Next generation sequencing reveals the association of DRB3*02:02 with type 1 diabetes.
Diabetes
; 62(7): 2618-22, 2013 Jul.
Article
en En
| MEDLINE
| ID: mdl-23462545
ABSTRACT
The primary associations of the HLA class II genes, HLA-DRB1 and HLA-DQB1, and the class I genes, HLA-A and HLA-B, with type 1 diabetes (T1D) are well established. However, the role of polymorphism at the HLA-DRB3, HLA-DRB4, and HLA-DRB5 loci remains unclear. In two separate studies, one of 500 subjects and 500 control subjects and one of 366 DRB1*0301-positive samples from selected multiplex T1D families, we used Roche 454 sequencing with Conexio Genomics ASSIGN ATF 454 HLA genotyping software analysis to analyze sequence variation at these three HLA-DRB loci. Association analyses were performed on the two HLA-DRB loci haplotypes (DRB1-DRB3, -DRB4, or -DRB5). Three common HLA-DRB3 alleles (*0101, *0202, *0301) were observed. DRB1*0301 haplotypes carrying DRB3*0202 conferred a higher T1D risk than did DRB1*0301 haplotypes carrying DRB3*0101 in DRB1*0301/*0301 homozygotes with two DRB3*0101 alleles (odds ratio [OR] 3.4 [95% CI 1.46-8.09]), compared with those carrying one or two DRB3*0202 alleles (OR 25.5 [3.43-189.2]) (P = 0.033). For DRB1*0301/*0401 heterozygotes, however, the HLA-DRB3 allele did not significantly modify the T1D risk of the DRB1*0301 haplotype (OR 7.7 for *0202; 6.8 for *0101). These observations were confirmed by sequence analysis of HLA-DRB3 exon 2 in a targeted replication study of 281 informative T1D family members and 86 affected family-based association control (AFBAC) haplotypes. The frequency of DRB3*0202 was 42.9% in the DRB1*0301/*0301 patients and 27.6% in the DRB1*0301/*04 (P = 0.005) compared with 22.6% in AFBAC DRB1*0301 chromosomes (P = 0.001). Analysis of T1D-associated alleles at other HLA loci (HLA-A, HLA-B, and HLA-DPB1) on DRB1*0301 haplotypes suggests that DRB3*0202 on the DRB1*0301 haplotype can contribute to T1D risk.
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Banco de datos:
MEDLINE
Asunto principal:
Polimorfismo Genético
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Predisposición Genética a la Enfermedad
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Diabetes Mellitus Tipo 1
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Cadenas HLA-DRB3
Tipo de estudio:
Risk_factors_studies
Límite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Diabetes
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos