Extreme genetic risk for type 1A diabetes

Type 1A diabetes (T1D) is an autoimmune disorder the risk of which is increased by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. The genotype associated with the highest risk for T1D is the DR3/4-DQ8 (DQ8 is DQA1*0301, DQB1*0302) heterozygous genotype. We determined HLA-DR and -DQ genotypes at birth and analyzed DR3/4-DQ8 siblings of patients with T1D for identical-by-descent HLA haplotype sharing (the number of haplotypes inherited in common between siblings). The children were clinically followed with prospective measurement of anti-islet autoimmunity and for progression to T1D. Risk for islet autoimmunity dramatically increased in DR3/4-DQ8 siblings who shared both HLA haplotypes with their diabetic proband sibling (63% by age 7, and 85% by age 15) compared with siblings who did not share both HLA haplotypes with their diabetic proband sibling (20% by age 15, P < 0.01). 55% sharing both HLA haplotypes developed diabetes by age 12 versus 5% sharing zero or one haplotype (P = 0.03). Despite sharing both HLA haplotypes with their proband, siblings without the HLA DR3/4-DQ8 genotype had only a 25% risk for T1D by age 12. The risk for T1D in the DR3/4-DQ8 siblings sharing both HLA haplotypes with their proband is remarkable for a complex genetic disorder and provides evidence that T1D is inherited with HLA-DR/DQ alleles and additional MHC-linked genes both determining major risk. A subset of siblings at extremely high risk for T1D can now be identified at birth for trials to prevent islet autoimmunity.

[1]  G. Thomson.  Investigation of the mode of inheritance of the HLA associated diseases by the method of antigen genotype frequencies among diseased individuals. , 2008, Tissue antigens.

[2]  Grant Morahan,et al.  Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families. , 2005, Diabetes.

[3]  H. Erlich,et al.  Human leukocyte antigen class I B and C loci contribute to Type 1 Diabetes (T1D) susceptibility and age at T1D onset. , 2005, Human immunology.

[4]  J. Tuomilehto,et al.  Cumulative incidence of type 1 diabetes in 10,168 siblings of Finnish young-onset type 1 diabetic patients. , 2005, Diabetes.

[5]  Adrian Vella,et al.  Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. , 2004, Diabetes.

[6]  C. Larsen,et al.  The genetics of HLA-associated disease. , 2004, Current opinion in immunology.

[7]  E. Bonifacio,et al.  Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes. , 2004, The Journal of clinical investigation.

[8]  M. Rewers,et al.  Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). , 2004, The Journal of clinical endocrinology and metabolism.

[9]  Heather J Cordell,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. , 2004, The Journal of clinical endocrinology and metabolism.

[10]  B. Lie,et al.  Polymorphisms in the cytotoxic T lymphocyte antigen-4 gene region confer susceptibility to Addison's disease. , 2004, The Journal of clinical endocrinology and metabolism.

[11]  J. Ilonen,et al.  Genetic screening for individuals at high risk for type 1 diabetes in the general population using HLA Class II alleles as disease markers. A comparison between three European populations with variable rates of disease incidence , 2004, Diabetes/metabolism research and reviews.

[12]  M. Rewers,et al.  Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up. , 2004, Diabetes care.

[13]  T. Ogihara,et al.  Allelic variation in class I K gene as candidate for a second component of MHC-linked susceptibility to Type 1 diabetes in non-obese diabetic mice , 2004, Diabetologia.

[14]  Nunzio Bottini,et al.  A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes , 2004, Nature Genetics.

[15]  C. Polychronakos,et al.  Mechanisms of genetic susceptibility to type I diabetes: beyond HLA. , 2004, Molecular genetics and metabolism.

[16]  Pugliese Alberto.  Genetics of type 1 diabetes , 2004 .

[17]  Luc J. Smink,et al.  Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease , 2003, Nature.

[18]  P. Concannon,et al.  Mapping genes for autoimmunity in humans: type 1 diabetes as a model , 2002, Immunological reviews.

[19]  H. Weiner,et al.  Cutting edge: homologous recombination of the MHC class I K region defines new MHC-linked diabetogenic susceptibility gene(s) in nonobese diabetic mice. , 1999, Journal of immunology.

[20]  H. Erlich,et al.  Association between type 1 diabetes age of onset and HLA among sibling pairs. , 1999, Diabetes.

[21]  M. Atkinson,et al.  The NOD mouse model of type 1 diabetes: As good as it gets? , 1999, Nature Medicine.

[22]  P. H. Moghaddam,et al.  Genetic Structure of IDDM1: Two Separate Regions in the Major Histocompatibility Complex Contribute to Susceptibility or Protection , 1998, Diabetes.

[23]  W. Klitz,et al.  The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. , 1996, American journal of human genetics.

[24]  H. Inoko,et al.  Association of HLA-A24 With Complete β-Cell Destruction in IDDM , 1993, Diabetes.

[25]  M. Baur,et al.  Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. , 1988, American journal of human genetics.

[26]  G. Bottazzo,et al.  PREDICTING INSULIN-DEPENDENT DIABETES , 1988, The Lancet.

[27]  M. Busson,et al.  Effects of HLA genotype, age and birth order on empirical risk estimates for insulin-dependent diabetes in siblings of diabetic children. An actuarial evaluation. , 1986, Diabetes research.

[28]  A. Cudworth,et al.  Evidence for HL-A-linked genes in "juvenile" diabetes mellitus. , 1975, British medical journal.

[29]  H. Erlich,et al.  Rapid typing of HLA-DQB1 DNA polymorphism using nonradioactive oligonucleotide probes and amplified DNA , 2005, Immunogenetics.

[30]  J. Todd,et al.  Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex distinct from HLA-DQB1, -DQA1 and –DRB1 , 2003, Genes and Immunity.

[31]  A. Pugliese,et al.  The insulin gene in diabetes , 2002, Diabetes/metabolism research and reviews.

[32]  H. Erlich,et al.  The HLA class II locus DPB1 can influence susceptibility to type 1 diabetes. , 2000, Diabetes.

[33]  N. Tatsumi,et al.  HLA DPB1*0201 gene confers disease susceptibility in japanese with childhood onset type I diabetes, independent of HLA-DR and DQ genotypes. , 2000, Diabetes research and clinical practice.

[34]  G. Thomson,et al.  Homozygous parent affected sib pair method for detecting disease predisposing variants: Application to insulin dependent diabetes mellitus , 1993, Genetic epidemiology.

[35]  G. Möller,et al.  HLA and disease susceptibility. , 1983, Immunological reviews.