A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients


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.

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Figure 1: Multipoint linkage analysis of chromosome X in 580 families with conditioning by IDDM1/MHC HLA-DR genotype.


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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.

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Correspondence to John A. Todd.

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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

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