Context: 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 was recently reported in Pima Indians.

Objective: To investigate the broader significance of this association for type 2 diabetes, replication studies in distinct ethic populations are required. We investigated ATF6 for its association with type 2 diabetes in Dutch Caucasians.

Design: Genetic association study

Setting: Academic research laboratory

Study participants: Two independent Dutch cohorts. 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 type 2 diabetes, impaired glucose tolerance, impaired fasting glucose, and normoglycaemic control subjects and was used to investigate ATF6 polymorphisms for their contribution to disturbed glucose homeostasis and type 2 diabetes.

Main outcome measures: Sixteen tag-SNPs were genotyped in all subjects of both cohorts. Those SNPs 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 type 2 diabetes. (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 type 2 diabetes.