HLA-DQB1 genotypes and islet cell antibodies in the identification of siblings at risk for insulin-dependent diabetes (IDDM) in Finland. Childhood Diabetes in Finland (DiMe) Study Group.
The risk of progression to IDDM can be evaluated by diabetes-related autoantibodies such as cytoplasmic islet cell antibodies (ICA) or genetic determinants as markers. In this prospective study we wanted to estimate the predictive value of the combination of these markers in siblings of diabetic children. A sample of 770 siblings was observed from the time of diagnosis in the index case for a median period of 5.8 years (range 0.01-7.3 years) for development of ICA and insulin autoantibodies (IAA) and progression to clinical diabetes. The most important susceptibility and protection associated DQB1 alleles were defined by four sequence-specific oligonucleotide probes. DNA samples were available from 89 originally non-diabetic ICA positive siblings of whom 28 presented with IDDM during the study period, as well 100 randomly chosen ICA negative control siblings. More than half (11/28; 55%) of the siblings who had the high risk DQB1 genotypes progressed to clinical IDDM compared to 6/37 (16%) of those who had protective/neutral genotypes (P = 0.006). Of all genotyped secondary cases, 36% (n = 33) had a genotype associated with the highest risk (DQB1*0302/0201), whereas 27% had genotypes without any susceptibility alleles (P values < 0.0001 and = 0.0002, respectively, compared with ICA negative siblings). The results demonstrate the feasibility of the combination of genetic and immunological markers in the prediction of the risk for IDDM within families.
Department of Virology, University of Turku, Finland.
H
H
Reijonen
P
P
Vähäsalo
J
J
Karjalainen
J
J
Ilonen
H K
HK
Akerblom
M
M
Knip
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001323:Autoantibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D018450:Disease Progression; D004198:Disease Susceptibility / Q000276:immunology; D005387:Finland / Q000453:epidemiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007223:Infant; D007515:Islets of Langerhans / Q000276:immunology*; D009679:Nuclear Family; D015345:Oligonucleotide Probes; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology; D011237:Predictive Value of Tests; D015995:Prevalence; D011446:Prospective Studies; D012306:Risk
D001323:Autoantibodies; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D015345:Oligonucleotide Probes