Genetic prediction of autoimmunity: initial oligogenic prediction of anti-islet autoimmunity amongst DR3/DR4-DQ8 relatives of patients with type 1A diabetes.
In this study, the combined risk for expressing anti-islet autoantibodies and type 1A diabetes (T1D) was prospectively examined in 85 sampled relatives who had the high-risk HLA genotype (DR3-DQ8 DR4-DQ2). An insulin gene polymorphism, -23 HphI, and a lymphocyte tyrosine phosphatase gene polymorphism at position 1858C>T (amino acid 620 Arg to Trp), PTPN22/LYP, were analyzed. Life tables were created evaluating time to anti-islet autoantibody development and T1D. Of relatives with the high-risk HLA type followed for 3years, 9 of 43 (28.1%) with the high-risk -23 HphI polymorphism developed anti-islet autoantibodies versus two of 36 (5.6%) relatives with the lower-risk -23 HphI genotypes (p=0.048). Of relatives with the high-risk HLA type followed for 5years, eight of 32 (25.0%) with the high-risk -23 HphI polymorphism (A/A) developed T1D versus zero of 26 (0%) relatives with the lower-risk -23 HphI genotypes (A/T and T/T) (p=0.006). The PTPN22/LYP polymorphism, with genotypes C/C, C/T, and T/T, did not show a significant difference in risk by genotype. These results highlight the multiplicative risk of combined high-risk genotypes at different loci in terms of time to autoantibody and autoimmune disease development.
Aly
Theresa A
TA
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 4200 East 9th Avenue B-140, Denver, CO 80262, USA. theresa.aly@uchsc.edu
Ide
Akane
A
Humphrey
Kurt
K
Barker
Jennifer M
JM
Steck
Andrea
A
Erlich
Henry A
HA
Yu
Liping
L
Miao
Dongmei
D
Redondo
Maria J
MJ
McFann
Kim
K
Roberts
Christine M
CM
Babu
Sunanda R
SR
Norris
Jill M
JM
Eisenbarth
George S
GS
Rewers
Marian J
MJ
D000293:Adolescent; D015551:Autoimmunity / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005192:Family Health; D005820:Genetic Testing; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007515:Islets of Langerhans / Q000276:immunology*; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests
D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens