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

Wellcome Trust Centre for Human Genetics, Nuffield Department of Surgery, University of Oxford, Headington, UK.
Nature Genetics (Impact Factor: 29.65). 06/1998; 19(3):301-302.

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,
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,
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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