EVIDENCE FOR ASSOCIATION BETWEEN THE CLASS-I SUBSET OF THE INSULIN GENE MINISATELLITE (IDDM2 LOCUS) AND IDDM IN THE JAPANESE POPULATION

Although the shortest (class I) minisatellite (i.e., variable number o f tandem repeats [VNTR]) alleles in the 5' region of the insulin gene are positively associated with IDDM in Caucasians, the majority of Jap anese are homozygous for class I alleles. Here, we determined the exac t length, in number of repeat units (RUs), of class I alleles in Japan ese subjects. The distribution of class I alleles in Japanese was trim odal, with peaks located at 32/33, 41, and 44 RUs. The shortest compon ent (i.e., IS [25-38 RUs]) alleles were significantly increased in the IDDM group compared with the control group (54 vs. 46%; P = 0.040). T he 1S/1S genotype was significantly increased in the IDDM patients (34 vs. 20%; P = 0.005; relative risk 2.1). Furthermore, the transmission disequilibrium test of Japanese families with 1S/1M or 1S/1L heterozy gous parents confirmed the association of 1S alleles: 17 alleles of 1S and 6 alleles of 1M (39-41 RUs) or 1L (42-44 RUs) were transmitted to affected offspring (P = 0.022). In addition, we found tight linkage o f 1S with allele 9 of the tyrosine hydroxylase gene microsatellite and allele (-) of the IGF-II gene Apa I polymorphism, but neither 9 nor ( -) alleles were significantly associated with IDDM. The present study suggests that a class I subset may have a role in IDDM susceptibility in Japan. It was revealed that the difference between 1S alleles and 1 M or 1L alleles is almost consistently characterized by a sequence var iation generated by deletion of two copies of an ACAGGGGTCC CGGGG repe at element, implying that sequence variation of class I alleles may in fluence disease susceptibility.