title: Activating transcription factor 6 (ATF6) sequence polymorphisms in type 2 diabetes and pre-diabetic traits.
abstract: 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.
authors.affiliation: Division of Endocrinology 111J-1/LR, Department of Medicine, University of Arkansas for Medical Sciences, John L. McClellan Memorial Veterans Hospital, 4700 W. 7th Street, Little Rock, AR 72205, USA.
authors.forename: Winston S
authors.initials: WS
authors.lastname: Chu
authors.forename: Swapan Kumar
authors.initials: SK
authors.lastname: Das
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Juliana C
authors.initials: JC
authors.lastname: Chan
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.forename: Coleen
authors.initials: C
authors.lastname: Damcott
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.forename: Steven C
authors.initials: SC
authors.lastname: Elbein
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics*; D001741:Black or African American; D001131:Arkansas; D044466:Asian People; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D007198:Indians, North American; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011236:Prediabetic State / Q000235:genetics*; D014589:Utah; D044465:White People
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6