The ATF6-Met[67]val substitution is associated with increased plasma cholesterol levels

Steven J.R. Meex, Daphna Weissglas-Volkov, Carla J.H. Van Der Kallen, Donna J. Thuerauf, Marleen M.J. Van Greevenbroek, Casper G. Schalkwijk, Coen D.A. Stehouwer, Edith J.M. Feskens, Lonneke Heldens, Torik A. Ayoubi, Marten H. Hofker, Bradly G. Wouters, Robert Vlietinck, Janet S. Sinsheimer, Marja Riitta Taskinen, Johanna Kuusisto, Markku Laakso, Tjerk W.A. De Bruin, Päivi Pajukanta, Christopher C. Glembotski

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

OBJECTIVE-: Activating transcription factor 6 (ATF6) is a sensor of the endoplasmic reticulum stress response and regulates expression of several key lipogenic genes. We used a 2-stage design to investigate whether ATF6 polymorphisms are associated with lipids in subjects at increased risk for cardiovascular disease (CVD). METHODS AND RESULTS-: In stage 1, 13 tag-SNPs were tested for association in Dutch samples ascertained for familial combined hyperlipidemia (FCHL) or increased risk for CVD (CVR). In stage 2, we further investigated the SNP with the strongest association from stage 1, a Methionine/Valine substitution at amino-acid 67, in Finnish FCHL families and in subjects with CVR from METSIM, a Finnish population-based cohort. The combined analysis of both stages reached region-wide significance (P=9×10), but this association was not seen in the entire METSIM cohort. Our functional analysis demonstrated that Valine at position 67 augments ATF6 protein and its targets Grp78 and Grp94 as well as increases luciferase expression through Grp78 promoter. CONCLUSIONS-: A common nonsynonymous variant in ATF6 increases ATF6 protein levels and is associated with cholesterol levels in subjects at increased risk for CVD, but this association was not seen in a population-based cohort. Further replication is needed to confirm the role of this variant in lipids.

Original languageEnglish (US)
Pages (from-to)1322-1327
Number of pages6
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume29
Issue number9
DOIs
StatePublished - Sep 2009
Externally publishedYes

Keywords

  • Activating transcription factor 6
  • Association
  • Cardiovascular risk
  • Cholesterol
  • Lipids

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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