Extreme genetic risk for type 1A diabetes

Abstract

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.

Fig. 1.

Haplotype sharing analysis. Haplotype sharing is illustrated in three representative families in which the DR3/4-DQ8 DAISY sibling shares both (family A), one (family B), or no (family C) haplotypes with the diabetic proband.

Fig. 2.

Haplotype sharing survival curves. Shown is progression to anti-islet autoimmunity (A) and type 1A diabetes (B) in DR3/4-DQ8 siblings stratified by the number of HLA haplotypes shared with their proband siblings. n = 48 for A and B; error bars for all panels represent the SEM.

Fig. 3.

Haplotype sharing and insulin genotype survival curves. Shown is progression to anti-islet autoantibody positivity (A) and type 1 diabetes (B) in DR3/4-DQ8 siblings sharing both HLA haplotypes with their sibling probands stratified by genotypes of the insulin gene at the HphI polymorphism. The survival curves represent the high-risk genotypes (AA; n = 13) versus the lower-risk genotypes (AT, TT; n = 14). Error bars represent the SEM.