, 39:807 | Cite as

Newborn screening for HLA markers associated with IDDM: Diabetes Autoimmunity Study in the Young (DAISY)

  • M. Rewers
  • T. L. Bugawan
  • J. M. Norris
  • A. Blair
  • B. Beaty
  • M. Hoffman
  • R. S. McDuffie
  • R. F. Hamman
  • G. Klingensmith
  • G. S. Eisenbarth
  • H. A. Erlich


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.


Insulin-dependent diabetes mellitus HLA class II alleles newborn screening autoimmunity 



Insulin-dependent diabetes mellitus


polymerase chain reaction


sequence-specific oligonucleotide


Diabetes Autoimmunity Study in the Young


horseradish peroxidase


tetramethyl ben-zidine


saline-sodium phosphate-EDTA


  1. 1.
    Atkinson MA, Mclaren NK (1994) Mechanisms of disease: the pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med 331: 1428–1436PubMedCrossRefGoogle Scholar
  2. 2.
    Cudworth AG, Woodrow JC (1975) Evidence for HLA-linked genes in “juvenile” diabetes mellitus. BMJ 2: 133–135CrossRefGoogle Scholar
  3. 3.
    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: 6012–6016PubMedCrossRefGoogle Scholar
  4. 4.
    Todd JA, Bell JI, McDevitt HO (1987) HLA-DQβ genes contribute to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329: 599–604PubMedCrossRefGoogle Scholar
  5. 5.
    Erlich H, Bugawan TL, Scharf S, Nepom GT, Tait B, Griffith RL (1990) HLA-DQβ sequence polymorphism and genetic susceptibility to IDDM. Diabetes 39: 96–103PubMedCrossRefGoogle Scholar
  6. 6.
    Owerbach D, Nerup J (1982) Restriction fragment length polymorphism of the insulin gene in diabetes mellitus. Diabetes 31: 275–277PubMedCrossRefGoogle Scholar
  7. 7.
    Davies JL, Kawaguchi Y, Bennett ST et al. (1994) A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371: 130–136PubMedCrossRefGoogle Scholar
  8. 8.
    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: 161–164PubMedCrossRefGoogle Scholar
  9. 9.
    Field LL, Tobias R, Magnus T (1993) A locus on chromosome 15q26 (IDDM3) produces susceptibility to IDDM. Nature Genetics 8: 189–194CrossRefGoogle Scholar
  10. 10.
    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: 132–136PubMedCrossRefGoogle Scholar
  11. 11.
    Pilcher CC, Dickens K, Elliott RB (1991) ICA only develop in early childhood. Diabetes Res Clin Pract 14 [Suppl 1]: s82Google Scholar
  12. 12.
    Nepom G, Erlich HA (1991) MHC class II molecules and autoimmunity. Ann Rev Immunol 9: 493–525CrossRefGoogle Scholar
  13. 13.
    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: 358–364PubMedCrossRefGoogle Scholar
  14. 14.
    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 713–722Google Scholar
  15. 15.
    Bugawan TL, Erlich HA (1991) Rapid typing of HLA-DQB1 DNA polymorphism using non-radioactive oligonu-cleotide probes and amplified DNA. Immunogenetics 33: 163–170PubMedCrossRefGoogle Scholar
  16. 16.
    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: 33–55CrossRefGoogle Scholar
  17. 17.
    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: 527–530CrossRefGoogle Scholar
  18. 18.
    Gay EC, Hamman RF, Carosone-Link PJ et al. (1989) Colorado IDDM registry: lower incidence of IDDM in Hispanics. Diabetes Care 12: 708–710CrossRefGoogle Scholar
  19. 19.
    Cruickshanks KJ, Jobim LF, Lawner-Heavner J et al. (1994) Ethnic differences in human leukocyte antigen markers of susceptibility to IDDM. Diabetes Care 17: 132–137PubMedCrossRefGoogle Scholar
  20. 20.
    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: 284–292PubMedCrossRefGoogle Scholar
  21. 21.
    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 431–439Google Scholar
  22. 22.
    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: 1462–1468PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • M. Rewers
    • 1
  • T. L. Bugawan
    • 2
  • J. M. Norris
    • 1
  • A. Blair
    • 2
  • B. Beaty
    • 1
  • M. Hoffman
    • 1
  • R. S. McDuffie
    • 4
  • R. F. Hamman
    • 1
  • G. Klingensmith
    • 3
  • G. S. Eisenbarth
    • 3
  • H. A. Erlich
    • 2
  1. 1.Department of Preventive Medicine and BiometricsUniversity of Colorado, School of MedicineDenverUSA
  2. 2.Human Genetics DepartmentRoche Molecular Systems, Inc.AlamedaUSA
  3. 3.Barbara Davis Center for Childhood DiabetesDenverUSA
  4. 4.Department of Obstetrics and GynecologyKaiser Permanente and St. Joseph’s HospitalDenverUSA

Personalised recommendations