Genetic susceptibility to type 1 diabetes in childhood - estimation of HLA class II associated disease risk and class II effect in various phases of islet autoimmunity
Objective The HLA‐DR/DQ region remains the major determinant of susceptibility to type 1 diabetes (T1D) despite the more than 50 risk affecting loci outside human leukocyte antigen (HLA) region that have been identified. We aimed at developing a simple risk estimation based on HLA class II genotypin...
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| Published in | Pediatric diabetes Vol. 17; no. S22; pp. 8 - 16 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Former Munksgaard
John Wiley & Sons A/S
01.07.2016
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Objective
The HLA‐DR/DQ region remains the major determinant of susceptibility to type 1 diabetes (T1D) despite the more than 50 risk affecting loci outside human leukocyte antigen (HLA) region that have been identified. We aimed at developing a simple risk estimation based on HLA class II genotyping, which was also tested by analyzing HLA class II effect on the autoantibody seroconversion and further progression to diabetes.
Subjects and methods
A total of 2991 trio families with a diabetic child from the Finnish Pediatric Diabetes Register were genotyped and the risk contributed by each DR‐DQ haplotype calculated through transmission analysis. The genotype risk was estimated based on the summary effect of haplotypes. Genotype grouping was further tested in a subcohort of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study
Results
The summary effect of haplotypes was generally seen in genotypes, while the expected synergistic effect of DR3‐DQ2 and DR4‐DQ8 (DRB1*04:03 excluded) combination was also clear in the T1D risk association analysis. This highest risk DR/DQ genotype was found in 21.6% of patients and 2.0% of controls, odds ratio (OR) = 13.2 (10.1–17.2), whereas the lowest risk genotype contained only 0.8% of patients and 28.0% of controls, OR = 0.02 (0.01–0.03). In the subcohort from the DIPP study the risk grades correlated clearly with seroconversion for islet autoantibodies and T1D development. In contrast, DR/DQ risk groups did not associate with the progression rate from advanced autoimmunity to clinical diabetes.
Conclusions
Class II HLA genotype groups improve the estimation of T1D risk. Class II effect is limited to the early phase of the disease process characterized by seroconversion for islet autoantibodies. |
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| AbstractList | The HLA-DR/DQ region remains the major determinant of susceptibility to type 1 diabetes (T1D) despite the more than 50 risk affecting loci outside human leukocyte antigen (HLA) region that have been identified. We aimed at developing a simple risk estimation based on HLA class II genotyping, which was also tested by analyzing HLA class II effect on the autoantibody seroconversion and further progression to diabetes.OBJECTIVEThe HLA-DR/DQ region remains the major determinant of susceptibility to type 1 diabetes (T1D) despite the more than 50 risk affecting loci outside human leukocyte antigen (HLA) region that have been identified. We aimed at developing a simple risk estimation based on HLA class II genotyping, which was also tested by analyzing HLA class II effect on the autoantibody seroconversion and further progression to diabetes.A total of 2991 trio families with a diabetic child from the Finnish Pediatric Diabetes Register were genotyped and the risk contributed by each DR-DQ haplotype calculated through transmission analysis. The genotype risk was estimated based on the summary effect of haplotypes. Genotype grouping was further tested in a subcohort of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) StudySUBJECTS AND METHODSA total of 2991 trio families with a diabetic child from the Finnish Pediatric Diabetes Register were genotyped and the risk contributed by each DR-DQ haplotype calculated through transmission analysis. The genotype risk was estimated based on the summary effect of haplotypes. Genotype grouping was further tested in a subcohort of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) StudyThe summary effect of haplotypes was generally seen in genotypes, while the expected synergistic effect of DR3-DQ2 and DR4-DQ8 (DRB1*04:03 excluded) combination was also clear in the T1D risk association analysis. This highest risk DR/DQ genotype was found in 21.6% of patients and 2.0% of controls, odds ratio (OR) = 13.2 (10.1-17.2), whereas the lowest risk genotype contained only 0.8% of patients and 28.0% of controls, OR = 0.02 (0.01-0.03). In the subcohort from the DIPP study the risk grades correlated clearly with seroconversion for islet autoantibodies and T1D development. In contrast, DR/DQ risk groups did not associate with the progression rate from advanced autoimmunity to clinical diabetes.RESULTSThe summary effect of haplotypes was generally seen in genotypes, while the expected synergistic effect of DR3-DQ2 and DR4-DQ8 (DRB1*04:03 excluded) combination was also clear in the T1D risk association analysis. This highest risk DR/DQ genotype was found in 21.6% of patients and 2.0% of controls, odds ratio (OR) = 13.2 (10.1-17.2), whereas the lowest risk genotype contained only 0.8% of patients and 28.0% of controls, OR = 0.02 (0.01-0.03). In the subcohort from the DIPP study the risk grades correlated clearly with seroconversion for islet autoantibodies and T1D development. In contrast, DR/DQ risk groups did not associate with the progression rate from advanced autoimmunity to clinical diabetes.Class II HLA genotype groups improve the estimation of T1D risk. Class II effect is limited to the early phase of the disease process characterized by seroconversion for islet autoantibodies.CONCLUSIONSClass II HLA genotype groups improve the estimation of T1D risk. Class II effect is limited to the early phase of the disease process characterized by seroconversion for islet autoantibodies. Objective The HLA‐DR/DQ region remains the major determinant of susceptibility to type 1 diabetes (T1D) despite the more than 50 risk affecting loci outside human leukocyte antigen (HLA) region that have been identified. We aimed at developing a simple risk estimation based on HLA class II genotyping, which was also tested by analyzing HLA class II effect on the autoantibody seroconversion and further progression to diabetes. Subjects and methods A total of 2991 trio families with a diabetic child from the Finnish Pediatric Diabetes Register were genotyped and the risk contributed by each DR‐DQ haplotype calculated through transmission analysis. The genotype risk was estimated based on the summary effect of haplotypes. Genotype grouping was further tested in a subcohort of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study Results The summary effect of haplotypes was generally seen in genotypes, while the expected synergistic effect of DR3‐DQ2 and DR4‐DQ8 (DRB1*04:03 excluded) combination was also clear in the T1D risk association analysis. This highest risk DR/DQ genotype was found in 21.6% of patients and 2.0% of controls, odds ratio (OR) = 13.2 (10.1–17.2), whereas the lowest risk genotype contained only 0.8% of patients and 28.0% of controls, OR = 0.02 (0.01–0.03). In the subcohort from the DIPP study the risk grades correlated clearly with seroconversion for islet autoantibodies and T1D development. In contrast, DR/DQ risk groups did not associate with the progression rate from advanced autoimmunity to clinical diabetes. Conclusions Class II HLA genotype groups improve the estimation of T1D risk. Class II effect is limited to the early phase of the disease process characterized by seroconversion for islet autoantibodies. Objective The HLA-DR/DQ region remains the major determinant of susceptibility to type 1 diabetes (T1D) despite the more than 50 risk affecting loci outside human leukocyte antigen (HLA) region that have been identified. We aimed at developing a simple risk estimation based on HLA class II genotyping, which was also tested by analyzing HLA class II effect on the autoantibody seroconversion and further progression to diabetes. Subjects and methods A total of 2991 trio families with a diabetic child from the Finnish Pediatric Diabetes Register were genotyped and the risk contributed by each DR-DQ haplotype calculated through transmission analysis. The genotype risk was estimated based on the summary effect of haplotypes. Genotype grouping was further tested in a subcohort of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study Results The summary effect of haplotypes was generally seen in genotypes, while the expected synergistic effect of DR3-DQ2 and DR4-DQ8 (DRB1*04:03 excluded) combination was also clear in the T1D risk association analysis. This highest risk DR/DQ genotype was found in 21.6% of patients and 2.0% of controls, odds ratio (OR)=13.2 (10.1-17.2), whereas the lowest risk genotype contained only 0.8% of patients and 28.0% of controls, OR=0.02 (0.01-0.03). In the subcohort from the DIPP study the risk grades correlated clearly with seroconversion for islet autoantibodies and T1D development. In contrast, DR/DQ risk groups did not associate with the progression rate from advanced autoimmunity to clinical diabetes. Conclusions Class II HLA genotype groups improve the estimation of T1D risk. Class II effect is limited to the early phase of the disease process characterized by seroconversion for islet autoantibodies. The HLA-DR/DQ region remains the major determinant of susceptibility to type 1 diabetes (T1D) despite the more than 50 risk affecting loci outside human leukocyte antigen (HLA) region that have been identified. We aimed at developing a simple risk estimation based on HLA class II genotyping, which was also tested by analyzing HLA class II effect on the autoantibody seroconversion and further progression to diabetes. A total of 2991 trio families with a diabetic child from the Finnish Pediatric Diabetes Register were genotyped and the risk contributed by each DR-DQ haplotype calculated through transmission analysis. The genotype risk was estimated based on the summary effect of haplotypes. Genotype grouping was further tested in a subcohort of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study The summary effect of haplotypes was generally seen in genotypes, while the expected synergistic effect of DR3-DQ2 and DR4-DQ8 (DRB1*04:03 excluded) combination was also clear in the T1D risk association analysis. This highest risk DR/DQ genotype was found in 21.6% of patients and 2.0% of controls, odds ratio (OR) = 13.2 (10.1-17.2), whereas the lowest risk genotype contained only 0.8% of patients and 28.0% of controls, OR = 0.02 (0.01-0.03). In the subcohort from the DIPP study the risk grades correlated clearly with seroconversion for islet autoantibodies and T1D development. In contrast, DR/DQ risk groups did not associate with the progression rate from advanced autoimmunity to clinical diabetes. Class II HLA genotype groups improve the estimation of T1D risk. Class II effect is limited to the early phase of the disease process characterized by seroconversion for islet autoantibodies. |
| Author | Simell, O Ilonen, J Toppari, J Lempainen, J Kiviniemi, M Knip, M Veijola, R |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27411431$$D View this record in MEDLINE/PubMed |
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| Copyright | 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. |
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| DOI | 10.1111/pedi.12327 |
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| Keywords | HLA class II type 1 diabetes genetics islet autoimmunity |
| Language | English |
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| Notes | Academy of Finland Table S1. Genotypes of diabetic children and affected family-based artificial controls formed from non-transmitted haplotypes ArticleID:PEDI12327 istex:FA27A40BEBF926C4A06CD2C0509EE8F0216B3D9E Sigrid Jusélius Foundation ark:/67375/WNG-N1SZHX3L-X Juvenile Diabetes Research Foundation ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
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| PublicationTitle | Pediatric diabetes |
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| References | Varney MD, Valdes AM, Carlson JA et al. HLA DPA1, DPB1 alleles and haplotypes contribute to the risk associated with type 1 diabetes: analysis of the type 1 diabetes genetics consortium families. Diabetes 2010: 59: 2055-2062. Nejentsev S, Howson JM, Walker NM et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 2007: 450: 887-892. Kiviniemi M, Hermann R, Nurmi J et al. A high-throughput population screening system for the estimation of genetic risk for type 1 diabetes: an application for the TEDDY (the Environmental Determinants of Diabetes in the Young) study. Diabetes Technol Ther 2007: 9: 460-472. Ilonen J, Herva E, Tiilikainen A, Akerblom HK, Koivukangas T, Kouvalainen K. HLA-Dw2 as a marker of resistance against juvenile diabetes mellitus. Tissue Antigens 1978: 11: 144-146. Mbunwe E, Van der Auwera BJ, Weets I et al. In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A*24 and HLA-B*18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions. Diabetologia 2013: 56: 1964-1970. Thomson G. HLA disease associations: models for the study of complex human genetic disorders. Crit Rev Clin Lab Sci 1995: 32: 183-219. Thomsen M, Platz P, Andersen OO et al. MLC typing in juvenile diabetes mellitus and idiopathic Addison's disease. Transplant Rev 1975: 22: 125-147. Hekkala A, Ilonen J, Knip M, Veijola R. Family history of diabetes and distribution of class II HLA genotypes in children with newly diagnosed type 1 diabetes: effect on diabetic ketoacidosis. Eur J Endocrinol 2011: 165: 813-817. Hu X, Deutsch AJ, Lenz TL et al. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nat Genet 2015: 47: 898-905. Lipponen K, Gombos Z, Kiviniemi M et al. Effect of HLA class I and class II alleles on progression from autoantibody positivity to overt type 1 diabetes in children with risk-associated class II genotypes. Diabetes 2010: 59: 3253-3256. Hermann R, Turpeinen H, Laine AP et al. HLA DR-DQ-encoded genetic determinants of childhood-onset type 1 diabetes in Finland: an analysis of 622 nuclear families. Tissue Antigens 2003: 62: 162-169. Skyler JS. Prevention and reversal of type 1 diabetes - past challenges and future opportunities. Diabetes Care 2015: 38: 997-1007. Lempainen J, Laine AP, Hammais A et al. Non-HLA gene effects on the disease process of type 1 diabetes: from HLA susceptibility to overt disease. J Autoimmun 2015: 61: 45-53. Undlien DE, Friede T, Rammensee HG et al. HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection. Diabetes 1997: 46: 143-149. Harjutsalo V, Sund R, Knip M, Groop P-H. Incidence of type 1 diabets in Finland. JAMA 2013: 310: 427-428. Mikk ML, Kiviniemi M, Laine AP et al. The HLA-B*39 allele increases type 1 diabetes risk conferred by HLA-DRB1*04:04-DQB1*03:02 and HLA-DRB1*08-DQB1*04 class II haplotypes. Hum Immunol 2014: 75: 65-70. Khalil I, d'Auriol L, Gobet M et al. A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus. J Clin Invest 1990: 85: 1315-1319. Ilonen J, Hammais A, Laine AP et al. Patterns of beta-cell autoantibody appearance and genetic associations during the first years of life. Diabetes 2013: 62: 3636-3640. Thomson G, Valdes AM, Noble JA et al. Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis. Tissue Antigens 2007: 70: 110-127. Todd JA, Bell JI, McDevitt HO. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 1987: 329: 599-604. Park Y, Eisenbarth GS. Genetic susceptibility factors of type 1 diabetes in Asians. Diabetes Metab Res Rev 2001: 17: 2-11. Lambert AP, Gillespie KM, Thomson G et al. Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom. J Clin Endocrinol Metab 2004: 89: 4037-4043. Nejentsev S, Reijonen H, Adojaan B et al. The effect of HLA-B allele on the IDDM risk defined by DRB1*04 subtypes and DQB1*0302. Diabetes 1997: 46: 1888-1892. Noble JA, Valdes AM, Varney MD et al. HLA class I and genetic susceptibility to type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium. Diabetes 2010: 59: 2972-2979. Ilonen J, Kocova M, Lipponen K, Sukarova-Angelovska E, Jovanovska A, Knip M. HLA-DR-DQ haplotypes and type 1 diabetes in Macedonia. Hum Immunol 2009: 70: 461-463. Onengut-Gumuscu S, Chen WM, Burren O et al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet 2015: 47: 381-386. Noble JA, Valdes AM. Genetics of the HLA region in the prediction of type 1 diabetes. Curr Diab Rep 2011: 11: 533-542. Zavattari P, Lampis R, Motzo C et al. Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, −DRB1 disease loci. Hum Mol Genet 2001: 10: 881-889. Bilbao JR, Calvo B, Aransay AM et al. Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease. Genes Immun 2006: 7: 550-554. Trowsdale J, Knight JC. Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet 2013: 14: 301-323. Valdes AM, Erlich HA, Noble JA. Human leukocyte antigen class I B and C loci contribute to type 1 diabetes (T1D) susceptibility and age at T1D onset. Hum Immunol 2005: 66: 301-313. 2010; 59 2015; 38 1978; 11 1987; 329 2013; 62 1997; 46 2004; 89 1995; 32 2006; 7 2011; 11 2007; 70 2005; 66 1990; 85 2015; 47 2013; 14 2009; 70 2015; 61 2013; 56 2007; 450 2013; 310 2007; 9 1975; 22 2001; 17 2003; 62 2011; 165 2014; 75 2001; 10 |
| References_xml | – reference: Ilonen J, Hammais A, Laine AP et al. Patterns of beta-cell autoantibody appearance and genetic associations during the first years of life. Diabetes 2013: 62: 3636-3640. – reference: Kiviniemi M, Hermann R, Nurmi J et al. A high-throughput population screening system for the estimation of genetic risk for type 1 diabetes: an application for the TEDDY (the Environmental Determinants of Diabetes in the Young) study. Diabetes Technol Ther 2007: 9: 460-472. – reference: Park Y, Eisenbarth GS. Genetic susceptibility factors of type 1 diabetes in Asians. Diabetes Metab Res Rev 2001: 17: 2-11. – reference: Lipponen K, Gombos Z, Kiviniemi M et al. Effect of HLA class I and class II alleles on progression from autoantibody positivity to overt type 1 diabetes in children with risk-associated class II genotypes. Diabetes 2010: 59: 3253-3256. – reference: Undlien DE, Friede T, Rammensee HG et al. HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection. Diabetes 1997: 46: 143-149. – reference: Bilbao JR, Calvo B, Aransay AM et al. Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease. Genes Immun 2006: 7: 550-554. – reference: Mbunwe E, Van der Auwera BJ, Weets I et al. In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A*24 and HLA-B*18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions. Diabetologia 2013: 56: 1964-1970. – reference: Skyler JS. Prevention and reversal of type 1 diabetes - past challenges and future opportunities. Diabetes Care 2015: 38: 997-1007. – reference: Hu X, Deutsch AJ, Lenz TL et al. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nat Genet 2015: 47: 898-905. – reference: Hekkala A, Ilonen J, Knip M, Veijola R. Family history of diabetes and distribution of class II HLA genotypes in children with newly diagnosed type 1 diabetes: effect on diabetic ketoacidosis. Eur J Endocrinol 2011: 165: 813-817. – reference: Ilonen J, Kocova M, Lipponen K, Sukarova-Angelovska E, Jovanovska A, Knip M. HLA-DR-DQ haplotypes and type 1 diabetes in Macedonia. Hum Immunol 2009: 70: 461-463. – reference: Khalil I, d'Auriol L, Gobet M et al. A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus. J Clin Invest 1990: 85: 1315-1319. – reference: Todd JA, Bell JI, McDevitt HO. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 1987: 329: 599-604. – reference: Noble JA, Valdes AM. Genetics of the HLA region in the prediction of type 1 diabetes. Curr Diab Rep 2011: 11: 533-542. – reference: Ilonen J, Herva E, Tiilikainen A, Akerblom HK, Koivukangas T, Kouvalainen K. HLA-Dw2 as a marker of resistance against juvenile diabetes mellitus. Tissue Antigens 1978: 11: 144-146. – reference: Hermann R, Turpeinen H, Laine AP et al. HLA DR-DQ-encoded genetic determinants of childhood-onset type 1 diabetes in Finland: an analysis of 622 nuclear families. Tissue Antigens 2003: 62: 162-169. – reference: Thomson G, Valdes AM, Noble JA et al. Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis. Tissue Antigens 2007: 70: 110-127. – reference: Harjutsalo V, Sund R, Knip M, Groop P-H. Incidence of type 1 diabets in Finland. JAMA 2013: 310: 427-428. – reference: Trowsdale J, Knight JC. Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet 2013: 14: 301-323. – reference: Lempainen J, Laine AP, Hammais A et al. 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The HLA‐DR/DQ region remains the major determinant of susceptibility to type 1 diabetes (T1D) despite the more than 50 risk affecting loci outside... The HLA-DR/DQ region remains the major determinant of susceptibility to type 1 diabetes (T1D) despite the more than 50 risk affecting loci outside human... Objective The HLA-DR/DQ region remains the major determinant of susceptibility to type 1 diabetes (T1D) despite the more than 50 risk affecting loci outside... |
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| SubjectTerms | Adult Autoimmunity Case-Control Studies Child Diabetes Mellitus, Type 1 - genetics Diabetes Mellitus, Type 1 - immunology Female Genes, MHC Class II Genetic Predisposition to Disease genetics Haplotypes HLA class II Humans islet autoimmunity Islets of Langerhans - immunology Male Risk Assessment type 1 diabetes |
| Title | Genetic susceptibility to type 1 diabetes in childhood - estimation of HLA class II associated disease risk and class II effect in various phases of islet autoimmunity |
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