Cucca, Francesco and Goy, Juliet V. and Kawaguchi, Yoshihiko and Esposito, Laura and Merriman, Marilyn E. and Wilson, Amanda J. and Cordell, Heather J. and Bain, Stephen Charles and Todd, John A. (1998) A Male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients. Nature Genetics, Vol. 19 (3), p. 301-302. eISSN 1546-1718. Article.
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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 ratio. 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 cases. 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=9.3x10-7), 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 'DR4associated' and 'DR3-associated' diabetes. 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=2.7x10-4; single point MLS=4.5, P=2.7x10-5). 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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