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Human Molecular Genetics Advance Access published online on September 9, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg314
© 2003 by Oxford University Press
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©2003 Oxford University Press

Article

Association of Extreme Blood Lipid Profile Phenotypic Variation with 11 Reverse Cholesterol Transport Genes and 10 Nongenetic Cardiovascular Disease Risk Factors

Alfredo Morabia 1*, Eftihia Cayanis 2, Michael C. Costanza 1, Barbara M Ross 2, Maria Sol Flaherty 2, Gabriela B. Alvin 2, Kamna Das 2, and T. Conrad Gilliam 2

1 Division of Clinical Epidemiology, Geneva University Hospitals, 25 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland
2 Columbia Genome Center; and Departments of Genetics & Development, and Psychiatry, Columbia University, 1150 St. Nicholas Avenue, New York NY 10032, USA

* To whom correspondence should be addressed. E-mail: Alfredo.Morabia{at}hcuge.ch.


  Abstract

This study explored the genetic basis of the combination of extreme blood levels of HDL-C and LDL-C, a well-studied endophenotype for CVD, which has several attractive features as a target for genetic analysis: 1) the trait is moderately heritable; 2) nongenetic risk factors account for a significant but still limited portion of the phenotypic variance; 3) it is known to be moderated by number of gene products. We exhaustively surveyed 11 candidate genes for allelic variation in a random population-based sample characterized for known CVD risk factors and blood lipid profiles. With the goal of generating specific etiological hypotheses, we compared two groups of subjects with extreme lipid phenotypes, from the same source population, using a case-control design. Cases (n = 186) were subjects, within the total sample of 1708 people, who scored in the upper tertile of LDL-C and the lowest tertile of HDL-C, while controls (n = 185) scored in the lowest tertile of LDL-C and the upper tertile of HDL-C. We used logistic regression and a four-tiered, systematic model building strategy with internal cross-validation and bootstrapping to investigate the relationships between the trait and 275 genetic-variants in the presence of 10 nongenetic risk factors. Our results implicate a subset of nine genetic variants, spanning 7 candidate genes, together with five environmental risk factors in the etiology of extreme lipoprotein phenotypes. We propose a model involving these 14 genetic and nongenetic risk factors for evaluation in future independent studies.


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