Activating transcription factor 6 polymorphisms and haplotypes are associated with impaired glucose homeostasis and type 2 diabetes in Dutch Caucasians.
BACKGROUND
Activating transcription factor 6 (ATF6) is critical for initiation and full activation of the unfolded protein response. An association between genetic variation in ATF6 and type 2 diabetes (DM2) was recently reported in Pima Indians.


OBJECTIVE
To investigate the broader significance of this association for DM2, replication studies in distinct ethic populations are required. We investigated ATF6 for its association with DM2 in Dutch Caucasians.


METHODS
A genetic association study was conducted at an academic research laboratory.


METHODS
Two independent Dutch cohorts were studied. Cohort 1 (n = 154) was used to evaluate genetic variation in the ATF6 gene in relation to glucose homeostasis in the general population. Cohort 2 (n = 798) consisted of patients with DM2, impaired glucose tolerance, impaired fasting glucose, and normoglycemic control subjects, and was used to investigate ATF6 polymorphisms for their contribution to disturbed glucose homeostasis and DM2.


METHODS
There were 16 tag single nucleotide polymorphisms genotyped in all subjects of both cohorts. Those single nucleotide polymorphisms included three nonsynonymous coding variants and captured all common allelic variation of ATF6.


RESULTS
Our data show that common ATF6 variants are associated with elevated glucose levels in the general population (cohort 1, P = 0.005-0.05). Furthermore, the majority of these variants, and haplotypes thereof, were significantly associated with impaired fasting glucose, impaired glucose tolerance, and DM2 (cohort 2, P = 0.006-0.05). Associated variants differ from those identified in Pima Indians.


CONCLUSIONS
Our results strengthen the evidence that one or more variants in ATF6 are associated with disturbed glucose homeostasis and DM2.
Meex
Steven J R
SJ
Cardiovascular Research Institute Maastricht, Department of Internal Medicine, University of Maastricht, 6200 MD Maastricht, The Netherlands. steven.meex@intmed.unimaas.nl
van Greevenbroek
Marleen M J
MM
Ayoubi
Torik A
TA
Vlietinck
Robert
R
van Vliet-Ostaptchouk
Jana V
JV
Hofker
Martin H
MH
Vermeulen
Vicky M M-J
VM
Schalkwijk
Casper G
CG
Feskens
Edith J M
EJ
Boer
Jolanda M A
JM
Stehouwer
Coen D A
CD
van der Kallen
Carla J H
CJ
de Bruin
Tjerk W A
TW
D051702:Activating Transcription Factor 6 / Q000235:genetics*; D000368:Aged; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology* / Q000235:genetics* / Q000378:metabolism; D005215:Fasting; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D018149:Glucose Intolerance / Q000208:ethnology* / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D011110:Polymorphism, Genetic; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D001786:Blood Glucose