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The HLA-DPB1–Associated Component of the IDDM1 and Its Relationship to the Major Loci HLA-DQB1, -DQA1, and -DRB1. Prese

The HLA-DPB1–Associated Component of the IDDM1 and Its Relationship to the Major Loci HLA-DQB1, -DQA1, and -DRB1. Presented by: Asifa Ackbarali.

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The HLA-DPB1–Associated Component of the IDDM1 and Its Relationship to the Major Loci HLA-DQB1, -DQA1, and -DRB1. Prese

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  1. The HLA-DPB1–Associated Component of the IDDM1 and Its Relationship to the Major Loci HLA-DQB1, -DQA1, and -DRB1. Presented by: Asifa Ackbarali F. Cucca, et al. 2001. The HLA-DPB1–Associated Component of the IDDM1 and Its Relationship to the Major Loci HLA-DQB1, -DQA1, and -DRB1. Diabetes 50:1200-1205.

  2. Introduction. • HLA region on chromosome 6p21 contains the major locus of IDDM1. • Allelic variants at class II HLA-DRB1, -DQA1 and –DQB1 loci account for IDDM1. • HLA-DPB1 locus.

  3. Previous Studies. • Positive association of DPB1*0301 allele with Type1 diabetes (from study of 42 Mexican-American families). • Linkage disequilibrium with high risk DR-DQ haplotypes not factored in experiment. • Same in consequent study of 180 white European-derived nuclear families.

  4. Previous Studies (cont’d). • DPB1*0402 allele decreased in DR3 haplotypes of the IDDM patients in the both studies. • DPB1*0301 and DPB1*0202 are primarily predisposing, while DPB1*0402 and DPB1*0401 have protective effects. • Main conclusion: DPB1 contributes susceptibility to, rather than protection from Type 1 diabetes.

  5. Goal. • To directly compare the effect of DPB1 variation on the relative predisposition of DR-DQ haplotypes taking into account linkage disequilibrium between DPB1 and the DRB1, DQA1 and DQB1 loci.

  6. The Experiment. • Utilization of a combination of association tests. • 408 Type 1 diabetic white European families (200 from Sardinia and 208 from the U.K.).

  7. The Study Group. • Chosen because the overall contribution of DPB1 to IDDM is small. • DPB1 appears to contribute to IDDM1 through the protection associated with DPB1*0402 on DR4-negative haplotypes. • Derived Hypothesis:HLA-DP molecule itself contributes to IDDM1.

  8. Method 1. • Compare association of DPB1 locus to the DRB1 and DQB1 loci. • Single point analysis with the extended transmission/disequilibrium test (ETDT). • Association of HLA-DPB1 with IDDM1strong (P=5.3 x 10-10), but not as significant as the associations of HLA-DRB1 and –DQB1 (P=2.1 x 10-90 and 8.5 x 10-83, respectively). • DPB1 contributes to the association of HLA region to IDDM1, but overall genetic effect is much smaller than that of DRB1 and DQB1.

  9. Method 2. • Investigation of the single point association of different DPB1 alleles using transmission/disequilibrium test (TDT).

  10. Method 3. • To evaluate the relative transmission or predisposition of the DPB1*0301, DPB1*0202, and DPB1*0402 alleles according to which DRB1, -DQA1, DQB1 haplotypes were on. • Haplotype method was used (HM) combined with TDT (HM-TDT).

  11. Protective effect of DPB1*0402 allele.

  12. Discussion. • All the methods performed show that haplotypes identical at DRB1, DQA1,and DQB1 loci but different at the DPB1 locus. • These haplotypes even though identical, all have differentassociations with type 1 diabetes. • It cannot be concluded that the associations brought about by the DPB1 locus is attributable to its own polymorphisms.

  13. Conclusion. • It is strongly suggested that DPB1 contributes in a primary way to type 1diabetes predisposition/resistance. • Overall contribution of DPB1 to IDDM1 is small. • The DPB1 locus could have a larger effectin populations in which these DPB1*0402-positive haplotypesare more frequent.

  14. References. 1. Erlich HA, Rotter JI, Chang JD, Shaw SJ, Raffel LJ, Klitz W, Bugawan TL, Zeidler A: Association of HLA-DPB1*0301 with IDDM in Mexican-Americans. Diabetes 45:610–614, 1996 2. Noble JA, Valdes AM, Thomson G, Erlich HA: The HLA class II locus DPB1 can influence susceptibility to type 1 diabetes. Diabetes 49:121–125, 2000 3. Sham PC, Curtis D: An extended transmission/disequilibrium test (TDT) for multi-allele marker loci. Ann Hum Genet 59:323–336, 1995 4. Valdes AM, Thomson G: Detecting disease-predisposing variants: the haplotype method. Am J Hum Genet 60:703–716, 1997

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