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Suggestive evidence for association of human chromosome 18q12-q21 and its orthologue on rat and mouse chromosome 18 with several autoimmune diseases

Merriman, Tony R. and Cordell, Heather J. and Eaves, Iain A. and Danoy, Patrick A. and Coraddu, Francesca and Barber, Rachael and Cucca, Francesco and Broadley, Simon and Sawcer, Stephen and Compston, Alastair and Wordsworth, Paul and Laval, Steven H. and Jirholt, Johan and Holmdahl, Rikard and Theofilopoulos, Argyrios N. and Kono, Dwight H. and Tuomilehto, Jaakko and Tuomilehto Wolf, Eva and Buzzetti, Raffaella and Marrosu, Maria Giovanna and Undlien, Dag Erik and Rønningen, Kjersti Skjold and Ionescu Tirgoviste, Constantin and Shield, Julian P. and Pociot, Flemming and Nerup, Jørn and Jacob, Chaim O. and Polychronakos, Constantin and Bain, Stephen Charles and Todd, John A. (2001) Suggestive evidence for association of human chromosome 18q12-q21 and its orthologue on rat and mouse chromosome 18 with several autoimmune diseases. Diabetes, Vol. 50 (1), p. 184-194. ISSN 0012-1797. Article.

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DOI: 10.2337/diabetes.50.1.184

Abstract

Some immune system disorders, such as type 1 diabetes, multiple sclerosis (MS), and rheumatoid arthritis (RA), share common features: the presence of autoantibodies and serf-reactive T-cells, and a genetic association with the major histocompatibility complex. We have previously published evidence, from 1,708 families, for linkage and association of a haplotype of three markers in the D18S487 region of chromosome 18q21 with type 1 diabetes. Here, the three markers were typed in an independent set of 627 families and, although there was evidence for linkage (maximum logarithm of odds score [MLS] = 1.2; P = 0.02), no association was detected. Further linkage analysis revealed suggestive evidence for linkage of chromosome 18q21 to type 1 diabetes in 882 multiplex families (MLS = 2.2; λs = 1.2; P = 0.001), and by meta-analysis the orthologous region (also on chromosome 18) is linked to diabetes in rodents (P = 9 × 10-4). By meta-analysis, both human chromosome 18q12-q21 and the rodent orthologous region show positive evidence for linkage to an autoimmune phenotype (P = 0.004 and 2 × 10-8, respectively, empirical P = 0.01 and 2 × 10-4, respectively). In the diabetes-linked region of chromosome 18q12-q21, a candidate gene, deleted in colorectal carcinoma (DCC), was tested for association with human autoimmunity in 3,380 families with type 1 diabetes, MS, and RA. A haplotype ("2-10") of two newly characterized microsatellite markers within DCC showed evidence for association with autoimmunity (P = 5 × 10-6). Collectively, these data suggest that a locus (or loci) exists on human chromosome 18q12-q21 that influences multiple autoimmune diseases and that this association might be conserved between species. As much as 5% of the population suffers from autoimmune disease, a failure of the homeostatic regulation of the immune system to prevent tissue damage and maintain self-tolerance. Predisposition to autoimmune disease is universally associated with alleles of the major histocompatibility complex (MHC) genes on chromosome 6p21 (1). However, the MHC is not sufficient to explain disease occurrence, and non-MHC susceptibility genes are predicted. In type 1 diabetes in humans, the evidence for non-MHC genes is incomplete (2,3), owing to the small, statistically underpowered data sets analyzed so far. In rodent models of disease, however, the existence and location of several non-MHC loci are established (1). It has also been shown in humans and mice that autoimmunity loci, mapped in a variety of autoimmune disease models, including those for type 1 diabetes and multiple sclerosis (MS), cluster significantly (1,4,5). Furthermore, congenic strains conclusively show that Idd3, a mouse non-MHC type 1 diabetes susceptibility locus, also influences susceptibility to experimental allergic encephalomyelitis (EAE), a model of MS (6), and iddm4 in rats may be a universal autoimmunity locus (7). In addition to the well-established linkage and association of the MHC region to multiple autoimmune phenotypes, the CTLA-4 gene locus on human chromosome 2 has been reported to be either linked or associated with type 1 diabetes, Graves' disease, and MS (8,9,10). Previously, we reported some positive evidence of linkage (P = 0.005) and association (Pc = 0.01) of diabetes to chromosome 18q21 in the vicinity of D18S487 (provisionally designated IDDM6) (11,12,13). In the present study, we were unable to replicate the D18S487 association result, but we have consolidated evidence of linkage of the region to type 1 diabetes by analysis of 882 families and by metaanalyses of other linkage studies of a variety of autoimmune diseases in humans and rodents. Finally, a large family-based study suggests that the human deleted in colorectal carcinoma (DCC) gene region of chromosome 18q21 is associated with autoimmune disease.

Item Type:Article
ID Code:4226
Status:Published
Refereed:Yes
Uncontrolled Keywords:Dependent diabetes-mellitus, collagen-induced arthritis, genome-wide search, experimental allergic encephalomyelitis, systemic-lupus-erythematosus, inflammatory bowel-disease, major susceptibility locus, multiple-sclerosis, genetic-analysis, polygenic control
Subjects:Area 06 - Scienze mediche > MED/03 Genetica medica
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:American Diabetes Association
ISSN:0012-1797
Deposited On:21 Jul 2010 11:03

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