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

G. Thomson, A. M. Valdes, J. A. Noble, I. Kockum, M. N. Grote, J. Najman, H. A. Erlich, F. Cucca, A. Pugliese, A. Steenkiste, J. S. Dorman, S. Caillat-Zucman, R. Hermann, J. Ilonen, A. P. Lambert, P. J. Bingley, K. M. Gillespie, Å Lernmark, C. B. Sanjeevi, K. S. RønningenD. E. Undlien, E. Thorsby, A. Petrone, R. Buzzetti, B. P.C. Koeleman, B. O. Roep, G. Saruhan-Direskeneli, F. A. Uyar, H. Günoz, C. Gorodezky, C. Alaez, B. O. Boehm, W. Mlynarski, H. Ikegami, M. Berrino, M. E. Fasano, E. Dametto, S. Israel, C. Brautbar, A. Santiago-Cortes, T. Frazer De Llado, Jin-Xiong She, T. L. Bugawan, J. I. Rotter, L. Raffel, A. Zeidler, F. Leyva-Cobian, B. R. Hawkins, S. H. Chan, L. Castano, F. Pociot, J. Nerup

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)110-127
Number of pages18
JournalTissue Antigens
Volume70
Issue number2
DOIs
StatePublished - Aug 1 2007

Fingerprint

Medical problems
Type 1 Diabetes Mellitus
Haplotypes
Meta-Analysis
Genotype
Genes
Heterozygote
HLA Antigens
Population
Amino Acids
Penetrance
Population Groups
Ethnic Groups

Keywords

  • Human leukocyte antigen class II DRB1-DQB1
  • Meta-analysis
  • Type 1 diabetes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Biochemistry
  • Genetics

Cite this

Thomson, G., Valdes, A. M., Noble, J. A., Kockum, I., Grote, M. N., Najman, J., ... Nerup, J. (2007). Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: A meta-analysis. Tissue Antigens, 70(2), 110-127. https://doi.org/10.1111/j.1399-0039.2007.00867.x

Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes : A meta-analysis. / Thomson, G.; Valdes, A. M.; Noble, J. A.; Kockum, I.; Grote, M. N.; Najman, J.; Erlich, H. A.; Cucca, F.; Pugliese, A.; Steenkiste, A.; Dorman, J. S.; Caillat-Zucman, S.; Hermann, R.; Ilonen, J.; Lambert, A. P.; Bingley, P. J.; Gillespie, K. M.; Lernmark, Å; Sanjeevi, C. B.; Rønningen, K. S.; Undlien, D. E.; Thorsby, E.; Petrone, A.; Buzzetti, R.; Koeleman, B. P.C.; Roep, B. O.; Saruhan-Direskeneli, G.; Uyar, F. A.; Günoz, H.; Gorodezky, C.; Alaez, C.; Boehm, B. O.; Mlynarski, W.; Ikegami, H.; Berrino, M.; Fasano, M. E.; Dametto, E.; Israel, S.; Brautbar, C.; Santiago-Cortes, A.; Frazer De Llado, T.; She, Jin-Xiong; Bugawan, T. L.; Rotter, J. I.; Raffel, L.; Zeidler, A.; Leyva-Cobian, F.; Hawkins, B. R.; Chan, S. H.; Castano, L.; Pociot, F.; Nerup, J.

In: Tissue Antigens, Vol. 70, No. 2, 01.08.2007, p. 110-127.

Research output: Contribution to journalArticle

Thomson, G, Valdes, AM, Noble, JA, Kockum, I, Grote, MN, Najman, J, Erlich, HA, Cucca, F, Pugliese, A, Steenkiste, A, Dorman, JS, Caillat-Zucman, S, Hermann, R, Ilonen, J, Lambert, AP, Bingley, PJ, Gillespie, KM, Lernmark, Å, Sanjeevi, CB, Rønningen, KS, Undlien, DE, Thorsby, E, Petrone, A, Buzzetti, R, Koeleman, BPC, Roep, BO, Saruhan-Direskeneli, G, Uyar, FA, Günoz, H, Gorodezky, C, Alaez, C, Boehm, BO, Mlynarski, W, Ikegami, H, Berrino, M, Fasano, ME, Dametto, E, Israel, S, Brautbar, C, Santiago-Cortes, A, Frazer De Llado, T, She, J-X, Bugawan, TL, Rotter, JI, Raffel, L, Zeidler, A, Leyva-Cobian, F, Hawkins, BR, Chan, SH, Castano, L, Pociot, F & Nerup, J 2007, 'Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: A meta-analysis', Tissue Antigens, vol. 70, no. 2, pp. 110-127. https://doi.org/10.1111/j.1399-0039.2007.00867.x
Thomson, G. ; Valdes, A. M. ; Noble, J. A. ; Kockum, I. ; Grote, M. N. ; Najman, J. ; Erlich, H. A. ; Cucca, F. ; Pugliese, A. ; Steenkiste, A. ; Dorman, J. S. ; Caillat-Zucman, S. ; Hermann, R. ; Ilonen, J. ; Lambert, A. P. ; Bingley, P. J. ; Gillespie, K. M. ; Lernmark, Å ; Sanjeevi, C. B. ; Rønningen, K. S. ; Undlien, D. E. ; Thorsby, E. ; Petrone, A. ; Buzzetti, R. ; Koeleman, B. P.C. ; Roep, B. O. ; Saruhan-Direskeneli, G. ; Uyar, F. A. ; Günoz, H. ; Gorodezky, C. ; Alaez, C. ; Boehm, B. O. ; Mlynarski, W. ; Ikegami, H. ; Berrino, M. ; Fasano, M. E. ; Dametto, E. ; Israel, S. ; Brautbar, C. ; Santiago-Cortes, A. ; Frazer De Llado, T. ; She, Jin-Xiong ; Bugawan, T. L. ; Rotter, J. I. ; Raffel, L. ; Zeidler, A. ; Leyva-Cobian, F. ; Hawkins, B. R. ; Chan, S. H. ; Castano, L. ; Pociot, F. ; Nerup, J. / Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes : A meta-analysis. In: Tissue Antigens. 2007 ; Vol. 70, No. 2. pp. 110-127.
@article{776a73923b154326acb1e808d1fba79f,
title = "Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: A meta-analysis",
abstract = "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 = "Human leukocyte antigen class II DRB1-DQB1, Meta-analysis, Type 1 diabetes",
author = "G. Thomson and Valdes, {A. M.} and Noble, {J. A.} and I. Kockum and Grote, {M. N.} and J. Najman and Erlich, {H. A.} and F. Cucca and A. Pugliese and A. Steenkiste and Dorman, {J. S.} and S. Caillat-Zucman and R. Hermann and J. Ilonen and Lambert, {A. P.} and Bingley, {P. J.} and Gillespie, {K. M.} and {\AA} Lernmark and Sanjeevi, {C. B.} and R{\o}nningen, {K. S.} and Undlien, {D. E.} and E. Thorsby and A. Petrone and R. Buzzetti and Koeleman, {B. P.C.} and Roep, {B. O.} and G. Saruhan-Direskeneli and Uyar, {F. A.} and H. G{\"u}noz and C. Gorodezky and C. Alaez and Boehm, {B. O.} and W. Mlynarski and H. Ikegami and M. Berrino and Fasano, {M. E.} and E. Dametto and S. Israel and C. Brautbar and A. Santiago-Cortes and {Frazer De Llado}, T. and Jin-Xiong She and Bugawan, {T. L.} and Rotter, {J. I.} and L. Raffel and A. Zeidler and F. Leyva-Cobian and Hawkins, {B. R.} and Chan, {S. H.} and L. Castano and F. Pociot and J. Nerup",
year = "2007",
month = "8",
day = "1",
doi = "10.1111/j.1399-0039.2007.00867.x",
language = "English (US)",
volume = "70",
pages = "110--127",
journal = "HLA",
issn = "2059-2302",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes

T2 - A meta-analysis

AU - Thomson, G.

AU - Valdes, A. M.

AU - Noble, J. A.

AU - Kockum, I.

AU - Grote, M. N.

AU - Najman, J.

AU - Erlich, H. A.

AU - Cucca, F.

AU - Pugliese, A.

AU - Steenkiste, A.

AU - Dorman, J. S.

AU - Caillat-Zucman, S.

AU - Hermann, R.

AU - Ilonen, J.

AU - Lambert, A. P.

AU - Bingley, P. J.

AU - Gillespie, K. M.

AU - Lernmark, Å

AU - Sanjeevi, C. B.

AU - Rønningen, K. S.

AU - Undlien, D. E.

AU - Thorsby, E.

AU - Petrone, A.

AU - Buzzetti, R.

AU - Koeleman, B. P.C.

AU - Roep, B. O.

AU - Saruhan-Direskeneli, G.

AU - Uyar, F. A.

AU - Günoz, H.

AU - Gorodezky, C.

AU - Alaez, C.

AU - Boehm, B. O.

AU - Mlynarski, W.

AU - Ikegami, H.

AU - Berrino, M.

AU - Fasano, M. E.

AU - Dametto, E.

AU - Israel, S.

AU - Brautbar, C.

AU - Santiago-Cortes, A.

AU - Frazer De Llado, T.

AU - She, Jin-Xiong

AU - Bugawan, T. L.

AU - Rotter, J. I.

AU - Raffel, L.

AU - Zeidler, A.

AU - Leyva-Cobian, F.

AU - Hawkins, B. R.

AU - Chan, S. H.

AU - Castano, L.

AU - Pociot, F.

AU - Nerup, J.

PY - 2007/8/1

Y1 - 2007/8/1

N2 - 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.

AB - 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.

KW - Human leukocyte antigen class II DRB1-DQB1

KW - Meta-analysis

KW - Type 1 diabetes

UR - http://www.scopus.com/inward/record.url?scp=34347389454&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34347389454&partnerID=8YFLogxK

U2 - 10.1111/j.1399-0039.2007.00867.x

DO - 10.1111/j.1399-0039.2007.00867.x

M3 - Article

C2 - 17610416

AN - SCOPUS:34347389454

VL - 70

SP - 110

EP - 127

JO - HLA

JF - HLA

SN - 2059-2302

IS - 2

ER -