Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: The role of MICA polymorphism

Norris, Suzanne; Kondeatis, E; Collins, R. W.; Satsangi, Jack; Clare, Mike; Chapman, Roger W.; Stephens, Henry A.F.; Harrison, Phillip; Vaughan, R. W.; Donaldson, Peter

doi:10.1053/gast.2001.24041

Cited by 102 publications

(60 citation statements)

References 39 publications

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“…In contrast, the MICA*008 allele, which is the main allele carrying the MICA5.1 microsatellite allele, was recently reported to be increased among PSC patients, as a result of an increase in MICA*008 homozygous patients. 36 This association was found to be independent of linkage with B7 and B8, whereas stratification for DR3 and DR2 was not performed. We found the number of MICA5.1(MICA*008)-positive PSC patients to be higher than among British patients studied by Norris et al (90% vs. 74%, respectively).…”

Section: Discussionmentioning

confidence: 89%

Primary sclerosing cholangitis is associated to an extended B8-DR3 haplotype including particular MICA and MICB alleles

WIENCKE¹,

SPURKLAND²,

SCHRUMPF³

et al. 2001

Hepatology

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Susceptibility to primary sclerosing cholangitis (PSC) is associated with HLA-B8, -DR3, -DR2, and -DR6. It is not established whether these HLA genes or closely linked genes confer the primary disease susceptibility. MICA and MICB genes are found in the class I region between HLA-B and DRB. MICA is expressed in gastrointestinal epithelium and activates ␥␦ T cells in the gut. Because PSC is strongly associated with inflammatory bowel disease, we investigated whether MICA and MICB contribute to the HLA-associated genetic susceptibility to develop PSC. The study included 130 PSC patients and 306 healthy controls, previously typed for HLA class I and II genes, typed for 5 MICA and 15 MICB microsatellite alleles. The phenotype frequencies of MICA5.1 and MICB24 were significantly increased among PSC patients compared with controls (90% vs. 74%; odds ratio [OR] ‫؍‬ 3.2; P c ‫؍‬ 3 ؋ 10 ؊3 and 58% vs. 29%; OR ‫؍‬ 3.3; P c < 1 ؋ 10 ؊7 , respectively). When stratified for B8-or DR3-positive and -negative individuals, the association of these markers to PSC was no longer evident. However, we observed that B8 and DR3 were associated to PSC only in the presence of both MICA5.1 and MICB24 markers. The frequency of individuals carrying all 4 alleles was significantly increased among the PSC patients compared with controls (49% vs. 18%; OR ‫؍‬ 4.5; P c < 1 ؋ 10 ؊7 ). Our data indicate that PSC is associated to the extended B8-MICA5.1-MICB24-DR3 haplotype. (HEPATOLOGY 2001;34:625-630.)Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by inflammatory and fibrotic bile duct lesions forming multiple strictures and ectatic dilatations of the intra-and extrahepatic bile ducts.

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Section: Discussionmentioning

confidence: 89%

Primary sclerosing cholangitis is associated to an extended B8-DR3 haplotype including particular MICA and MICB alleles

WIENCKE¹,

SPURKLAND²,

SCHRUMPF³

et al. 2001

Hepatology

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“…To date, 10 of these 56 have been evaluated in PSC including the human leukocyte antigen (HLA) class I A, B, and Cw genes; the HLA class II DRB, DQA, DQB, and DPB genes; and two genes from the MHC class III region, MICA and TNFA. 60,62,63 Six different MHC haplotypes have been associated with PSC (Table 5), 3 with an increased and 3 with a reduced risk of disease. Some haplotypes appear to carry several risk alleles (B8-TNFA*2-MICA*008-DRB1*0301 haplotype), while others carry only one (MICA*002).…”

Section: Sessions Three and Four Pathogenesismentioning

confidence: 99%

Primary sclerosing cholangitis: Summary of a workshop

et al. 2006

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Primary sclerosing cholangitis (PSC) is a rare but important liver disease that leads to cirrhosis and need for liver transplantation in a high proportion of cases. The disease occurs in approximately 1 per 100,000 population per year, usually presents in adulthood, and affects men more often than women. Typical serum biochemical results, autoantibodies and liver biopsy are suggestive but not diagnostic of PSC, the diagnosis requiring cholangiographic demonstration of stricturing and dilatation of the intra-and/or extra-hepatic bile ducts. The natural history of PSC is variable, the average survival being 12 to 17 years. The cause of PSC is still unknown. Although considered an autoimmune disease, PSC has several atypical features and a strong genetic component. The therapy of PSC is unsatisfactory. Standard doses of ursodeoxycholic acid (UDCA) lead to improvements in biochemical abnormalities but not in histology, cholangiographic appearance or survival. Several innovative therapies have been tried in PSC, but with scant evidence of benefit. For patients with high grade strictures, endoscopic dilatation is beneficial. Liver transplantation is successful for end-stage liver disease due to PSC and improves survival. PSC may recur after transplantation but is rarely progressive. The most dreaded complication of PSC is cholangiocarcinoma. Diagnosis of this highly malignant tumor is difficult, and there are no biomarkers for its early detection. Liver transplantation for cholangiocarcinoma has an exceedingly poor outcome, although transplantation with neoadjuvant chemoirradiation holds promise in selected patients. Thus, significant opportunities remain for basic and clinical research into the cause, natural history, and therapy of PSC. 44:746-764.)

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“…A HLA association in PSC was first identified for HLA-B8 (i.e., H LA -B* 0801) a n d D R 3 (i .e., DRB1*0301) [24,50] . Later studies have verified that PSC associations exist also for the other alleles of the AH8.1 (the HLA-A1 allele [51] , the HLA-C7 allele [52] , the major histocompatibility complex classⅠchain-related A (MICA) *008/5.1 allele [53,54] , and the tumour necrosis factor alpha (TNFα) promoter -308 A allele [55,56] ). This haplotype is associated with a wide range of autoimmune diseases [57,58] .…”

Section: The Hla Complex and Genetic Associations Observed In Pscmentioning

confidence: 98%

“…The PSC-associated MICA*008/5.1 allele has been proposed as a common denominator between the PSCassociated A*01-C*07-B*08-DRB1*0301-DQB1*0201 a n d A * 0 3 -C * 0 7 -B * 0 7 -D R B 1 * 1 5 0 1 -D Q B 1 * 0 6 0 2 haplotypes [53,59] . MICA functions as a ligand for the activating NKG2D receptor on NK cells [66] .…”

Section: The Hla Complex and Genetic Associations Observed In Pscmentioning

confidence: 99%

Genetic epidemiology of primary sclerosing cholangitis

Karlsen

Schrumpf²,

Boberg³

2007

WJG

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The aetiology of primary sclerosing cholangitis (PSC) is not known. A more than 80-fold increased risk of PSC among first-degree relatives emphasizes the importance of genetic factors. Genetic associations within the human leukocyte antigen (HLA) complex on chromosome 6p21 were detected in PSC 25 years ago. Subsequent studies have substantiated beyond doubt that one or more genetic variants located within this genetic region are important. The true identities of these variants, however, remain to be identified. Several candidate genes at other chromosomal loci have also been investigated. However, according to strict criteria for what may be denominated a susceptibility gene in complex diseases, no such gene exists for PSC today. This review summarises present knowledge on the genetic susceptibility to PSC, as well as genetic associations with disease progression and clinical subsets of particular interest (inflammatory bowel disease and cholangiocarcinoma).

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Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: The role of MICA polymorphism

Cited by 102 publications

References 39 publications

Primary sclerosing cholangitis is associated to an extended B8-DR3 haplotype including particular MICA and MICB alleles

Primary sclerosing cholangitis is associated to an extended B8-DR3 haplotype including particular MICA and MICB alleles

Primary sclerosing cholangitis: Summary of a workshop

Genetic epidemiology of primary sclerosing cholangitis

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