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

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-alpha)-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-alpha-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.

Killer immunoglobulin-like receptor ligand HLA-Bw4 protects against multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system. A human leukocyte antigen (HLA) class II association is well established (DRB1*1501-DQB1*0602), but more recently HLA class II-independent associations with HLA class I variants have also been reported. The HLA class I (HLA-A, -B, -C) molecules serve as ligands for both T-cell receptors and killer immunoglobulin-like receptors (KIRs). We investigated the HLA class I alleles defined by their KIR binding motifs and the KIR genes to evaluate whether these genes could influence MS susceptibility or severity, alone or in combination. METHODS: We typed Norwegian MS patients (n = 631) and controls (n = 555) for HLA-A, -B, -C and -DRB1 alleles as well as the presence or absence of genes encoding inhibitory (KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5, KIR3DL1, KIR3DL2, KIR3DL3) and activating (KIR2DS1, KIR2DS2, KIR2DS3, KIR2DL4, KIR2DS4, KIR2DS5, KIR3DS1) KIRs. RESULTS: The frequency of the HLA-Bw4 specificity, which is the ligand for the inhibitory KIR3DL1, was significantly reduced in MS patients as compared with controls (41.4% vs 55.1%, p(uncorrected (uc)) = 4.6 x 10(-6)). Also after stratifying for known HLA class II associations, the HLA-Bw4 association was seen (p(uc) = 0.002). No significant differences in gene carrier frequencies of inhibitory and activating KIRs were observed. However, our data indicate that MS patients who carry the activating KIR2DS2 and the inhibitory KIR2DL2 genes have more severe disease than patients not carrying these genes. INTERPRETATION: Carriage of the ligand of the inhibitory KIR3DL1 receptor, HLA-Bw4, was found to protect against MS in an HLA-DRB1 independent manner.