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Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis.

Author:
  • G Thomson
  • AM Valdes
  • JA Noble
  • I Kockum
  • MN Grote
  • J Najman
  • HA Erlich
  • F Cucca
  • A Pugliese
  • A Steenkiste
  • JS Dorman
  • S Caillat-Zucman
  • R Hermann
  • J Ilonen
  • AP Lambert
  • PJ Bingley
  • KM Gillespie
  • Åke Lernmark
  • CB Sanjeevi
  • KS Rønningen
  • DE Undlien
  • E Thorsby
Publishing year: 2007
Language: English
Pages: 110-127
Publication/Series: Tissue Antigens
Volume: 70
Issue: 2
Document type: Journal article
Publisher: Wiley-Blackwell

Abstract english

The direct involvement of the human leukocyte antigen class II DR-DQ genes in type 1 diabetes (T1D) is well established, and these genes display a complex hierarchy of risk effects at the genotype and haplotype levels. We investigated, using data from 38 studies, whether the DR-DQ haplotypes and genotypes show the same relative predispositional effects across populations and ethnic groups. Significant differences in risk within a population were considered, as well as comparisons across populations using the patient/control (P/C) ratio. Within a population, the ratio of the P/C ratios for two different genotypes or haplotypes is a function only of the absolute penetrance values, allowing ranking of risk effects. Categories of consistent predisposing, intermediate ('neutral'), and protective haplotypes were identified and found to correlate with disease prevalence and the marked ethnic differences in DRB1-DQB1 frequencies. Specific effects were identified, for example for predisposing haplotypes, there was a statistically significant and consistent hierarchy for DR4 DQB1*0302s: DRB1*0405 =*0401 =*0402 > *0404 > *0403, with DRB1*0301 DQB1*0200 (DR3) being significantly less predisposing than DRB1*0402 and more than DRB1*0404. The predisposing DRB1*0401 DQB1*0302 haplotype was relatively increased compared with the protective haplotype DRB1*0401 DQB1*0301 in heterozygotes with DR3 compared with heterozygotes with DRB1*0101 DQB1*0501 (DR1). Our results show that meta-analyses and use of the P/C ratio and rankings thereof can be valuable in determining T1D risk factors at the haplotype and amino acid residue levels.

Keywords

  • Endocrinology and Diabetes
  • human leukocyte antigen class II DRB1-DQB1
  • meta-analysis
  • type 1 diabetes

Other

Published
  • Diabetes and Celiac Unit
  • ISSN: 0001-2815
E-mail: ake [dot] lernmark [at] med [dot] lu [dot] se

Principal investigator

Diabetes and Celiac Unit

+46 40 39 19 01

+46 70 616 47 79

60:11:015

Jan Waldenströms gata 35, Malmö

33

Lund University Diabetes Centre, CRC, SUS Malmö, Jan Waldenströms gata 35, House 91:12. SE-214 28 Malmö. Telephone: +46 40 39 10 00