It is generally assumed that the male:female (M:F) ratio in patients with type 1 (insulin-dependent) diabetes mellitus (IDDM) is 1. A recent survey, however, revealed that high incidence countries (mainly European) have a high M:F ratio and low incidence ones (Asian and African) have a low M:F ratio1. We have now analysed the M:F ratio according to genotype at the major locus, the major histocompatibility complex (MHC; IDDM1). There are two main IDDM1 susceptibility haplotypes, HLA-DR3 and -DR4, which are present in 95% of Caucasian cases2,3,4. We report here that in medium/high incidence Caucasian populations from the United States of America, United Kingdom and Sardinia (1307 cases), the bias in male incidence is largely restricted to the DR3/X category of patients (X ≠ DR4) with a M:F ratio of 1.7 (P = 9.3 × 10–7), compared with a ratio of 1.0 in the DR4/Y category (Y ≠ DR3). This is additional evidence for significant heterogeneity between the aetiology of 'DR4-associated' and 'DR3-associated' diabetes5,6,7,8,9,10,11,12,13. We analysed linkage of type 1 diabetes to chromosome X, and as expected, most of the linkage to Xp13–p11 was in the DR3/X affected sibpair families (n = 97; peak multipoint MLS at DXS1068 = 3.5, P = 2.7 × 10–4; single point MLS = 4.5, P = 2.7 × 10–5). This is evidence for aetiological heterogeneity at the IDDM1/MHC locus and, therefore, in the search for non-MHC loci in type 1 diabetes, conditioning of linkage data by HLA type is advised.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Karvonen, M. et al. Sex difference in the incidence of insulin-dependent diabetes mellitus: an analysis of recent epidemiological data. Diabetes Metab. Rev. 13, 275–291 (1997).
Cucca, F. & Todd, J.A. in HLA/MHC: genes, molecules and function (eds Browning, M.J. & McMichael, A.J.) 383– 406 (ßIOS Scientific Publishers, Oxford, 1996 ).
Thorsby, E. & Undlien, D. The HLA associated predisposition to type 1 diabetes and other autoimmune diseases. J. Pediatric Endocrinol. Metab. 9, 75–88 (1996).
She, J.-X. Susceptibility to type 1 diabetes: HLA-DQ and DR revisited. Immunol. Today 17, 323–329 (1996).
Ziegler, R. et al. Specific Association of HLA-DR4 With Increased Prevalence and Level of Insulin Autoantibodies in First-Degree Relatives of Patients With Type 1 Diabetes . Diabetes 40, 709–714 (1991).
Serjeantson, S.W. et al. Antibodies to glutamic acid decarboxylase are associated with HLA-DR genotypes in both Australians and Asians with type 1 (insulin-dependent) diabetes mellitus . Diabetologia 35, 996– 1001 (1992).
Vandewalle, C.L. et al. Insulin autoantibodies and high titre islet cell antibodies are preferentially associated with the HLA DQA1*0301-DQB1*0302 haplotype at clinical onset of Type 1 (insulin-dependent) diabetes mellitus before age 10 years, but not at onset between age 10 and 40 years. Diabetologia 36, 1155–1162 (1993).
Genovese, S. et al. Association of IA-2 autoantibodies with HLA-DR4 phenotypes in IDDM. Diabetologia 39, 1223–1226 (1996).
Sanjeevi, C.B., Falorni, A., Kockum, I., Hagopian, W.A. & Lernmark, A. HLA and glutamic acid decarboxylase in human insulin-dependent diabetes mellitus. Diabet. Med. 13, 209– 217 (1996).
Harrison, L.C. et al. Inverse relationship between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes. Lancet 341, 1365–1369 ( 1993).
Roep, B.O. et al. HLA-associated inverse correlation between T cell and antibody responsiveness to islet autoantigen in recent-onset insulin-dependent diabetes mellitus. Eur. J. Immunol. 26, 1285–1289 (1996).
Bottazzo, G.F., Florin-Christensen, A. & Doniach, D. Islet cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 2, 1279–1283 (1974).
Thomson, G. et al. Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of caucasians with insulin-dependent diabetes mellitus. Am. J. Hum. Genet. 43, 799–816 (1988).
Cucca, F. et al. Combinations of specific DRB1, DQA1, DQB1 haplotypes are associated with insulin-dependent diabetes mellitus in Sardinia. Hum. Immunol. 37, 85–94 (1993).
Davies, J.L. et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371, 130–136 ( 1994).
Cordell, H.J., Kawaguchi, Y., Todd, J.A. & Farrall, M. An extension of the maximum lod score method to X-linked loci. Ann. Hum. Genet. 59, 435–44 ( 1995).
Ilonen, J. et al. Rapid HLA-DQB1 genotyping for four alleles in the assessment of risk for IDDM in the Finnish population. Diabetes Care 19, 795–800 (1996).
Jackerott, M., Hornum, L., Andreasen, B.D. & Markholst, H. Segregation of autoimmune type 1 diabetes in a cross between diabetic BB and Brown Norway rats. J. Autoimmun. 10, 35– 41 (1997).
Bain, S.C., Todd, J.A. & Barnett, A.H. The British Diabetic Association - Warren Repository. Autoimmunity 7, 83–85 ( 1990).
Lernmark, A. et al. Family cell lines available for research. Am. J. Hum. Genet. 47, 1028–1030 (1990).
Bunce, M. et al. Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 and DQB1 by PCR with 144 primer mixes utilising sequence-specific primers (PCR-SSP). Tissue Antigens 46, 355– 367 (1995).
Wordsworth, B.P., Allsopp, C.E.M., Young, R.P. & Bell, J.I. HLA-DR typing using DNA amplification by the polymerase chain reaction and sequence hybridization to sequence-specific oligonucleotide probes. Immunogenet. 32, 413–418 (1990).
Kruglyak, L. & Lander, E.S. Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am. J. Hum. Genet. 57, 439–454 (1995).
We thank the Wellcome Trust, the Medical Research Council, the Italian Telethon, the Juvenile Diabetes Foundation and the British Diabetic Association for financial support; A. Cao, E. Angius, M. Silvetti, S. De Virgiliis, P. Zavattari, M. Congia, R.D. Jores and P. Reed for their help; M. Chessa, P. Frongia, R. Lampis, A.P. Mulargia, D. Macis and M. Loddo for help with Sardinian samples; the Human Biological Data Interchange for USA family DNA samples and HLA typing data; and the British Diabetic Association for provision of UK families. F.C. and J.A.T. are recipients of a Wellcome Trust Biomedical Research Collaboration Grant. J.A.T. is a Wellcome Trust Principal Research Fellow.
About this article
Cite this article
Cucca, F., Goy, J., Kawaguchi, Y. et al. A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients. Nat Genet 19, 301–302 (1998). https://doi.org/10.1038/995
The International Journal of Health Planning and Management (2019)
HLA-DQB1 Position 57 Defines Susceptibility to Isolated and Polyglandular Autoimmunity in Adults: Interaction With Gender
The Journal of Clinical Endocrinology & Metabolism (2019)
Journal of Epidemiology and Global Health (2017)
Inflammatory Bowel Diseases (2016)