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BIOLOGICAL SCIENCES / GENETICS
Extreme genetic risk for type 1A diabetes
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Barbara Davis Center for Childhood Diabetes and Human Medical Genetics Program, University Colorado Health Sciences Center, Aurora, CO 80045; Roche Molecular Systems, Alameda, CA 94501; and ¶Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262
Communicated by David W. Talmage, University of Colorado Health Sciences Center, Denver, CO, July 31, 2006 (received for review May 15, 2006)
Type 1A diabetes (T1D) is an autoimmune disorder the risk of which is increased by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. The genotype associated with the highest risk for T1D is the DR3/4-DQ8 (DQ8 is DQA1*0301, DQB1*0302) heterozygous genotype. We determined HLA-DR and -DQ genotypes at birth and analyzed DR3/4-DQ8 siblings of patients with T1D for identical-by-descent HLA haplotype sharing (the number of haplotypes inherited in common between siblings). The children were clinically followed with prospective measurement of anti-islet autoimmunity and for progression to T1D. Risk for islet autoimmunity dramatically increased in DR3/4-DQ8 siblings who shared both HLA haplotypes with their diabetic proband sibling (63% by age 7, and 85% by age 15) compared with siblings who did not share both HLA haplotypes with their diabetic proband sibling (20% by age 15, P < 0.01). 55% sharing both HLA haplotypes developed diabetes by age 12 versus 5% sharing zero or one haplotype (P = 0.03). Despite sharing both HLA haplotypes with their proband, siblings without the HLA DR3/4-DQ8 genotype had only a 25% risk for T1D by age 12. The risk for T1D in the DR3/4-DQ8 siblings sharing both HLA haplotypes with their proband is remarkable for a complex genetic disorder and provides evidence that T1D is inherited with HLA-DR/DQ alleles and additional MHC-linked genes both determining major risk. A subset of siblings at extremely high risk for T1D can now be identified at birth for trials to prevent islet autoimmunity.
haplotype | human leukocyte antigen | major histocompatibility complex
Author contributions: T.A.A., A.I., M.M.J., K.J.B., J.M.N., M.J.R., and G.S.E. designed research; T.A.A., A.I., M.M.J., M.S.F., S.R.B., L.Y., and D.M. performed research; T.A.A., A.I., M.M.J., J.M.B., M.S.F., S.R.B., P.R.F., and G.S.E. analyzed data; H.A.E. contributed new reagents/analytic tools; K.J.B. database preparation and management; and T.A.A. and G.S.E. wrote the paper.
The authors declare no conflict of interest.
||To whom correspondence should be addressed. E-mail: george.eisenbarth{at}uchsc.edu
© 2006 by The National Academy of Sciences of the USA
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