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Evidence of linkage of HDL level variation to APOC3 in two samples with different ascertainment

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Abstract

The APOA1-C3-A4-A5 gene complex encodes genes whose products are implicated in the metabolism of HDL and/or triglycerides. Although the relationship between polymorphisms in this gene cluster and dyslipidemias was first reported more than 15 years ago, association and linkage results have remained inconclusive. This is due, in part, to the oligogenic and multivariate nature of dyslipidemic phenotypes. Therefore, we investigate evidence of linkage of APOC3 and HDL using two samples of dyslipidemic pedigrees: familial combined hyperlipidemia (FCHL) and isolated low-HDL (ILHDL). We used a strategy that deals with several difficulties inherent in the study of complex traits: by using a Bayesian Markov Chain Monte Carlo (MCMC) approach we allow for oligogenic trait models, as well as simultaneous incorporation of covariates, in the context of multipoint analysis. By using this approach on extended pedigrees we provide evidence of linkage of APOC3 and HDL level variation in two samples with different ascertainment. In addition to APOC3, we estimate that two to three genes, each with a substantial effect on total variance, are responsible for HDL variation in both data sets. We also provide evidence, using the FCHL data set, for a pleiotropic effect between HDL, HDL3 and triglycerides at the APOC3 locus.

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Acknowledgements

We are thankful to the families for their participation in the study. We are grateful for the meticulous technical assistance of Andy Louie. Computer support was provided by Hiep D. Nguyen. The database was constructed and maintained by Ted Holzman. Genotyping for the FCHL pedigrees was provided by the NHLBI mammalian genotyping service. Supported by National Institute of Health grant HL30086 and GM46255. F. Gagnon was the recipient of a postdoctoral fellowship from the Canadian Institutes of Health Research (CIHR — formally MRC Canada). G. Jarvik was a Pew Biomedical Scholar during the analysis of these data.

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Authors and Affiliations

  1. Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada

    France Gagnon

  2. Division of Medical Genetics, Department of Medicine, University of Washington, Box 357720, Seattle, WA, 98195-7720, USA

    France Gagnon, Gail P. Jarvik, Arno G. Motulsky, Samir S. Deeb & Ellen M. Wijsman

  3. Department of Genome Sciences, University of Washington, Seattle, Washington, USA

    Gail P. Jarvik, Arno G. Motulsky, Samir S. Deeb & Ellen M. Wijsman

  4. Division of Metabolism and Endocrinology, Department of Medicine, University of Washington, Seattle, Washington, USA

    John D. Brunzell

  5. Department of Biostatistics, University of Washington, Seattle, Washington, USA

    Ellen M. Wijsman

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  1. France Gagnon
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  2. Gail P. Jarvik
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  3. Arno G. Motulsky
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  4. Samir S. Deeb
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  5. John D. Brunzell
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  6. Ellen M. Wijsman
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Correspondence to Ellen M. Wijsman.

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Gagnon, F., Jarvik, G.P., Motulsky, A.G. et al. Evidence of linkage of HDL level variation to APOC3 in two samples with different ascertainment. Hum Genet 113, 522–533 (2003). https://doi.org/10.1007/s00439-003-1006-5

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  • DOI: https://doi.org/10.1007/s00439-003-1006-5

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