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

Johannes R. Hov, Ana Lleo, Carlo Selmi, Bente Woldseth, Luca Fabris, Mario Strazzabosco, Tom H. Karlsen, Pietro Invernizzi

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Background & Aims: The HLA complex on chromosome 6p21 is firmly established as a risk locus for primary sclerosing cholangitis (PSC). We aimed to exploit genetic differences between Northern Europe and Italy in an attempt to define a causative locus in this genetic region. Methods: Seventy-eight North-Italian PSC patients and 79 controls were included. We performed sequencing-based genotyping of HLA-C, HLA-B, and HLA-DRB1. The major histocompatibility chain-related A (MICA) transmembrane microsatellite was analysed using PCR fragment length determination. The tumour necrosis factor-alpha (TNF-α)-308G→A polymorphism was genotyped with TaqMan®. Allele frequencies were compared with Chi-square tests. Uncorrected p-values <0.05 were considered statistically significant when replicating findings in previous studies. The p-values of novel associations were corrected for multiple comparisons (Bonferroni). Results: The frequency of the strong inhibitory HLA-C2 killer-immunoglobulin receptor (KIR) ligand variant was significantly reduced in PSC vs. controls (0.39 vs. 0.58, p = 0.0006). Consequently, HLA-C1 homozygosity was associated with an increased risk of PSC (OR 3.1; 95% CI 1.4-6.7, p = 0.004). Importantly, there were no significant associations with the HLA-Bw4 KIR ligand variant, at the neighbouring MICA locus or with TNF-α-308G→A. At HLA-DRB1, we confirmed positive and negative associations with DRB1*15 and DRB1*07, respectively, while there were no associations with the DRB1*03, *04 or *1301 alleles typically detected in PSC in Northern Europe. Conclusions: The strong inhibitory of the KIR ligand HLA-C2 protects against PSC development in all populations hitherto studied. Further studies on the role of natural killer cells and T-lymphocytes expressing KIRs in PSC pathogenesis are warranted.

Original languageEnglish (US)
Pages (from-to)712-717
Number of pages6
JournalJournal of Hepatology
Volume52
Issue number5
DOIs
StatePublished - May 2010
Externally publishedYes

Keywords

  • HLA
  • Killer immunoglobulin-like receptors
  • Natural killer cells
  • Primary sclerosing cholangitis

ASJC Scopus subject areas

  • Hepatology

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