Two single nucleotide polymorphisms identify the highest-risk diabetes HLA genotype: potential for rapid screening.
OBJECTIVE
People with the HLA genotype DRB1*0301-DQA1*0501-DQB1*0201/DRB1*04-DQA1*0301-DQB1*0302 (DR3/4-DQ8) are at the highest risk of developing type 1 diabetes. We sought to find an inexpensive, rapid test to identify DR3/4-DQ8 subjects using two single nucleotide polymorphisms (SNPs).


METHODS
SNPs rs2040410 and rs7454108 were associated with DR3-DQB1*0201 and DR4-DQB1*0302. We correlated these SNPs with HLA genotypes and with publicly available data on 5,019 subjects from the Type 1 Diabetes Genetic Consortium (T1DGC). Additionally, we analyzed these SNPs in samples from 143 HLA-typed children who participated in the Diabetes Autoimmunity Study of the Young (DAISY) using Taqman probes (rs7454108) and restriction digest analysis (rs2040410).


RESULTS
With a simple combinatorial rule, the SNPs of interest identified the presence or absence of the DR3/4-DQ8 genotype. A wide variety of genotypes were tested for both SNPs. In T1DGC samples, the two SNPs were 98.5% (1,173 of 1,191) sensitive and 99.7% (3,815 of 3,828) specific for DR3/4-DQ8. In the DAISY population, the test was 100% (69 of 69) sensitive and 100% (74 of 74) specific. Overall, the sensitivity and specificity for the test were 98.57 and 99.67%, respectively.


CONCLUSIONS
A two-SNP screening test can identify the highest risk heterozygous genotype for type 1 diabetes in a time- and cost-effective manner.
Barker
Jennifer M
JM
Barbara Davis Center for Childhood Diabetes, University of Coloradoat Denver, Colorado, USA. jennifer.barker@uchsc.edu
Triolo
Taylor M
TM
Aly
Theresa A
TA
Baschal
Erin E
EE
Babu
Sunanda R
SR
Kretowski
Adam
A
Rewers
Marian J
MJ
Eisenbarth
George S
GS
D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D006681:HLA-D Antigens / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D006681:HLA-D Antigens; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens