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

Nature Genetics volume 19, pages 301–302 (1998)Cite this article

Abstract

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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Acknowledgements

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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Authors and Affiliations

  1. Nuffield Department of Surgery, Wellcome Trust Centre for Human Genetics, University of Oxford, Windmill Road, Headington, OX3 7BN, Oxford, UK

    Francesco Cucca, Juliet V. Goy, Yoshihiko Kawaguchi, Laura Esposito, Marilyn E. Merriman, Amanda J. Wilson & John A. Todd

  2. Istituto di Clinica e Biologia dell'Eta' Evolutiva, Via Jenner, University of Cagliari, Cagliari, Italy

    Francesco Cucca

  3. Department of Epidemiology and Biostatistics, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, 44109, Ohio, USA

    Heather J. Cordell

  4. Department of Medicine, University of Birmingham, Birmingham Heartlands Hospital, Birmingham, B9 5SS, UK

    Stephen C. Bain

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  1. Francesco Cucca
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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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