Summary
The question of HLA susceptibility to Type 1(insulin-dependent) diabetes mellitus remains unresolved. In the present study, 127 diabetic patients and 177 unrelated control subjects have been analysed for their class I and class II serological antigens, class II (DR, DQ) DNA restriction fragment length polymorphisms and DQA1 and B1 exon-2 nucleotide sequences and their corresponding amino acid residues. By using the aetiologic fraction (δ) as an almost absolute measure of the strongest linkage disequilibrium of an HLA marker to the putative Type 1 diabetes susceptibility locus, it has been found that the strength of association of the HLA markers may be quantified as follows: DR4 < DR3 < DR3 or DR4 < non-Aspartate 57 ßDQ and Arginine 52 αDQ < Arginine 52 αDQ. Thus, molecular HLA-DQ markers appear to be more accurate as susceptibility markers than the classic serologically defined ones (DR3 and DR4); however, any effect of DQ markers disapears when non-DR3/DR4 individuals are considered, suggesting that DR factors (or others in between DQ and DR) are also important. In addition, a dominant non-Aspartate 57 ßDQ susceptibility theory does not hold (but a recessive one does) in our diabetic population (probably due to the high frequency of the protective DR7-non-Aspartate 57 ßDQ haplotypes); Arginine 52 aDQ is the best single HLA marker found in our population, both as a recessive or as a dominant one. Also there are 13 patients in our sample who bear neither Arginine 52 aDQ nor non-Aspartate 57 ßDQ susceptibility factors. On the other hand, a predominant Type 1 diabetes association of Spanish patients to the B18-DR3-Dw25 haplotype (and not to B8-DR3-Dw24) has been found; this distinctive association has also been recorded in adult systemic lupus patients and may reflect the existence of common pathogenetic HLA factors for both diseases present only in the B18-DR3-Dw25 haplotype in the Spanish population. These factors are probably placed at the non-coding regions which are different from the B8-DR3-Dw24 haplotype.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Rubinstein P, Suciu-Foca N, Nicholson JF (1977) Genetics of juvenile diabetes mellitus. N Eng] J Med 297:1036–1040
Serrano-Rios M, Regueiro JR, Severino R, Lopez-Larrea C, Arnaiz-Villena A (1983) Several HLA haplotypic factors for both Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes. Diabetologia 25: 71 (Letter)
Todd JA, Mijovic C, Fletcher D, Jenkins D, Bradwell AR, Barnett AH (1989) Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. Nature 338:587–589
Bashir H, Juji T, Moffitt P (1983) Diabetes mellitus. In: Simons MJ, Tait BD (eds) Proceedings of the Second Asia and Ocean Histocompatibility Workshop Conference. Toorak, Immunopublishing, pp 332–342
Svejgaard A, Platz P, Ryder LP (1980) Insulin-dependent diabetes mellitus. In: Terasaki PI (ed) Histocompatibility testing 1980. UCLA Tissue Typing Laboratory, Los Angeles, pp 638–656
Todd JA, Bell JI, McDevitt HO (1987) HLA-DQP gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329: 599–604
Klitz W (1988) Inheritance of insulin dependent diabetes. Nature 333:710
Yamagata K, Nakajima H, Hanafusa T et al. (1989) Aspartic acid at position 57 of DQ β chain does not protect against Type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. Diabetologia 32: 762–764
Khalil I, d'Auriol L, Gobet M et al. (1990) A combination of HLA-DQP asp 57 negative and HLA DQa arg 52 confers susceptibility to IDDM. J Clin Invest 85:1315–1319
Sheehy MJ, Scharf SJ, Rowe JR et al. (1989) A diabetes-susceptible haplotype is better defined by a combination of HLA-DR and -DO alleles. J Clin Invest 83: 830–835
Carrier CM, Mollen WC, Rothman WC et al. (1989) Definition of IDDM-associated HLA-DQ and DX RFLP by segregation analysis of multiplex sibling. Hum Immunol 24:51–63
National Diabetes Data Group (1979) Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:1039–1057
Danilovs J, Terasaki PI, Park MS, Ayoub G (1980) B lymphocyte isolation by thrombin-nylon wool. In: Terasaki PI (ed) Histocompatibility testing 1980. UCLA Tissue Typing Laboratory, Los Angeles, pp 287–288
Arnaiz-Villena A, Vicario JL, Martínez-Laso J et al. (1989) An Eco RI polymorphic site in the human C4 gene distinguishes juvenile rheumatoid arthritis (JRA) susceptibility bearing haplotypes. Mol Immunol 26: 427–430
Vicario JL, Martínez-Laso J, Corell A, Regueiro JR, Arnaiz-Villena A (1990) Both HLA class II and class III restriction fragment length polymorphism factors linked to rheumatoid juvenile arthritis. Clin Immunol Immunopathol 56: 22–28
Bidwell J, Jarrold E (1986) HLA-DR allogenotypingusing exonspecific cDNA probes and application of rapid minigel methods. Mol Immunol 10:1111–1116
Auffray C, Lillie JW, Arnot D, Grossberger D, Kappes D, Strominger JL (1984) Isotypic and allotypic variation of human class 11 histocompatibility antigen α-chain genes. Nature 308:227–333
Larhammar D, Schanning L, Gustafson K, Claesson L, Rask L, Peterson PA (1982) Complete amino acid sequence of an HLADR antigen-like β-chain as predicted from the nucleotide sequence. Similarities with immunoglobulins and HLA-A, -B, -C antigens. Proc Natl Acad Sci USA 79:3687–3691
Corell A, Martin-Villa JM, Varela P, Vicario JL, Martínez-Laso J, Arnaiz-Villena A (1990) Exon-2 DNA sequence of the DRw13b allele obtained from the genomes of five different individuals. Mol Immunol 27: 313–317
Nepom GT, Byers P, Seyfried C et al. (1989) HLA genes associated to rheumatoid arthritis. Identification of susceptibility alleles using specific oligonucleotide probes. Arthr Rheum 32: 15–19
Bidwell J (1988) DNA-RFLP analysis and genotyping of HLADR and DQ antigens. Immunology Today 1:18–23
Martínez-Laso J, Vicario JL, Corell A, Morales P, Regueiro JR, Arnaiz-Villena A (1989) A new HLA-DQA1 RFLP allele (DQα3b) distinguishes between genes of DQw2-DR3 and DQw3-DR5 haplotypes. Nuc Acids Res 12:4911
Martínez-Laso J, Vicario JL, Regueiro JR, Corell A, Paz-Artal E, Arnaiz-Villena A (1989) Description of an HLA-DQA1 RFLP allele (DQα4) defining DQw4/DRw8-bearing haplotypes. Nuc Acids Res 10: 4006
Bodmer JG, Marsh SGE, Albert ED et al. (1991) Nomenclature for factors of the HLA system, 1990. Hum Immunol 31:186–194
Bengtsson B, Thomson G (1981) Measuring the strength of associations between HLA antigens and diseases. Tissue Antigens 18:356–363
Thomson G, Motro V, Selvin S (1983) Statistical aspects of measuring the strength of associations between HLA antigens and diseases. Tissue Antigens 21: 320–328
Segurado OG, Giles CM, Iglesias-Casarrubios P et al. (1991) C4 chido 3 and 6 distinguish two diabetogenic haplotypes: HLAB49, SC01, DR3, DQw2. Immunobiology 182:506–510
Segurado OG, Iglesias-Casarrubios P, Martínez-Laso J, Vicario JL, Corell A, Arnaiz-Villena A (1990) Two novel HLA-DRB Taq I RFLPs distinguish HLA-DR7-DQw9 (DRB4 null) from other DRB4 positive (including DR9-DQw9 haplotypes). Nuc Acids Res 18:1084
Morales P, Martínez-Laso J, Martin-Villa JM et al. (1991) High frequency of the HLA-DRB1*0405-(Dw15)-DQw8 haplotype in Spaniards and its relationship to diabetes susceptibility. Hum Immunol 32:170–175
Martínez-Laso J, Vicario JL, Corell A et al. (1991) Exclusive HLA-DQ factors do not explain susceptibility to insulin-dependent diabetes. Hum Immunol 31:134–138
Parham P (1990) A diversity of diabetes. Nature 345:662–663
Hitman GA, Niven MJ, Festestein H et al. (1987) HLA class II alpha gene polymorphisms in patients with insulin dependent diabetes mellitus, dermatitis herpetiformis and celiac disease. J Clin Invest 79:609–615
Lund T, O'Reilly J, Hutchins P et al. (1990) Prevention of insulindependent diabetes mellitus in non obese diabetic mice by transgenes encoding modified I-A β-chain or normal I-E α chain. Nature 345: 727–729
Maur MP, Danilovs JA (1980) Population analysis of HLA-A, B, C, DR, and other genetic markers. In: Terasaki PI (ed) Histocompatibility testing 1980. UCLA Tissue Typing Laboratory, Los Angeles, pp 955–993
Arnaiz-Villena A, Regueiro JR, Martínez-Laso J et al. (1989) HLA y alotipos del complemento (C4 y Bf) en diabéticos espanoles tipos I y II. Inmunologia 8:56–59
Contu L, Deschamps I, Lestradet H et al. (1982) HLA haplotype study of 53 juvenile insulin-dependent diabetic (IDD) families. Tissue Antigens 20:123–140
Cambon-de Mouzon A, Ohayon E, Hauptmann G et al. (1982) HLA-A, B, C, DR antigens Bf, C4 and GLO I polymorphisms in French Basques with insulin-dependent diabetes mellitus (IDDM). Tissue Antigens 19:366–379
Mercier P, Vallo JJ, Vialettes B, Vague Ph (1985) HLA-A, B, DR antigens and insulin-dependent diabetes in Algerians. Tissue Antigens 26:20–24
Roep BO, Arden SD, De Vries RP, Hutton JC (1990) T-cell clones from a type I diabetes patient respond to insulin secretory granule proteins. Nature 345: 632–634
Segurado OG, Iglesias-Casarrubios P, Martínez-Laso J, Corell A, Martin-Villa JM, Arnaiz-Villena A (1991) Autoimmunogenic HLA-DRB1*0301 allele (DR3) may be distinguished at the DRB1 non-coding regions of HLA-B8, DR3, Dw24 and B18, DR3, Dw25 haplotypes. Mol Immunol 28:189–192
Bignon JD, Semana G, Tiercy JM, Simons M, Lalouel JM, Cohen D (1989) DNA-RFLP analysis: HLA-DRP workshop report. In: Dupont B (ed) Immunobiology of HLA. Histocompatibility testing 1987, Vol I. Springer, New York, pp 851–860
Gomez-Reino JJ, Martínez-Laso J, Vicario JL et al. (1991) Immunogenetics of systemic lupus erythematosus in Spanish patients: differential HLA markers. Immunobiology 182: 465–471
Arnaiz-Villena A, Vazquez-Rodriguez JJ, Vicario JL et al. (1989) Congenital heart block immunogenetics. Evidence of an additional role of HLA class II antigens and independence of Ro autoantibodies. Arthr Rheum 32:1421–1426
Leiter EH, Serreze DV, Prochazka M (1990) The genetics and epidemiology of diabetes in NOD mice. Immunology Today 11: 147–149
Author information
Authors and Affiliations
Additional information
The contribution by J. L. Vicario and Jorge Martinez-Laso is equal and the order of authorship is arbitrary
Rights and permissions
About this article
Cite this article
Vicario, J.L., Martinez-Laso, J., Corell, A. et al. Comparison between HLA-DRB and DQ DNA sequences and classic serological markers as Type 11 (insulin-dependent)diabetes mellitus predictive risk markers in the Spanish population. Diabetologia 35, 475–481 (1992). https://doi.org/10.1007/BF02342447
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02342447