title: 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.
authors.affiliation: Barbara Davis Center for Childhood Diabetes and Human Medical Genetics Program, University Colorado Health Sciences Center, Aurora, CO 80045, USA.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Aly
authors.forename: Akane
authors.initials: A
authors.lastname: Ide
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Jahromi
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Barker
authors.forename: Maria S
authors.initials: MS
authors.lastname: Fernando
authors.forename: Sunanda R
authors.initials: SR
authors.lastname: Babu
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.forename: Dongmei
authors.initials: D
authors.lastname: Miao
authors.forename: Henry A
authors.initials: HA
authors.lastname: Erlich
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Fain
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Barriga
authors.forename: Jill M
authors.initials: JM
authors.lastname: Norris
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Rewers
authors.forename: George S
authors.initials: GS
authors.lastname: Eisenbarth
mesh_terms: 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
chemical_list: D006684:HLA-DR Antigens