Summary
Autoimmunity causing insulin-dependent diabetes mellitus (IDDM) begins in early childhood due to interactions between genes and unknown environmental factors that may be identified through follow-up of a large cohort of genetically susceptible children. Such a cohort has been established using a simple and rapid cord blood screening for HLA alleles. The DRB1 and DQB1 second exon sequences were co-amplified using the polymerase chain reaction and hybridized with single and pooled sequence-specific oligonucleotide probes. Four individual probes were used to detect the susceptibility alleles DRB1*03, DRB1*04, and DQBl*0302 as well as the usually protective DRB1*15/16 (DR2) alleles. In addition, pooled probes allow the distinction of DR3/3 from the DR3/x genotype (where x is neither DR2, 3, nor 4) and DR4/4 from DR4/x. Among 5000 newborns from the general Denver population, we have found the high-risk genotype (DRBl*03/ DRB1*04, DQBl*0302) to be present in 2.4% of non-Hispanic whites, 2.8% of Hispanics, and 1.6% of African Americans. The moderate-risk genotypes (DRB1*04, DQBl*0302/DRBl*04, DQB1*0302, DRB1*04, DQBl*0302/x, or DRBl*03/DRBl*03) are present in 17 % of American non-Hispanic whites, 24% of Hispanics and in 10% of African Americans. These results demonstrate the feasibility of a large-scale newborn screening for genes associated with IDDM. The ultimate role for such a screening in future routine prediction and prevention of IDDM will depend on the availability of an effective and acceptable form of clinical intervention.
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Abbreviations
- IDDM:
-
Insulin-dependent diabetes mellitus
- PCR:
-
polymerase chain reaction
- SSO:
-
sequence-specific oligonucleotide
- DAISY:
-
Diabetes Autoimmunity Study in the Young
- HRP:
-
horseradish peroxidase
- TMB:
-
tetramethyl ben-zidine
- SSPE:
-
saline-sodium phosphate-EDTA
References
Atkinson MA, Mclaren NK (1994) Mechanisms of disease: the pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med 331: 1428–1436
Cudworth AG, Woodrow JC (1975) Evidence for HLA-linked genes in “juvenile” diabetes mellitus. BMJ 2: 133–135
Horn G, Bugawan T, Long C, Erlich H (1988) Allelic sequence variation of the HLA-DQ loci: relationship to serology and insulin-dependent diabetes susceptibility. Proc Natl Acad Sci USA 85: 6012–6016
Todd JA, Bell JI, McDevitt HO (1987) HLA-DQβ genes contribute to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329: 599–604
Erlich H, Bugawan TL, Scharf S, Nepom GT, Tait B, Griffith RL (1990) HLA-DQβ sequence polymorphism and genetic susceptibility to IDDM. Diabetes 39: 96–103
Owerbach D, Nerup J (1982) Restriction fragment length polymorphism of the insulin gene in diabetes mellitus. Diabetes 31: 275–277
Davies JL, Kawaguchi Y, Bennett ST et al. (1994) A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371: 130–136
Hashimoto L, Habita C, Beressi JP et al. (1994) Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q. Nature 371: 161–164
Field LL, Tobias R, Magnus T (1993) A locus on chromosome 15q26 (IDDM3) produces susceptibility to IDDM. Nature Genetics 8: 189–194
Owerbach D, Gabbay KH (1995) The HOXD8 locus (2q31) is linked to type I diabetes: interaction with chromosomes 6 and 11 disease susceptibility genes. Diabetes 44: 132–136
Pilcher CC, Dickens K, Elliott RB (1991) ICA only develop in early childhood. Diabetes Res Clin Pract 14 [Suppl 1]: s82
Nepom G, Erlich HA (1991) MHC class II molecules and autoimmunity. Ann Rev Immunol 9: 493–525
Erlich HA, Rotter JI, Chang J et al. (1993) HLA class II alleles and susceptibility and resistance to insulin-dependent diabetes mellitus in Mexican-American families. Nature Genetics 3: 358–364
Rønningen KS, Spurkland A, Tait BD et al. (1992) HLA class II associations in insulin-dependent diabetes mellitus among Blacks, Caucasoids, and Japanese. In: Tsui K, Aizawa M, Sasazuki T (eds) HLA 1991, Vol. 1. Oxford University Press, Oxford, pp 713–722
Bugawan TL, Erlich HA (1991) Rapid typing of HLA-DQB1 DNA polymorphism using non-radioactive oligonu-cleotide probes and amplified DNA. Immunogenetics 33: 163–170
Erlich HA, Bugawan T, Begovich A et al. (1991) HLA-DR, DQ, and DP typing using PCR amplification and immobilized probes. Eur J Immunogenetics 18: 33–55
Van der Auvera B, Van Waeyenberge C, Schuit F et al. and the Belgian Diabetes Registry (1995) DRBl*0403 protects against IDDM in Caucasians with the high-risk heterozygous DQAl*0301-DQBl*0302/DQAl*0501-DQBl*0201 genotype. Diabetes 44: 527–530
Gay EC, Hamman RF, Carosone-Link PJ et al. (1989) Colorado IDDM registry: lower incidence of IDDM in Hispanics. Diabetes Care 12: 708–710
Cruickshanks KJ, Jobim LF, Lawner-Heavner J et al. (1994) Ethnic differences in human leukocyte antigen markers of susceptibility to IDDM. Diabetes Care 17: 132–137
Bennett ST, Lucassen AM, Gough SCL et al. (1995) Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nature Genetics 9: 284–292
Rubinstein P, Ginsberg-Fellner F (1990) The genetics of insulin-dependent diabetes mellitus susceptibility differs among Caucasoids: New York families of Askenazi Jews of Northern European descent. Third International Congress on Jewish Genetic Diseases Tel Aviv, Oxford University Press, Oxford, pp 431–439
Bain SC, Rowe BR, Barnett AH, Todd JA (1994) Parental origin of diabetes-associated HLA types in sibling pairs with type I diabetes. Diabetes 43: 1462–1468
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Rewers, M., Bugawan, T.L., Norris, J.M. et al. Newborn screening for HLA markers associated with IDDM: Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia 39, 807–812 (1996). https://doi.org/10.1007/s001250050514
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DOI: https://doi.org/10.1007/s001250050514