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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1322.)
© 2009 American Heart Association, Inc.

National Cholesterol Awareness Month

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

From the Department of Internal Medicine and the Cardiovascular Research Institute Maastricht (S.J.R.M., C.J.H.v.d.K., M.M.J.v.G., C.G.S., C.D.A.S., L.H., T.W.A.d.B.); the Division of Human Nutrition (E.J.M.F.), Wageningen University, The Netherlands; the Departments of Genetics and Cell Biology (T.A.A., R.V.), Molecular Genetics (M.H.H.), and Radiation Oncology and the GROW Research Institute (B.G.W.), Maastricht, the Netherlands; the Division of Signaling Biology (B.G.W.), Ontario Cancer Institute, University Health Network and Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Canada; the Department of Pathology and Laboratory Medicine (M.H.H.), University Medical Center Groningen and University of Groningen, The Netherlands; the Department of Human Genetics (D.W.-V., J.S.S., P.P.), David Geffen School of Medicine at UCLA, Los Angeles, Calif; the Department of Biology and the San Diego State University Heart Institute (D.J.T., C.C.G.), Calif; Helsinki University Central Hospital (M.-R.T.), University of Helsinki, Finland; the Department of Medicine, University of Kuopio and Kuopio University Hospital (J.K., M.L.), Finland.

Correspondence to Dr Steven Meex, Department of Internal Medicine, Division of General Internal Medicine at Maastricht University, PO Box 616, 6200MD Maastricht, The Netherlands. E-mail steven.meex{at}intmed.unimaas.nl

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=9x10^–4), 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.

We report the association of the ATF6-methionine [67]valine amino-acid substitution with plasma cholesterol levels. Association analyses in 2674 subjects and functional data suggest that the ATF6 gene may influence cholesterol levels in subjects at increased risk to develop cardiovascular disease.

Key Words: activating transcription factor 6 • cardiovascular risk • cholesterol • association • lipids