TRINUCLEOTIDE REPEATS AT THE RAD LOCUS - ALLELE DISTRIBUTIONS IN NIDDM AND MAPPING TO A 3-CM REGION ON CHROMOSOME 16Q

A 10-allele polymorphism was identified in rad (ras associated with di abetes), a gene that is overexpressed in non-insulin-dependent diabete s mellitus (NIDDM) muscle. The polymorphism, designated RAD1, consists of a variable number of trinucleotide repeats (GTT and ATT) located i n the poly(A) region of an intronic Alu sequence. Based on the number of GTT and ATT repetitions, the alleles can be grouped into four class es (III). RAD1 allele frequencies were determined in 210 NIDDM patient s and 133 nondiabetic control subjects, all Caucasians, One allele (nu mber 8, class III) accounted for >80% of the chromosomes in both group s. However, an excess of minor alleles, all belonging to class I, II, or TV, was observed among NIDDM chromosomes (P < 0.025), suggesting a possible association between RAD1 and NIDDM predisposition. To promote further studies to test the hypothesis that genetic variability at th e rad locus contributes to NIDDM, we mapped rad on the human genome. U sing the fluorescence in situ chromosomal hybridization technique, rad was unequivocally assigned to chromosomal band 16q22. In families tha t were informative for RAD1, the rad locus was mapped within a 3-cM re gion defined by the markers D16S265, D16S186, and D16S397 (logarithm o f odds scores = 10.08, 10.9, and 10.84 at recombination fractions of 0 .024, 0.001, and 0.03, respectively). The high degree of heterozygosit y of these markers mill allow large-scale family studies to be perform ed to test the presence of linkage between rad and NIDDM.