Early expression and high prevalence of islet autoantibodies for DR3/4 heterozygous and DR4/4 homozygous offspring of parents with Type I diabetes: the German BABYDIAB study.
OBJECTIVE
Islet autoantibodies precede the clinical onset of Type I (insulin-dependent) diabetes mellitus. The cumulative development of such autoantibodies in infants followed from birth and in particular infants with high-risk HLA genotypes is poorly defined, but such information is essential to design trials to prevent islet autoimmunity.


METHODS
HLA genotypes were determined in offspring of parents with Type I diabetes who were followed from birth for at least 2 years (median follow-up: 3.1 years) and who were characterised for the expression of insulin, GAD65, IA-2 and islet cell autoantibodies at birth, 9 months, 2 and 5 years of age.


RESULTS
The HLA genotypes DRB1*03/04(DQB1*57non-Asp) and DRB1*04/04(DQB1*57non-Asp) were present in 7.1% and 5.0% of offspring of parents with Type I diabetes. The frequency of both genotypes was increased in offspring who developed islet autoantibodies within the first 2 years of life (27.3% vs 5.5%, odds ratio 6.3 [p = 0.002] and 22.7% vs 4.2%, odds ratio 6.6 [p = 0.003]) and half of all offspring who developed antibodies had these genotypes. Other genotypes were not associated with an increase in risk. By life-table analysis, the cumulative risk of developing islet autoantibodies by the age of 2 years was 20% (95% CI 9.4,30.6) for offspring carrying either the DRB1*03104(DQB1*57non-Asp) or the DRB1*04/04(DQB1*57non-Asp) genotype compared with 2.7% (95% CI 1.2,4.2) for offspring without these genotypes (p < 0.0001).


CONCLUSIONS
These data show that early appearance of islet autoantibodies is remarkably frequent for DR3/4 heterozygous and DR4/4 homozygous offspring and indicate that primary prevention could be considered once available in an offspring cohort selected for these genotypes.
Schenker
M
M
Third Medical Department, Munich-Schwabing Hospital and Diabetes Research Institute, Germany.
Hummel
M
M
Ferber
K
K
Walter
M
M
Keller
E
E
Albert
E D
ED
Janka
H U
HU
Kastendiek
C
C
Sorger
M
M
Louwen
F
F
Ziegler
A G
AG
D000328:Adult; D001323:Autoantibodies / Q000032:analysis / Q000096:biosynthesis*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000276:immunology; D015803:HLA-DR3 Antigen / Q000235:genetics*; D015804:HLA-DR4 Antigen / Q000235:genetics*; D006579:Heterozygote; D006650:Histocompatibility Testing; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D010375:Pedigree; D011322:Primary Prevention; D011446:Prospective Studies; D012307:Risk Factors
D001323:Autoantibodies; D015803:HLA-DR3 Antigen; D015804:HLA-DR4 Antigen; C024211:islet cell antibody; D005968:Glutamate Decarboxylase