Distinguishing covariation from causation in diabetes: a lesson from the protein disulfide isomerase mRNA abundance trait.
Protein disulfide isomerase (Pdi) is reported to be an insulin-regulated gene whose expression level is increased in the livers of rats with streptozotocin-induced diabetes. We found that Pdi mRNA is approximately 20-fold more abundant in the diabetes-susceptible BTBR mouse strain relative to the diabetes-resistant C56BL/6 (B6) strain. A genetic analysis was carried out to determine whether there is a causal relationship between elevated Pdi expression and diabetes phenotype in BTBR-ob/ob mice. We mapped Pdi mRNA abundance as a quantitative trait in 108 (B6 x BTBR)F(2)-ob/ob mice segregating for diabetes. We detected a single linkage at the telomeric end of chromosome 11, where the Pdi gene itself resides (logarithm of odds score >30.0). No linkage was detected for the Pdi mRNA trait in the regions where we have previously identified quantitative trait loci for diabetes traits. Sequencing of the Pdi promoter and cDNA revealed several single nucleotide polymorphisms between these two mouse strains. We conclude that in our experimental model, elevated Pdi expression is cis regulated and is not linked to diabetes susceptibility. Genetic analysis is a powerful tool for distinguishing covariation from causation in expression array studies of disease traits.
Lan
Hong
H
Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.
Rabaglia
Mary E
ME
Schueler
Kathryn L
KL
Mata
Christine
C
Yandell
Brian S
BS
Attie
Alan D
AD
D000818:Animals; D003920:Diabetes Mellitus / Q000201:enzymology / Q000209:etiology* / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D008297:Male; D051379:Mice; D008820:Mice, Obese; D019704:Protein Disulfide-Isomerases / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012333:RNA, Messenger; D019704:Protein Disulfide-Isomerases