Identification of novel non-insulin-dependent diabetes mellitus susceptibility loci in the Otsuka Long-Evans Tokushima fatty rat by MQM-mapping method

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for ob ese-type, non-insulin-dependent diabetes mellitus (NIDDM) in humans. We hav e previously identified 11 quantitative trait loci (QTLs) responsible for N IDDM susceptibility on Chromosomes (Chrs) 1, 5, 7, 8, 9, 11, 12, 14, and 16 (Nidd1-11/of for Non-insulin-dependent diabetes1-11/oletf) by using the in terval mapping method in 160 F-2 progenies obtained by mating the OLETF and the Fischer-344 (F344) rats. MQM-mapping, which was applied for QTL analys is based on multiple-QTL models, is reported to be more powerful than inter val mapping, because in the process of mapping one QTL the genetic backgrou nd, which contains the other QTLs, is controlled. Application of MQM-mappin g in the F-2 intercrosses has led to a revelation of three novel QTLs on ra t Chrs 5 (Nidd12/of), 7 (Nidd13/of), and 17 (Nidd14/of), in addition to Nid d1-11/of loci. The three QTLs, together with the Nidd1-11/of, account for a total of similar to 70% and similar to 85% of the genetic variance of the fasting and postprandial glucose levels, respectively, in the F-2. While th e OLETF allele corresponds with increased glucose levels as expected for Ni dd12 and 14/of, the Nidd13/of exhibits heterosis: heterozygotes showing sig nificantly higher glucose levels than OLETF or F344 homozygotes. There is e pistatic interaction between Nidd2 and 14/of. Additionally, our results ind icated that the novel QTLs could show no linkage with body weight, but Nidd 12/of has an interaction with body weight.