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DOI: 10.2337/diabetes.55.03.06.db05-1002
© 2006 by the American Diabetes Association
Brief Genetics Reports |
Association of Amino Acid Variants in the Activating Transcription Factor 6 Gene (ATF6) on 1q21-q23 With Type 2 Diabetes in Pima Indians
1 Clinical Diabetes and Nutrition Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
2 Department of Medicine, Division of Nephrology, University of Texas Health Science Center at San Antonio, San Antonio, Texas
3 Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas
Address correspondence to Michal Prochazka, MD, Diabetes Molecular Genetics Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 N. 5th St., Suite 210, Phoenix, AZ 85004. E-mail: mprochazka{at}phx.niddk.nih.gov
Abbreviations:
ATF6, activating transcription factor 6; LOD, logarithm of odds; SNP, single nucleotide polymorphism
Activating transcription factor 6 (ATF6) is important for protective cell response to accumulation of unfolded and misfolded proteins in endoplasmic reticulum, and disturbances of this process can contribute to ß-cell apoptosis. We analyzed the structural gene located within a region on 1q21-q23 linked with type 2 diabetes in several populations for variants in the Pima Indians. Functionally important segments of ATF6 were sequenced in 15 diabetic and 15 nondiabetic Pimas and representative single nucleotide polymorphisms (SNPs) tested for association with type 2 diabetes in 900–1,000 subjects. We identified 20 variants including three amino acid substitutions [Met(67)Val, Pro(145)Ala, and Ser(157)Pro]. Pro(145)Ala and Ser(157)Pro were in a complete linkage disequilibrium and showed a nominal association with type 2 diabetes (P = 0.05; odds ratio 2.3 [95% CI 1.0–5.2]) and with 30-min plasma insulin during oral glucose tolerance test in 287 nondiabetic individuals (P = 0.045). Although the associations with type 2 diabetes and plasma insulin levels are marginal and their functional consequences are yet unknown, all three amino acid substitutions are located in a functionally important part of ATF6. Because these variants are not unique to the Pimas, it will be feasible to investigate their association with type 2 diabetes in other populations to better evaluate their significance for a predisposition to the disease.
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