Aryl hydrocarbon receptor nuclear translocator (ARNT) gene as a positional and functional candidate for type 2 diabetes and prediabetic intermediate traits: Mutation detection, case-control studies, and gene expression analysis.
BACKGROUND
ARNT, a member of the basic helix-loop-helix family of transcription factors, is located on human chromosome 1q21-q24, a region which showed well replicated linkage to type 2 diabetes. We hypothesized that common polymorphisms in the ARNT gene might increase the susceptibility to type 2 diabetes through impaired glucose-stimulated insulin secretion.


METHODS
We selected 9 single nucleotide polymorphisms to tag common variation across the ARNT gene. Additionally we searched for novel variants in functional coding domains in European American and African American samples. Case-control studies were performed in 191 European American individuals with type 2 diabetes and 187 nondiabetic European American control individuals, and in 372 African American individuals with type 2 diabetes and 194 African American control individuals. Metabolic effects of ARNT variants were examined in 122 members of 26 European American families from Utah and in 225 unrelated individuals from Arkansas. Gene expression was tested in 8 sibling pairs discordant for type 2 diabetes.


RESULTS
No nonsynonymous variants or novel polymorphisms were identified. No SNP was associated with type 2 diabetes in either African Americans or European Americans, but among nondiabetic European American individuals, ARNT SNPs rs188970 and rs11204735 were associated with acute insulin response (AIRg; p = or < 0.005). SNP rs2134688 interacted with body mass index to alter beta-cell compensation to insulin resistance (disposition index; p = 0.004). No significant difference in ARNT mRNA levels was observed in transformed lymphocytes from sibling pairs discordant for type 2 diabetes.


CONCLUSIONS
Common ARNT variants are unlikely to explain the linkage signal on chromosome 1q, but may alter insulin secretion in nondiabetic subjects. Our studies cannot exclude a role for rare variants or variants of small (< 1.6) effect size.
Das
Swapan K
SK
Division of Endocrinology and Metabolism, Department of Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. skdas@uams.edu
Sharma
Neeraj K
NK
Chu
Winston S
WS
Wang
Hua
H
Elbein
Steven C
SC
D000328:Adult; D001741:Black or African American; D000368:Aged; D001131:Arkansas; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011236:Prediabetic State / Q000235:genetics*; D017422:Sequence Analysis, DNA; D044465:White People
C497396:ARNT protein, human; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator