Expression analysis of loci associated with type 2 diabetes in human tissues.
OBJECTIVE
Genetic mapping has identified over 20 loci contributing to genetic risk of type 2 diabetes. The next step is to identify the genes and mechanisms regulating the contributions of genetic risk to disease. The goal of this study was to evaluate the effect of age, height, weight and risk alleles on expression of candidate genes in diabetes-associated regions in three relevant human tissues.


METHODS
We measured transcript abundance for WFS1, KCNJ11, TCF2 (also known as HNF1B), PPARG, HHEX, IDE, CDKAL1, CDKN2A, CDKN2B, IGF2BP2, SLC30A8 and TCF7L2 by quantitative RT-PCR in human pancreas (n = 50), colon (n = 195) and liver (n = 50). Tissue samples were genotyped for single nucleotide polymorphisms (SNPs) associated with type 2 diabetes. The effects of age, height, weight, tissue and SNP on RNA expression were tested by linear modelling.


RESULTS
Expression of all genes exhibited tissue bias. Immunohistochemistry confirmed the findings for HHEX, IDE and SLC30A8, which showed strongest tissue-specific mRNA expression bias. Neither age, height nor weight were associated with gene expression. We found no evidence that type 2 diabetes-associated SNPs affect neighbouring gene expression (cis-expression quantitative trait loci) in colon, pancreas and liver.


CONCLUSIONS
This study provides new evidence that tissue-type, but not age, height, weight or SNPs in or near candidate genes associated with increased risk of type 2 diabetes are strong contributors to differential gene expression in the genes and tissues examined.
Cotsapas
C
C
Broad Institute, Cambridge, MA, USA.
Prokunina-Olsson
L
L
Welch
C
C
Saxena
R
R
Weaver
C
C
Usher
N
N
Guiducci
C
C
Bonakdar
S
S
Turner
N
N
LaCroix
B
B
Hall
J L
JL
D000328:Adult; D000368:Aged; D001827:Body Height; D001835:Body Weight; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007339:Insulysin / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases; D000099161:Kcnj11 Channel
D027682:Cation Transport Proteins; D051360:Cyclin-Dependent Kinase 5; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051539:Hepatocyte Nuclear Factor 1-beta; D018398:Homeodomain Proteins; D007339:Insulysin; D008565:Membrane Proteins; D047495:PPAR gamma; D024661:Potassium Channels, Inwardly Rectifying; D016601:RNA-Binding Proteins; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases; D000099161:Kcnj11 Channel; C493966:CDKN2B protein, human; C078492:HHEX protein, human; C496495:HNF1B protein, human; C498779:IGF2BP2 protein, human; C492522:SLC30A8 protein, human; C544894:TCF7L2 protein, human; C114987:wolframin protein; C525110:CDKAL1 protein, human