Genetic factors of susceptibility and of severity in primary biliary cirrhosis☆

Background/Aims

In primary biliary cirrhosis (PBC), pathogenesis is influenced by genetic factors that remain poorly elucidated up to now. We investigated the impact of sequence diversity in candidate genes involved in immunity (CTLA-4 and TNFα), in bile formation (10 hepatobiliary transporter genes) and in the adaptative response to cholestasis (three nuclear receptor genes) on the susceptibility and severity of PBC.

Methods

A total of 42 Ht SNPs were identified and compared in 258 PBC patients and two independent groups of 286 and 269 healthy controls. All participants were white continental individuals with French ancestry.

Results

Ht SNPs of CTLA-4 and TNFα genes were significantly associated with susceptibility to PBC. The progression rate of liver disease under ursodeoxycholic acid (UDCA) therapy was significantly linked to SNPs of TNFα and SLC4A2/anion exchanger 2 (AE2) genes. A multivariate Cox regression analysis including clinical and biochemical parameters showed that SLC4A2/AE2 variant was an independent prognostic factor.

Conclusions

These data point to a primary role of genes encoding regulators of the immune system in the susceptibility to PBC. They also demonstrate that allelic variations in TNFα and SLC4A2/AE2 have a significant impact on the evolutive profile of PBC under UDCA therapy.

Abbreviations: PBC, primary biliary cirrhosis, CTLA-4, cytotoxic T-lymphocyte antigen 4, TNFα, tumor necrosis factor α, SNP, single nucleotide polymorphism, Ht SNP, haplotype-tagging single nucleotide polymorphism, MDR1, multidrug resistance 1, UDCA, ursodeoxycholic acid, AE2, anion exchanger 2, MDR3, multidrug resistance 3, BSEP, bile salt export pump, CFTR, cystic fibrosis transmembrane conductance regulator, FIC1, familial intrahepatic cholestasis 1, NTCP, Na-coupled taurocholate transport protein, LXRα, liver X receptor α, FXR, farnesoid X receptor, PXR, pregnane X receptor

Keywords: Cytotoxic T-lymphocyte antigen 4 (CTLA-4), Tumor necrosis factor α (TNFα), Anion exchanger 2 (AE2)/SLC4A2, Multidrug resistance 1 (MDR1)/ABCB1, Ursodeoxycholic acid (UDCA), Primary biliary cirrhosis (PBC)