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Activating Transcription Factor 6 (ATF6) Sequence Polymorphisms in Type 2 Diabetes and Pre-Diabetic Traits

¹ Division of Endocrinology, Department of Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
² Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region (SAR), China
³ Wellcome Trust Sanger Institute, Hinxton, U.K
⁴ Institut de Biologie de Lille, Lille, France
⁵ Faculty of Life Sciences, Imperial College, London, U.K
⁶ Phoenix Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
⁷ Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiaotong University No. 6 People’s Hospital, Shanghai, China
⁸ Oxford Centre for Diabetes, Endocrinology and Metabolism and Wellcome Trust Centre for Human Genetics, University of Oxford, U.K
⁹ Department of Medicine, University of Chicago, Chicago, Illinois
¹⁰ Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland

Address correspondence and reprint requests to Steven C. Elbein, MD, Professor of Medicine, University of Arkansas for Medical Sciences, Endocrinology 111J-1/LR, John L. McClellan Memorial Veterans Hospital, 4700 W. 7th St., Little Rock, AR 72205. E-mail: elbeinstevenc{at}uams.edu

Abbreviations: AIR_g, acute insulin response to glucose; FSIGT, frequently sampled intravenous glucose tolerance test; SNP, single nucleotide polymorphism

Activating transcription factor 6 (ATF6) is located within the region of linkage to type 2 diabetes on chromosome 1q21-q23 and is a key activator of the endoplasmic reticulum stress response. We evaluated 78 single nucleotide polymorphisms (SNPs) spanning >213 kb in 95 people, from which we selected 64 SNPs for evaluation in 191 Caucasian case subjects from Utah and between 165 and 188 control subjects. Six SNPs showed nominal associations with type 2 diabetes (P = 0.001–0.04), including the nonsynonymous SNP rs1058405 (M67V) in exon 3 and rs11579627 in the 3' flanking region. Only rs1159627 remained significant on permutation testing. The associations were not replicated in 353 African-American case subjects and 182 control subjects, nor were ATF6 SNPs associated with altered insulin secretion or insulin sensitivity in nondiabetic Caucasian individuals. No association with type 2 diabetes was found in a subset of 44 SNPs in Caucasian (n = 2,099), Pima Indian (n = 293), and Chinese (n = 287) samples. Allelic expression imbalance was found in transformed lymphocyte cDNA for 3' untranslated region variants, thus suggesting cis-acting regulatory variants. ATF6 does not appear to play a major role in type 2 diabetes, but further work is required to identify the cause of the allelic expression imbalance.

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