Association and linkage analysis of candidate chromosomal regions in multiple sclerosis: indication of disease genes in 12q23 and 7ptr–15

Xu, Chun; Dai, Y; Fredrikson, Sten; Hillert, Jan

doi:10.1038/sj.ejhg.5200251

Cited by 22 publications

(12 citation statements)

References 14 publications

(34 reference statements)

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“…However, subsequent data 8,27,47 including the present study show a surprising consistence. Thus, based on available data, the following loci are likely to contain MS susceptibility genes having shown evidence for linkage: 6p21 (HLA complex), 5p, 17q21-25, 7pter-15, 7q34-36, 12p13-12, and 12q23.…”

Section: Discussionmentioning

confidence: 69%

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Linkage analysis in multiple sclerosis of chromosomal regions syntenic to experimental autoimmune disease loci

Dai

Lorentzen

et al. 2001

Eur J Hum Genet

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Multiple sclerosis is a demyelinating disorder of the central nervous system with a putative autoimmune aetiology in which several genes are thought to be involved. Four published genomic screens have confirmed that a gene influencing MS resides within or close to the HLA class II region in 6p21. Still, this locus is likely to confer only a part of the genetic susceptibility in MS. Further, all four studies identified a number of other regions with possible linkage. We have investigated eight chromosomal intervals syntenic to loci of importance for experimental autoimmune model diseases in the rat in 74 Swedish MS families. Possible linkage (a non-parametric linkage NPL score of 1.16 by GENEHUNTER computer package) was observed with markers in 12p13.3, a region syntenic to the rat Oia2 locus which is importance for oil induced arthritis (OIA). Four markers in the T cell receptor b chain gene region in 7q35 showed possible linkage (highest NPL score of 1.16). This locus is syntenic to the rat Cia3 locus (collagen induced arthritis). These two loci at least partially overlap with chromosomal regions showing indicative evidence for linkage in the previous MS genomic screens. Indeed, both Oia2 and Cia3 were recently found to be linked also with experimental autoimmune encephalomyelitis, a commonly used model for MS. Markers in 2p12, 3p25, 10q11.23, 19q13.1, and 22q12-13 failed to provide evidence for linkage. We conclude that evidence is amounting that 12p13-12 and 7q34-36 may harbour genes with an importance for MS. The synteny with experimental loci may eventually facilitate their identification.

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Section: Discussionmentioning

confidence: 69%

“…10 In fact, also for this locus we have in the present material previously reported possible linkage as well as association. 27 One of the identified loci, 7q34-36, contains the TCRb gene cluster. The TCRb gene has indeed been intensively investigated as a candidate susceptibility gene in MS.…”

Section: Discussionmentioning

confidence: 99%

Linkage analysis in multiple sclerosis of chromosomal regions syntenic to experimental autoimmune disease loci

Dai

Lorentzen

et al. 2001

Eur J Hum Genet

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“…Cia25 is of great interest, as it is in a region known to harbour several autoimmune disease-regulatory loci in rats, [27][28][29] in mouse chromosome 5, [43][44][45] and in the human syntenic regions on chromosomes 7q, 12q and 22q [46][47][48][49] genomes, including the arthritis loci Pia4 23 and Cia12. 25 Taken together, these data Figure 4 Cia25 influences the levels of anticollagen autoantibodies in males.…”

Section: Discussionmentioning

confidence: 99%

Cia25 on rat chromosome 12 regulates severity of autoimmune arthritis induced with pristane and with collagen

Laragione¹,

Mello²,

Gulko

2007

Annals of the Rheumatic Diseases

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Background: A genomewide scan in a DA6ACI F2 intercross studied for collagen-induced arthritis (CIA) identified the severity quantitative trait locus Cia25 on rat chromosome 12. Cia25 co-localises with loci regulating several forms of autoimmune diseases in rats, mice and humans, suggesting a common gene. Objective: To characterise the effects of Cia25 on severity of arthritis in congenic rats. Methods: DA.ACI(Cia25) congenic rats were constructed according to a genotype-guided strategy, and tested for pristane-induced arthritis (PIA) and CIA, induced with rat type II collagen (CII). A well-established scoring system previously shown to correlate with histological damage, including cartilage and bone erosions, synovial hyperplasia and synovial inflammation, was used. Results: The introgression of ACI alleles at Cia25 into DA background, as in DA.ACI(Cia25) rats, was enough to significantly reduce arthritis severity by 60% in PIA and by 40% in CIA, both in males and females compared with DA rats of the same sex. Levels of IgG anti-CII in male DA.ACI(Cia25) rats were 83% lower than in male DA. Levels of anti-CII in females were not affected by the congenic interval. Conclusions: Cia25 contains a gene that regulates disease severity in two distinct models of autoimmune arthritis. Although both genders were protected in arthritis studies, only male congenic rats had a dramatic reduction in levels of anti-CII, suggesting the possibility of a second arthritis gene in this interval that operates via the regulation of autoantibodies in a sex-specific manner. The identification of the gene(s) accounting for Cia25 is expected to generate novel prognostic biomarkers and targets for therapy.

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“…In particular, among a total of 19 candidate regions tested in four independent studies, [79][80][81][82] the previous linkage score was replicated for 5p15, 5q11, HLA, 6q24, 7p21, 7q11, 17q22 and Xp11 in at least one study. In particular, among a total of 19 candidate regions tested in four independent studies, [79][80][81][82] the previous linkage score was replicated for 5p15, 5q11, HLA, 6q24, 7p21, 7q11, 17q22 and Xp11 in at least one study.…”

Section: Search For Multiple Sclerosis Loci By Whole Genome Linkage Smentioning

confidence: 89%

Genetics of Multiple Sclerosis

Giordano

D’Alfonso

Momigliano–Richiardi

2002

American Journal of PharmacoGenomics

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Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system caused by an interplay of environmental and genetic factors. The only genetic region that has been clearly demonstrated by linkage and association studies to contribute to MS genetic susceptibility is the human leukocyte antigen (HLA) system. The majority of HLA population studies in MS have focused on Caucasians of Northern European descent, where the predisposition to disease has been consistently associated with the class II DRB1*1501-DQA1*0102-DQB1*0602 haplotype. A positive association with DR4 was detected in Sardinians and in other Mediterranean populations. Moreover DR1, DR7, DR11 have been found to be protective in several populations. Systematic searches aimed at identifying non-HLA susceptibility genes were undertaken in several populations by means of linkage studies with microsatellite markers distributed across the whole genome. The conclusion of these studies was that there is no major MS locus, and genetic susceptibility to the disease is most likely explained by the presence of different genes each conferring a small contribution to the overall familial aggregation. The involvement of several candidate genes was tested by association studies, utilizing either a population-based (case control) or a family-based (transmission disequilibrium test) approach. Candidate genes were selected mainly on the basis of their involvement in the autoimmune pathogenesis and include immunorelevant molecules such as cytokines, cytokine receptors, immunoglobulin, T cell receptor subunits and myelin antigens. With the notable exception of HLA, association studies met only modest success. This failure may result from the small size of the tested samples and the small number of markers considered for each gene. New tools for large scale screening are needed to identify genetic determinants with a low phenotypic effect. Large collaborative studies are planned to screen several thousands of patients with MS with several thousands of genetic markers. The tests are increasingly based on the DNA pooling procedure.

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Association and linkage analysis of candidate chromosomal regions in multiple sclerosis: indication of disease genes in 12q23 and 7ptr–15

Cited by 22 publications

References 14 publications

Linkage analysis in multiple sclerosis of chromosomal regions syntenic to experimental autoimmune disease loci

Linkage analysis in multiple sclerosis of chromosomal regions syntenic to experimental autoimmune disease loci

Cia25 on rat chromosome 12 regulates severity of autoimmune arthritis induced with pristane and with collagen

Genetics of Multiple Sclerosis

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