Homozygosity for premature stop codon of the MHC class I chain-related gene A (MIC-A) is associated with early activation of islet autoimmunity of DR3/4-DQ2/8 high risk DAISY relatives.
We hypothesized that homozygosity for the major histocompatibility complex (MHC) class I chain-related gene A (MIC-A)5.1 allele with premature stop codon would increase diabetes risk of individuals followed from infancy in the DAISY study (Diabetes Autoimmunity Study in the young). Forty five percent (10/22) of relatives (siblings and offspring cohort, SOC) who developed anti-islet autoantibodies were MIC-A5.1/5.1 homozygous. Of SOC individuals without autoantibodies, 12/58 (19%, p = 0.02) were MIC-A5.1 homozygous. By life table analysis of expression of autoantibodies, DR3-DQ2/ DR4-DQ8 more than 50% of MIC-A5.1 homozygous children became autoantibody positive by 7 years of age, compared to delayed development of autoantibodies for non-MIC-A5.1/5.1 DR3-DQ2/ DR4-DQ8 children (p = 0.005). For DR3-DQ2/DR4-DQ8 nonrelatives, the risk of activating anti-islet autoimmunity remained low even with MIC-A5.1 homozygosity suggesting that there are additional factors contributing to the marked risk of relatives compared to the general population with the DR3-DQ2/DR4-DQ8 genotype.
Ide
Akane
A
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 1775 N Ursula Street, Aurora, Colorado, 80010, USA.
Babu
Sunanda R
SR
Robles
David T
DT
Wang
Tianbao
T
Erlich
Henry A
HA
Bugawan
Teodorica L
TL
Rewers
Marian
M
Fain
Pamela R
PR
Eisenbarth
George S
GS
D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000276:immunology*; D018388:Codon, Terminator / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D015803:HLA-DR3 Antigen / Q000235:genetics / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011446:Prospective Studies; D012307:Risk Factors; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D001323:Autoantibodies; D018389:Codon, Nonsense; D018388:Codon, Terminator; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; D015803:HLA-DR3 Antigen; D015804:HLA-DR4 Antigen; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A