Abstract
Genetic markers may be used to improve the prediction of insulin-dependent diabetes mellitus (type 1) in individuals with islet autoantibodies. In order to develop a risk assessment strategy for the Lombardy region of northern Italy based on genetic and immunological markers, we analyzed HLA DQA1 and DQB1 alleles in 60 type 1 probands and their first-degree relatives and 65 unrelated control subjects from the same area using polymerase chain reaction (PCR) and oligonucleotide probes. The major risk haplotypes were DQA1 *0501-DQB1 *0201 (39.1% of diabetic vs 8.9% of non-diabetic haplotypes) and DQA1 *0301-DQB1 *0302 (20% of diabetic vs 7.1% of non-diabetic haplotypes). Stratified analysis showed DQA1 *0102-DQB1 *0502 also to be associated with type 1 susceptibility when found together with DQA1 *0501-DQB1 *0201 or DQA1 *0301-DQB1 *0302. One type 1 patient had the type 1-protective DQA1 *0102-DQB1 *0602 haplotype. Overall, 88% of patients and 20% of unrelated control subjects had either DQA1 *0501-DQB1 *0201 or DQA1 *0301-DQB1 *0302 in the absence of DQA1 *0102-DQB1 *0602. These data suggest that typing for markers identifying these three haplotypes in the Lombardy population will achieve a sensitivity of almost 90% and exclude 80% of children from subsequent islet autoantibody testing.
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Bingley PJ, Bonifacio E, Gale EAM, Can we really predict IDDM? Diabetes 42:213–220, 1993
Gale EAM, Bingley PJ, Can we prevent diabetes? Diabetes Care 17:339–340, 1994
Skyler JS, Marks JB, Immune intervention in type I diabetes mellitus. Diabetes Rev 1:15–42, 1993
Bonifacio E, Bingley PJ, Shattock M, Dean BM, Dunger D, Gale EAM, Bottazzo GF, Quantification of islet cell antibodies and prediction of insulin-dependent diabetes. Lancet 335:147–149, 1990
Riley WJ, Maclaren NK, Krischer J, Spillar RP, Silverstein JH, Schatz DA, Schwartz S, Malone J, Shar S, Vadheim C, Rotter JI, A prospective study of the development of diabetes in relatives of patients with insulin-dependent diabetes. N Engl J Med 323: 1167–1172, 1990
Knip MP, Vahasalo P, Karjalainen J, Lounamaa R, Akerblom HK. The Childhood Diabetes in Finland Study Group, Natural history of preclinical IDDM in high risk siblings. Diabetologia 37:388–393, 1994
Dahlquist G, Blom L, Tuvemo T, Nystrom L, Sandstrom A, Wall S, The Swedish childhood diabetes study, Results from a nine year case register and a one year case-referent study indicating that type 1 (insulin-dependent) diabetes mellitus is associated with both type 2 (non-insulin-dependent) diabetes mellitus and autoimmune disorders. Diabetologia 32:2–6, 1989
Bingley PJ, Bonifacio E, Shattock M, Gillmor HA, Sawtell PA, Dunger DB, Scott RDM, Bottazzo GF, Gale EAM, Can islet cell antibodies predict IDDM in the general population? Diabetes Care 16:45–50, 1993
Bingley PJ, Christie MR, Bonifacio E, Bonfanti R, Shattock M, Fonte MT, Bottazzo GF, Gale EAM, Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives. Diabetes 43:1304–1310, 1994
Genovese S, Bingley PJ, Bonifacio E, Christie MR, Shattock M, Bonfanti R, Foxon R, Gale EAM, Bottazzo GF, Combined analysis of IDDM-related autoantibodies in healthy schoolchildren. Lancet 234:756, 1994
Bonifacio E, Genovese S, Braghi S, Bazzigaluppi E, Lampasona V, Bingley PJ, Rogge L, Pastore MR, Bognetti E, Bottazzo GF, Gale EAM, Bosi E, Islet autoantibody markers in IDDM: identification of screening strategies for risk assessment yielding high sensitivity. Diabetologia 38:816–822, 1994
Ziegler AG, Hillebrand B, Rabl W, Mayrhofer M, Hummel M, Mollenhauer U, Vordemann J, Lenz A, Standl E, On the appearance of islet associated autoimmunity in offspring of diabetic mothers: a prospective study from birth. Diabetologia 36:402–408, 1993
Todd JA, Bell JI, McDevitt HO, HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329:599–604, 1987
Morel PJ, Dorman J, Todd JA, McDevitt HO, Trucco M, Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study. Proc Natl Acad Sci USA 85:8111–8115, 1988
Khalil I, d'Auriol L, Gobet M, Morin L, Lepage V, Deschamps I, Park MS, Galibert F, Hors J, A combination of HLA-DQ Asp57-negative and HLA-DQ Arg52 confers susceptibility to insulin-dependent diabetes mellitus. J Clin Invest 85:1315–1319, 1990
Khalil I, Deschamps I, Lepage V, Al-Dakkar R, Degos L, Hors J, Dose effect ofcis andtrans encoded HLA-DQαβ heterodimers in IDDM susceptibility. Diabetes 41:378–385, 1992
Gutierrez-Lopez MD, Bertera S, Chantres MT, Vavassori C, Dorman JS, Trucco M, Serrano-Rios M, Susceptibility to type 1 (insulin-dependent) diabetes mellitus in Spanish patients correlates quantitatively with the expression of HLA-DQα arg52 and HLA-DQβ non-Asp57 alleles. Diabetologia 35:583–588, 1992
Buzzetti R, Nisticò L, Osborne JF, Giovannini C, Chersi A, Sorrentino R, HLA-DQA1 and DQB1 gene polymorphism in type I diabetic patients from central Italy and their use for risk prediction. Diabetes 42:1173–1178, 1993
Buyse I, Sandkuyl LA, Zamani Ghabanbasani M, Gu X-X, Bouillon R, Bex M, Dooms L, Emonds MP, Duhamel M, Marynen P, Cassiman JJ, Association of particular HLA class II alleles, haplotypes and genotypes with susceptibility to IDDM in the Belgian population. Diabetologia 37:808–817, 1994
Dorman JS, LaPorte RE, Stone RA, Trucco M, Worldwide differences in the incidence of type I diabetes are associated with amino acid variation at position 57 of the HLA-DQβ chain. Proc Natl Acad Sci USA 87:7370–7374, 1990
Maniatis TM, Fritsch EF, Sambrook J, Molecular cloning. A laboratory manual. Cold Spring Harbor Laboratory, New York, 1990
Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuci R, Horn GT, Mullis KB, Erlich HA, Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239:487–491, 1988
Thomson G, HLA disease associations: models for insulin dependent diabetes mellitus and the study of complex human genetic disorders. Annu Rev Genet 22:31–50, 1988
Santamaria P, Boyce-Jacino MT, Lindstrom AL, Barbosa JJ, Faras AJ, Rich S, Detection of novel sequence heterogeneity and haplotypic diversity of HLA class II genes. Immunogenetics 33:374–387, 1991
Ronningen KS, Spurklans A, Tait BD, et al, Joint report: HLA class I associations in insulin-dependent diabetes mellitus among blacks, caucasoids, and Japanese. In: Tsuji K et al (eds) HLA 1991. Proceedings of the 11 th International Histocompatibility Workshop and Conference, Vol 1. Oxford University Press, Oxford, pp 713–722, 1993
Vela M, D'Adorno D, Longo A, Papola F, Maccarone D, Centis D, Raponi MP, Candela A, Orsini M, Ferrara GB, HLA typing data on 100 type I (insulin-dependent) diabetic patients from central Italy show a negative association with DR5 rather than DR2. Clin Immunol Immunopathol 45:143–146, 1987
Sorrentino R, De Grazia U, Buzzetti R, Nisticò L, Iannicola C, Costanzi S, Tosi R, An explanation for the neutral effect of DR2 on IDDM susceptibility in central Italy. Diabetes 41:904–908, 1992
Carcassi C, Trucco G, Trucco M, Contu L, A new HLA-DR2 extended haplotype is involved in insulin-dependent diabetes mellitus susceptibility. Hum Immunol 31:159–164, 1991
Reijonen H, Ilonen J, Knip M, Akerblom HA, HLA-DQB1 alleles and absence of Asp 57 as susceptibility factors of IDDM in Finland. Diabetes 40:1640–1644, 1991
Lévy-Marchal C, Tichet J, Faraday I, Dubois XF, Czernichow P, Islet cell antibodies in normal schoolchildren. Diabetologia 35:577–582, 1992
Boehm BO, Manfras B, Seißler J, Schoffling K, Gluck M, Holzberger G, Seidl S, Kuhnl P, Trucco M, Scherbaum W, Epidemiology and immunogenetic background of islet cell antibody-positive nondiabetic schoolchildren. Diabetes 40:1435–1439, 1991
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Lampasona, V., Ferrari, M., Bonifacio, E. et al. HLA-DQ screening for risk assessment of insulin dependent diabetes in northern Italy. Acta Diabetol 32, 137–142 (1995). https://doi.org/10.1007/BF00838481
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DOI: https://doi.org/10.1007/BF00838481