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.
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.
Authors: Sekar Kathiresan; Cristen J Willer; Gina M Peloso; Serkalem Demissie; Kiran Musunuru; Eric E Schadt; Lee Kaplan; Derrick Bennett; Yun Li; Toshiko Tanaka; Benjamin F Voight; Lori L Bonnycastle; Anne U Jackson; Gabriel Crawford; Aarti Surti; Candace Guiducci; Noel P Burtt; Sarah Parish; Robert Clarke; Diana Zelenika; Kari A Kubalanza; Mario A Morken; Laura J Scott; Heather M Stringham; Pilar Galan; Amy J Swift; Johanna Kuusisto; Richard N Bergman; Jouko Sundvall; Markku Laakso; Luigi Ferrucci; Paul Scheet; Serena Sanna; Manuela Uda; Qiong Yang; Kathryn L Lunetta; Josée Dupuis; Paul I W de Bakker; Christopher J O'Donnell; John C Chambers; Jaspal S Kooner; Serge Hercberg; Pierre Meneton; Edward G Lakatta; Angelo Scuteri; David Schlessinger; Jaakko Tuomilehto; Francis S Collins; Leif Groop; David Altshuler; Rory Collins; G Mark Lathrop; Olle Melander; Veikko Salomaa; Leena Peltonen; Marju Orho-Melander; Jose M Ordovas; Michael Boehnke; Gonçalo R Abecasis; Karen L Mohlke; L Adrienne Cupples Journal: Nat Genet Date: 2008-12-07 Impact factor: 38.330
Authors: Martijn C G J Brouwers; Marleen M J van Greevenbroek; Coen D A Stehouwer; Jacqueline de Graaf; Anton F H Stalenhoef Journal: Nat Rev Endocrinol Date: 2012-02-14 Impact factor: 43.330
Authors: Eun-Jin Lee; Wei-Chieh Jerry Chiang; Heike Kroeger; Chloe Xiaoke Bi; Daniel L Chao; Dorota Skowronska-Krawczyk; Rebecca R Mastey; Stephen H Tsang; Leon Chea; Kyle Kim; Scott R Lambert; Julia Md Grandjean; Britta Baumann; Isabelle Audo; Susanne Kohl; Anthony T Moore; R Luke Wiseman; Joseph Carroll; Jonathan H Lin Journal: JCI Insight Date: 2020-04-09
Authors: Karina Meidtner; Eva Fisher; Lars Angquist; Claus Holst; Karani S Vimaleswaran; Jolanda M A Boer; Jytte Halkjær; Giovanna Masala; Jane N Ostergaard; Lotte M Mortensen; Daphne L van der A; Anne Tjønneland; Domenico Palli; Kim Overvad; Nicholas J Wareham; Ruth J F Loos; Thorkild I A Sørensen; Heiner Boeing Journal: Genes Nutr Date: 2014-02-05 Impact factor: 5.523