Life table analysis of the risk of type 1 (insulin-dependent) diabetes mellitus in siblings according to islet cell antibodies and HLA markers. An 8-year prospective study.
To determine whether genetic markers can improve the predictive value of islet cell antibodies for development of Type 1 (insulin-dependent) diabetes mellitus, 536 siblings aged 2-29 years were consecutively enrolled in a 8-year prospective survey. The risk of developing diabetes was estimated, using life-table methods, by years of follow-up and age, according to genetic factors (shared HLA-haplotypes, DR antigens, C4 allotypes) and islet cell antibody status. Fifteen siblings (2.8%) developed Type 1 diabetes during the study period (risk 4.4% after 8 years, 4% by age 22 years). DR3,4 heterozygosity identified higher risk (16% after 8 years, 12% by age 22 years, p less than 10(-5)) than HLA-identity (10% and 7%, respectively, p less than 0.01); risks for DR3 or DR4 positive and for haplo-identical siblings were low (4%, 3% and 4.4%, respectively, NS). C4BQO also conferred significant risk (11% vs 3% in non-C4BQO siblings, p less than 0.01). The predictive value of genetic markers alone was poor (12% for DR3,4, 7% for HLA-identity, 9% for C4BQO) compared with that of islet cell antibody levels greater than 4 Juvenile Diabetes Foundation units (41%, risk 56% after 8 years, p less than 10(-7)). HLA markers significantly contributed to risk prediction in combination with islet cell antibodies: islet cell antibody-positive DR3,4+ subjects had the highest risk (70% after 8 years, predictive value 58%, p less than 10(-7)) compared with islet cell antibody-positive DR3,4- (37% and 20%, respectively) and islet cell antibody-negative DR3,4+ (5% and 3.6%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Deschamps
I
I
Department of Pediatric Endocrinology and Diabetes, INSERM U30, Paris, France.
Boitard
C
C
Hors
J
J
Busson
M
M
Marcelli-Barge
A
A
Mogenet
A
A
Robert
J J
JJ
D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D015935:Complement C4b / Q000032:analysis / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005602:France / Q000453:epidemiology; D006680:HLA Antigens / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D015803:HLA-DR3 Antigen / Q000032:analysis / Q000235:genetics; D015804:HLA-DR4 Antigen / Q000032:analysis / Q000235:genetics; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology; D015993:Life Tables; D008297:Male; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012307:Risk Factors; D012801:Sibling Relations
D001323:Autoantibodies; D015415:Biomarkers; D006680:HLA Antigens; D015803:HLA-DR3 Antigen; D015804:HLA-DR4 Antigen; C024211:islet cell antibody; D015935:Complement C4b