Extreme genetic risk for type 1A diabetes.
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.
Aly
Theresa A
TA
Barbara Davis Center for Childhood Diabetes and Human Medical Genetics Program, University Colorado Health Sciences Center, Aurora, CO 80045, USA.
Ide
Akane
A
Jahromi
Mohamed M
MM
Barker
Jennifer M
JM
Fernando
Maria S
MS
Babu
Sunanda R
SR
Yu
Liping
L
Miao
Dongmei
D
Erlich
Henry A
HA
Fain
Pamela R
PR
Barriga
Katherine J
KJ
Norris
Jill M
JM
Rewers
Marian J
MJ
Eisenbarth
George S
GS
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002896:Chromosomes, Human, Pair 6; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007515:Islets of Langerhans / Q000276:immunology; D010375:Pedigree; D010641:Phenotype; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate
D006684:HLA-DR Antigens