Specific human leukocyte antigen DQ influence on expression of antiislet autoantibodies and progression to type 1 diabetes.
BACKGROUND
Human leukocyte antigen (HLA) DQ haplotypes have the strongest genetic association with type 1 diabetes (T1DM) risk.


OBJECTIVE
The objective of the study was to analyze whether HLA DQ alleles influence the development of antiislet autoantibodies, the progression to T1DM among autoantibody-positive relatives, or both.


METHODS
The Diabetes Prevention Trial-1 screened more than 90,000 nondiabetic relatives of patients for cytoplasmic islet-cell autoantibody (ICA) expression between 1994 and 2002.


METHODS
The study was conducted in the general community.


METHODS
The Diabetes Prevention Trial-1 found 2817 ICA-positive relatives who were tested for biochemical autoantibodies (GAD65, ICA512, and insulin) and HLA-DQ haplotypes, and 2796 of them were followed up for progression to diabetes for up to 8 yr (median, 3.6 yr).


METHODS
Progression to T1DM was measured.


RESULTS
High-risk DQ haplotypes and genotypes were associated with a higher percentage of relatives expressing multiple biochemical autoantibodies and higher T1DM risk (e.g., respectively, 59 and 36% at 5 yr for carriers of the DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 genotype). The number of autoantibodies expressed significantly increased T1DM risk and across different DQ genotypes, autoantibody positivity directly correlated with diabetes risk. However, multivariate analyses indicated that the influence of most genotypes on T1DM risk was not independent from autoantibody expression, with the possible exception of DQA1*0102-DQB1*0602. Specific genotypic combinations conferred 5-yr diabetes risks significantly lower (e.g. 7%-DQA1*0201-DQB1*0201/DQA1*0501-DQB1*0201 and 14%-DQA1*0301-DQB1*0301/DQA1*0501-DQB1*0201) than when those haplotypes were found in other combinations.


CONCLUSIONS
HLA DQ alleles determine autoantibody expression, which is correlated with diabetes progression. Among autoantibody-positive relatives, most HLA DQ genotypes did not further influence T1DM risk.
Redondo
Maria J
MJ
Department of Endocrinology, University Clinic of Navarra, 31008 Pamplona, Spain.
Babu
Sunanda
S
Zeidler
Adina
A
Orban
Tihamer
T
Yu
Liping
L
Greenbaum
Carla
C
Palmer
Jerry P
JP
Cuthbertson
David
D
Eisenbarth
George S
GS
Krischer
Jeffrey P
JP
Schatz
Desmond
D
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001323:Autoantibodies / Q000096:biosynthesis*; D002648:Child; D002675:Child, Preschool; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology*; D015993:Life Tables; D008297:Male; D016019:Survival Analysis
D001323:Autoantibodies; D006683:HLA-DQ Antigens