for large-scale studies. doi
  3. (1999). Analysis of human genetic linkage. 3rd edition. Baltimore, The Johns Hopkins doi
  4. (1990). Angiotensin I-converting enzyme and the changes in our concepts through the years: Lewis K Dahl Memorial Lecture. Hypertension doi
  5. (2002). Angiotensin-1-converting enzyme (ACE) plasma concentration is influenced by multiple ACE-linked quantitative trait nucleotides. Hum Mol Genet
  6. (2005). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. doi
  7. (2004). Atwood LD: Two quantitative trait loci affect ACE activities in Mexican-Americans. Hypertension doi
  8. (1982). Bias of the estimated recombination fraction and lod score due to an association between a disease gene and a marker gene. Ann Hum Genet doi
  9. (1980). Bonaiti-Pellie C: Epistasis effect: an alternative to the hypothesis of linkage disequilibrium in HLA associated diseases. Ann Hum Genet doi
  10. (1988). C: Familial resemblance of plasma angiotensin-converting enzyme level: the Nancy study.
  11. (2001). Cardon LR: Trans-ethnic fine mapping of a quantitative trait locus for circulating angiotensin I-converting enzyme (ACE). Hum Mol Genet
  12. (1991). Clauser E: Expression and characterization of recombinant human angiotensin I-converting enzyme. Evidence for a C-terminal transmembrane anchor and for a proteolytic processing of the secreted recombinant and plasma enzymes.
  13. (1989). Computer simulation methods in human linkage analysis. doi
  14. (1994). Cottingham RW Jr.: Avoiding recomputation in linkage analysis. Hum Hered doi
  15. (2003). Cusi D: ACE and alpha-adducin polymorphism as markers of individual response to diuretic therapy. Hypertension doi
  16. (1994). Demenais F: Detection of a major gene for heterocellular hereditary persistence of fetal hemoglobin after accounting for genetic modifiers.
  17. (1986). Effects of misspecifying genetic parameters in lod score analysis. Biometrics doi
  18. (1992). et al.: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement trial. doi
  19. (1993). for the Collaborative Study Group: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. doi
  20. (2002). Genome scan among Nigerians linking blood pressure to chromosomes 2, 3, and 19. Hypertension doi
  21. Genotyping Service Set 10. [ h t t p : / / research.marshfieldclinic.org/genetics].
  22. (1999). GM: Fine-mapping of an ancestral recombination breakpoint in DCP1. Nat Genet doi
  23. (1990). GM: SLINK: a general simulation program for linkage analysis.
  24. (2002). High-resolution genetic mapping of the ACElinked QTL influencing circulating ACE activity. doi
  25. (2006). Hydrochlorothiazide efficacy and polymorphisms doi
  26. (1995). Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet doi
  27. (1984). Lalouel JM: Easy calculations of lod scores and genetic risks on small computers.
  28. (2000). Linkage analysis in the presence of errors IV: joint pseudomarker analysis of linkage and/or linkage disequilibrium on a mixture of pedigrees and singletons when the mode of inheritance cannot be accurately specified. doi
  29. (2001). Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. doi
  30. (1997). LOD wars: the affected-sib-pair paradigm strikes back!
  31. (2002). LR: Merlin--rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet doi
  32. (1981). Maintenance of normal blood pressure by the renin-angiotensin system in normal man. Nature doi
  33. (1999). Maximum-likelihood generalized heritability estimate for blood pressure in Nigerian families. Hypertension doi
  34. (1998). Measured haplotype analysis of the angiotensin-I converting enzyme gene. Hum Mol Genet doi
  35. (2005). Mega2: data-handling for facilitating genetic linkage and association analyses. Bioinformatics doi
  36. (2003). Mice lacking endothelial ACE: normal blood pressure with elevated angiotensin II. Hypertension doi
  37. (2002). Mice lacking endothelial angiotensin-converting enzyme have a normal blood pressure. Circ Res doi
  38. (1997). Nonparametric linkage tests are model free. doi
  39. (1992). Numerical comparisons of two formulations of the logistic regressive models with the mixed model in segregation analysis of discrete traits. Genet Epidemiol doi
  40. (1995). of Infarct Survival) Collaborative Group: ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet doi
  41. (1999). Remuzzi G: Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with nonnephrotic proteinuria. Lancet doi
  42. (1983). Rimoin DL: The search for heterogeneity in insulin-dependent diabetes mellitus (IDDM): linkage studies, two-locus models, and genetic heterogeneity.
  43. (1992). Soubrier F: Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels.
  44. (1996). Soubrier F: Identification of new polymorphisms of the angiotensin Iconverting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis.
  45. (1996). Standardization of blood pressure measurement in an international comparative study. doi
  46. (1984). Strategies for multilocus linkage analysis in humans. doi
  47. (1996). The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. doi
  48. (2006). The genetic dissection of essential hypertension. Nat Rev Genet doi
  49. (2000). The Heart Outcomes Prevention Evaluation Study Investigators: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. doi
  50. (1997). The prevalence of hypertension in seven populations of West African origin. doi
  51. (1990). The renin angiotensin aldosterone system for normal regulation of blood pressure and sodium and potassium homeostasis. doi
  52. (1992). The SOLVD Investigators: Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. doi
  53. (2007). The Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. doi
  54. (1996). Thein SL: Dissecting the loci controlling fetal haemoglobin production on chromosomes 11p and 6q by the regressive approach. Nat Genet doi
  55. (1998). Thein SL: Haplotype mapping of a major quantitative-trait locus for fetal hemoglobin production on chromosome 6q23. doi
  56. (1993). Use of the regressive models in linkage analysis of quantitative traits. Genet Epidemiol doi
  57. (1986). White RL: Construction of human linkage maps: likelihood calculations for multilocus linkage analysis. Genet Epidemiol doi

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