Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population

Neri, Tauro Maria; Cavestro, Giulia Martina; Seghini, Pietro; Zanelli, Paola; Zanetti, Adele; Savi, M; Podda, Mauro; Zuin, Massimo; Colombo, Massimo; Floreani, Annarosa; Rosina, F.; Porro, G. Bianchi; Strazzabosco, Mario; Okolicsányi, Lajos

doi:10.1016/s1590-8658(03)00274-3

Cited by 28 publications

(21 citation statements)

References 42 publications

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“…In addition to HLA-BÃ08 and DRB1Ã03 (serologic B8 and DR3), the main HLA gene variants associated with PSC susceptibility are HLA-CwÃ07, a series of DRB1 alleles (DRB1Ã04, Ã07, Ã1301 and Ã15) and corresponding DRB3, DRB5, DQA, and DQB1 variants [6][7][8][9][10][11]. These associations could indicate that immune responses against specific (auto-) antigens are pathogenetically important in PSC.…”

Section: Introductionmentioning

confidence: 99%

Genetic associations in Italian primary sclerosing cholangitis: Heterogeneity across Europe defines a critical role for HLA-C

Hov

Lleo

Selmi

et al. 2010

Journal of Hepatology

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Section: Introductionmentioning

confidence: 99%

Genetic associations in Italian primary sclerosing cholangitis: Heterogeneity across Europe defines a critical role for HLA-C

Hov

Lleo

Selmi

et al. 2010

Journal of Hepatology

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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%

“…In individuals negative for DR3 and DR6, an association with haplotypes that carry the DR2 (i.e., DRB1*1501) allele can be found. Negative associations with HLA class Ⅱ alleles have been reported for the DR4, DR7 and DR11 alleles [37,59,60] , although primarily in populations of Northern European origin [56] . In Southern Europe, the picture is even more complex, since the DR4 allele seems to be consistent in LD with a predisposing variant in Italy [37,56] , whereas a protective effect is noted in Spain [37] .…”

Section: The Hla Complex and Genetic Associations Observed In Pscmentioning

confidence: 99%

“…Negative associations with HLA class Ⅱ alleles have been reported for the DR4, DR7 and DR11 alleles [37,59,60] , although primarily in populations of Northern European origin [56] . In Southern Europe, the picture is even more complex, since the DR4 allele seems to be consistent in LD with a predisposing variant in Italy [37,56] , whereas a protective effect is noted in Spain [37] . Due to strong LD, an important question in HLA genetics is whether genetic associations are due to variation in the HLA classⅠor Ⅱ genes (meaning that they arise because the patients are able to present particular antigens to the T-cell receptor) [61] , or due to variation in neighbouring genes [62] .…”

Section: The Hla Complex and Genetic Associations Observed In Pscmentioning

confidence: 99%

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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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“…In line with TGR5 involvement in glucose regulation, different CFTR genotypes do affect the risk of diabetes development, and intriguingly, other genes are probably also involved [28]. Studies of CFTR variation have been performed in PSC with variable conclusions [29,30,31,32,33], but reduced CFTR function have been reported in PSC patients [29,30], even in the absence of CFTR mutations [30]. In one study, dextran sodium sulfate-induced colitis in Cftr knockout mice led to significant bile duct injury at day 14, as evaluated by histology (mononuclear cell inflammatory infiltrates associated with bile duct proliferation) and alkaline phosphatase levels [34], while the wild-type mice were unaffected.…”

Section: Chromosome 2q35 and The Bile Acid Receptor Tgr5mentioning

confidence: 99%

TGR5 Sequence Variation in Primary Sclerosing Cholangitis

Hov

Keitel²,

Schrumpf³

et al. 2011

Dig Dis

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TGR5, the G-protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways and homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC), a chronic inflammatory bile duct disease associated with ulcerative colitis (UC). In addition, the TGR5 gene is localized at chromosome 2q35, close to a genetic variant associated with both PSC and UC in recent genome-wide association studies. This provided a strong rationale for a recent study searching for novel genetic variants of TGR5 in PSC. In the study, resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. In experimental studies, five of the nonsynonymous mutations were found to reduce or abolish TGR5 function by affecting localization or activity. Fine-mapping of the chromosome 2q35 locus in large patient panels revealed an overall association between a common TGR5 single-nucleotide polymorphism and PSC and UC, but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes. In conclusion, the data from the experimental evaluation of novel nonsynonymous mutations represent an important insight into the structural biology of TGR5. In addition, the combination of the known roles of the receptor, the genetic associations and the mutations which affect receptor function, suggests that TGR5 variation may contribute to PSC and UC susceptibility. However, this conclusion needs to be strengthened in further research.

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Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population

Cited by 28 publications

References 42 publications

Genetic associations in Italian primary sclerosing cholangitis: Heterogeneity across Europe defines a critical role for HLA-C

Genetic associations in Italian primary sclerosing cholangitis: Heterogeneity across Europe defines a critical role for HLA-C

Genetic epidemiology of primary sclerosing cholangitis

TGR5 Sequence Variation in Primary Sclerosing Cholangitis

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