Arteriosclerosis, thrombosis, and vascular biology · 2009
The ATF6-Met[67]Val substitution is associated with increased plasma cholesterol levels.
СтатьяМетаанализПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Meex Steven J R, Weissglas-Volkov Daphna, van der Kallen Carla J H, Thuerauf Donna J, van Greevenbroek Marleen M J, Schalkwijk Casper G, Stehouwer Coen D A, Feskens Edith J M, Heldens Lonneke, Ayoubi Torik A, Hofker Marten H, Wouters Bradly G, Vlietinck Robert, Sinsheimer Janet S, Taskinen Marja-Riitta, Kuusisto Johanna, Laakso Markku, de Bruin Tjerk W A, Pajukanta Päivi, Glembotski Christopher C
Аннотация
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 x 10(-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.
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 x 10(-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.
Предметные рубрики MeSH
Activating Transcription Factor 6Amino Acid SubstitutionApolipoproteins BCardiovascular DiseasesCholesterolCohort StudiesEndoplasmic Reticulum Chaperone BiPFinlandGenetic Predisposition to DiseaseHeLa CellsHeat-Shock ProteinsHumansHyperlipidemia, Familial CombinedMembrane GlycoproteinsMethionineNetherlandsPolymorphism, Single NucleotidePromoter Regions, GeneticRisk AssessmentTransfectionUp-RegulationValine