Article Text

Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes
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  1. J J McCarthy1,
  2. A Parker2,
  3. R Salem1,
  4. D J Moliterno6,
  5. Q Wang3,
  6. E F Plow3,
  7. S Rao3,
  8. G Shen3,
  9. W J Rogers4,
  10. L K Newby5,
  11. R Cannata3,
  12. K Glatt2,
  13. E J Topol3,
  14. for the GeneQuest Investigators*
  1. 1San Diego State University, San Diego, CA 92182, USA
  2. 2Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA
  3. 3Cleveland Clinic Foundation, Cleveland, OH 44195, USA
  4. 4University of Alabama, Birmingham, AL 35203, USA
  5. 5Duke University, Durham, NC 27708, USA
  6. 6University of Kentucky, Lexington, KY 40536, USA
  1. Correspondence to:
 E J Topol MD
 The Cleveland Clinic Foundation, Department of Cardiovascular Medicine, 9500 Euclid Ave., Desk F-25, Cleveland, Ohio 44195; Topoleccf.org

Abstract

Background: to date, only three groups have reported data from large scale genetic association studies of coronary heart disease using a case control design.

Methods and results: to extend our initial report of 62 genes, we present data for 210 polymorphisms in 111 candidate genes genotyped in 352 white subjects with familial, premature coronary heart disease (onset age for men, 45; for women, 50) and a random sample of 418 population based whites. Multivariate logistic regression analysis was used to compare the distributions of genotypes between cases and the comparison group while controlling for age, sex, body mass, diabetes, and hypertension. Significant associations were found with polymorphisms in thrombospondin-4 (THBS4), thrombospondin-2 (THBS2) and plasminogen activator inhibitor-2 (PAI2), the strongest being with the A387P variant in THBS4 (p = 0.002). The THBS2 and THBS4 associations have since been replicated. We evaluated polymorphisms in 40 genes previously associated with coronary heart disease and found significant (p<0.05) associations with 10: ACE, APOE, F7, FGB, GP1BA, IL1RN, LRP1, MTHFR, SELP, and THPO. For five of these genes, the polymorphism associated in our study was different from that previously reported, suggesting linkage disequilibrium as an explanation for failure to replicate associations consistently across studies. We found strong linkage disequilibrium between polymorphisms within and between genes, especially on chromosome 1q22-q25, a region containing several candidate genes.

Conclusions: despite known caveats of genetic association studies, they can be an effective means of hypothesis generation and complement classic linkage studies for understanding the genetic basis of coronary heart disease.

  • PAI2, plasminogen activator inhibitor-2
  • THBS2, thrombospondin-2
  • THBS4, thrombospondin-4

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Supplementary materials

  • Web-only Table

    Files in this Data Supplement:

    • [View PDF] - Table W1A complete list of the polymorphisms and their flanking sequences

Footnotes

  • * The names of investigators and their institutions are presented in reference 10.

  • Conflicts of interest: none declared.