This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 92/7/2720    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Meex, S. J. R. Articles by de Bruin, T. W. A. Search for Related Content PubMed PubMed Citation Articles by Meex, S. J. R. Articles by de Bruin, T. W. A. Related Collections Diabetes and Insulin Metabolism

Activating Transcription Factor 6 Polymorphisms and Haplotypes Are Associated with Impaired Glucose Homeostasis and Type 2 Diabetes in Dutch Caucasians

Cardiovascular Research Institute Maastricht, Department of Internal Medicine (S.J.R.M., M.M.J.v.G., V.M.M.-J.V., C.G.S., C.D.A.S., C.J.H.v.d.K., T.W.A.d.B.), Laboratory of Molecular Metabolism and Endocrinology, Department of Population Genetics (T.A.A., R.V.), Genomics and Bio-Informatics, and Department of Molecular Genetics (J.V.v.V.-O., M.H.H.), University of Maastricht, 6200 MD Maastricht, The Netherlands; Department of Human Genetics (R.V.), University of Leuven, Naamsestraat 69-3000 Leuven, Belgium; Department of Pathology and Laboratory Medicine (M.H.H.), University Medical Center Groningen and University of Groningen, 9700 RB Groningen, The Netherlands; Division of Human Nutrition (E.J.M.F.), Section of Nutrition and Epidemiology, Wageningen University, 6701 BH Wageningen, The Netherlands; Centre for Nutrition and Health, National Institute for Public Health and the Environment (J.M.A.B.), 3720 BA Bilthoven, The Netherlands; and GlaxoSmithKline (T.W.A.d.B.), Translational Medicine and Genetics, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Steven Meex, Department of Internal Medicine, Laboratory of Molecular Metabolism and Endocrinology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. E-mail: steven.meex{at}intmed.unimaas.nl.

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 (DM2) was recently reported in Pima Indians.

Objectives: 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.

Design/Setting: A genetic association study was conducted at an academic research laboratory.

Study Participants: 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.

Main Outcome Measures: 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.

This article has been cited by other articles:

				D. Scheuner and R. J. Kaufman The Unfolded Protein Response: A Pathway That Links Insulin Demand with {beta}-Cell Failure and Diabetes Endocr. Rev., May 1, 2008; 29(3): 317 - 333. [Abstract] [Full Text] [PDF]