TY - JOUR
T1 - Genetic associations in Italian primary sclerosing cholangitis
T2 - Heterogeneity across Europe defines a critical role for HLA-C
AU - Hov, Johannes R.
AU - Lleo, Ana
AU - Selmi, Carlo
AU - Woldseth, Bente
AU - Fabris, Luca
AU - Strazzabosco, Mario
AU - Karlsen, Tom H.
AU - Invernizzi, Pietro
PY - 2010/5
Y1 - 2010/5
N2 - 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.
AB - 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.
KW - HLA
KW - Killer immunoglobulin-like receptors
KW - Natural killer cells
KW - Primary sclerosing cholangitis
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U2 - 10.1016/j.jhep.2009.11.029
DO - 10.1016/j.jhep.2009.11.029
M3 - Article
C2 - 20347497
AN - SCOPUS:77951620945
VL - 52
SP - 712
EP - 717
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 5
ER -