GENETIC DISSECTION OF OLETF, A RAT MODEL FOR NON-INSULIN-DEPENDENT DIABETES-MELLITUS

To elucidate the genetic factors underlying non-insulin-dependent diab etes mellitus (NIDDM), we performed genome-wide quantitative trait loc us (QTL) analysis, using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The OLETF rat is an excellent animal model of NIDDM because the features of the disease closely resemble human NIDDM. Genetic dissecti on with two kinds of F2 intercross progeny, from matings between the O LETF rat and non-diabetic control rats F344 or BN, allowed us to ident ify on Chromosome (Chr) 1 a major QTL associated with features of NIDD M that was common to both crosses. We also mapped two additional signi ficant loci, on Chrs 7 and 14, in the (OLETF x F344)F-2 cross alone, a nd designated these three loci as Diabetes mellitus, OLETF type Dmo 1, Dmo2 and Dmo3 respectively. With regard to suggestive QTLs, we found loci on Chrs 10, 11, and 16 that were common to both crosses, as well as loci on Chrs 5 and 12 in the (OLETF x F344)F-2 cross and on Chrs 4 and 13 in the (OLETF x BN)F-2 cross. Our results showed that NIDDM in the OLETF rat is polygenic and demonstrated that different genetic bac kgrounds could affect ''fitness'' for QTLs and produce different pheno typic effects from the same locus.