Human Molecular Genetics, Vol 5, 1443-1448, Copyright © 1996 by Oxford University Press
JA Todd and M Farrall
Genome-wide scans for linkage of chromosome regions to type 1 diabetes in
affected sib pair families have revealed that the major susceptibility
locus resides within the major histocompatibility complex (MHC) on
chromosome 6p21 (lambda S = 2.4). It is recognized that the MHC contains
multiple susceptibility loci (referred to collectively as IDDM1), including
the class II antigen receptor genes, which control the major pathological
feature of the disease: T- lymphocyte-mediated autoimmune destruction of
the insulin-producing pancreatic beta cells. However, the MHC genes, and a
second locus, the insulin gene minisatellite on chromosome 11p15 (IDDM2;
lambda S = 1.25), cannot account for all of the observed clustering of
disease in families (lambda S = 15), and the scans suggested the presence
of other susceptibility loci scattered throughout the genome. There are
four additional loci for which there is currently sufficient evidence from
linkage and association studies to justify fine mapping experiments: IDDM4
(FGF3/11q13), IDDM5 (ESR/6q22), IDDM8 (D6S281/6q27) and IDDM12
(CTLA-4/2q33). IDDM4, 5 and 8 were detected by genome scanning, and IDDM12
by a candidate gene strategy. Seven other named loci are not discounted but
remain to be replicated widely. Multiple susceptibility loci were expected
as genome-wide scans of the mouse model of type 1 diabetes had shown that
although the MHC is the major mouse locus, at least 13 genes unlinked to
the MHC are involved in the development of disease. Genome-wide scans using
1000 affected sibpair families will be required to be confident that all
genes with effects on familial clustering equivalent to the insulin gene
locus (lambda S = 1.25) have been detected. The identification of
aetiological determinants requires exclusion of hitchhiking polymorphisms
in regions of linkage disequilibrium, as demonstrated for the MHC and the
insulin gene loci, and functional studies implicating the
disease-associated variant in pathogenesis. Ultimately, targeting of
specific candidate mutations in mice by homologous recombination and
replacement will be necessary to prove the primary role of any candidate
mutation.
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Panning for gold: genome-wide scanning for linkage in type 1 diabetes
Wellcome Trust Centre for Human Genetics, Nuffield Departments of Surgery, University of Oxford, Headington, UK.
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