The ATF6-Met[67]Val substitution is associated with increased plasma cholesterol levels.
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).


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.
Meex
Steven J R
SJ
Department of Internal Medicine and Cardiovascular Research Institute Maastricht, Wageningen University, The Netherlands. steven.meex@intmed.unimaas.nl
Weissglas-Volkov
Daphna
D
van der Kallen
Carla J H
CJ
Thuerauf
Donna J
DJ
van Greevenbroek
Marleen M J
MM
Schalkwijk
Casper G
CG
Stehouwer
Coen D A
CD
Feskens
Edith J M
EJ
Heldens
Lonneke
L
Ayoubi
Torik A
TA
Hofker
Marten H
MH
Wouters
Bradly G
BG
Vlietinck
Robert
R
Sinsheimer
Janet S
JS
Taskinen
Marja-Riitta
MR
Kuusisto
Johanna
J
Laakso
Markku
M
de Bruin
Tjerk W A
TW
Pajukanta
Päivi
P
Glembotski
Christopher C
CC
D051702:Activating Transcription Factor 6 / Q000097:blood / Q000235:genetics*; D019943:Amino Acid Substitution; D001055:Apolipoproteins B / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics*; D002784:Cholesterol / Q000097:blood*; D015331:Cohort Studies; D000091342:Endoplasmic Reticulum Chaperone BiP; D005387:Finland; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000097:blood / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008715:Methionine; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018570:Risk Assessment; D014162:Transfection; D015854:Up-Regulation; D014633:Valine
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D001055:Apolipoproteins B; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; C053387:endoplasmin; D002784:Cholesterol; D008715:Methionine; D014633:Valine