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 of tandem repeats [VNTR]) alleles in the 5' region of the insulin gene are positively associated with IDDM in Caucasians, the majority of Japanese are homozygous for class I alleles. Here, we determined the exact length, in number of repeat units (RUs), of class I alleles in Japanese subjects. The distribution of class I alleles in Japanese was trimodal, with peaks located at 32/33, 41, and 44 RUs. The shortest component (i.e., 1S [25-38 RUs]) alleles were significantly increased in the IDDM group compared with the control group (54 vs. 46%; P = 0.040). The 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 heterozygous 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 of 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 1M or 1L alleles is almost consistently characterized by a sequence variation generated by deletion of two copies of an ACAGGGGTCC CGGGG repeat element, implying that sequence variation of class I alleles may influence disease susceptibility.
Awata
T
T
Fourth Department of Internal Medicine, Saitama Medical School, Japan. awata@saitama-med.ac.jp
Kurihara
S
S
Kikuchi
C
C
Takei
S
S
Inoue
I
I
Ishii
C
C
Takahashi
K
K
Negishi
K
K
Yoshida
Y
Y
Hagura
R
R
Kanazawa
Y
Y
Katayama
S
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000235:genetics*; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D007564:Japan; D008875:Middle Aged; D018598:Minisatellite Repeats; D016133:Polymerase Chain Reaction; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
D007328:Insulin; D007335:Insulin-Like Growth Factor II; D014446:Tyrosine 3-Monooxygenase