title: A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients.
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 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 not = 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 'DR4-associated' 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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, Nuffield Department of Surgery, University of Oxford, Headington, UK.
authors.forename: F
authors.initials: F
authors.lastname: Cucca
authors.forename: J V
authors.initials: JV
authors.lastname: Goy
authors.forename: Y
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: L
authors.initials: L
authors.lastname: Esposito
authors.forename: M E
authors.initials: ME
authors.lastname: Merriman
authors.forename: A J
authors.initials: AJ
authors.lastname: Wilson
authors.forename: H J
authors.initials: HJ
authors.lastname: Cordell
authors.forename: S C
authors.initials: SC
authors.lastname: Bain
authors.forename: J A
authors.initials: JA
authors.lastname: Todd
mesh_terms: D000293:Adolescent; D000328:Adult; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D015803:HLA-DR3 Antigen / Q000235:genetics*; D006801:Humans; D008297:Male; D012727:Sex Characteristics; D014960:X Chromosome
chemical_list: D015803:HLA-DR3 Antigen