TY - JOUR
T1 - The ATF6-Met[67]val substitution is associated with increased plasma cholesterol levels
AU - Meex, Steven J.R.
AU - Weissglas-Volkov, Daphna
AU - Van Der Kallen, Carla J.H.
AU - Thuerauf, Donna J.
AU - Van Greevenbroek, Marleen M.J.
AU - Schalkwijk, Casper G.
AU - Stehouwer, Coen D.A.
AU - Feskens, Edith J.M.
AU - Heldens, Lonneke
AU - Ayoubi, Torik A.
AU - Hofker, Marten H.
AU - Wouters, Bradly G.
AU - Vlietinck, Robert
AU - Sinsheimer, Janet S.
AU - Taskinen, Marja Riitta
AU - Kuusisto, Johanna
AU - Laakso, Markku
AU - De Bruin, Tjerk W.A.
AU - Pajukanta, Päivi
AU - Glembotski, Christopher C.
PY - 2009/9
Y1 - 2009/9
N2 - 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.
AB - 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.
KW - Activating transcription factor 6
KW - Association
KW - Cardiovascular risk
KW - Cholesterol
KW - Lipids
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U2 - 10.1161/ATVBAHA.108.180240
DO - 10.1161/ATVBAHA.108.180240
M3 - Article
C2 - 19667116
AN - SCOPUS:69849116067
SN - 1079-5642
VL - 29
SP - 1322
EP - 1327
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 9
ER -