No abstract

In addition to the HLA-locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). Twenty-eight loci were followed up in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 novel risk loci (P<5×10−8) and replicated all previously associated loci. Three further novel loci were identified by meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A, and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.

Modification of the current allocation system for donor livers in the United States to incorporate recipient serum sodium concentration ([Na]) has recently been proposed. However, the impact of this parameter on posttransplantation mortality has not been previously examined in a large risk-adjusted analysis. We assessed the effect of recipient [Na] on the survival of all adults with chronic liver disease who received a first single organ liver transplant in the UK and Ireland during the period March 1, 1994 to March 31, 2005 (n ϭ 5,152) at 3 years, during the first 90 days, and beyond the first 90 days, adjusting for a wide range of recipient, donor, and graft characteristics. Compared to those with normal [Na] (135-145 meq/L; n ϭ 3,066), severely hyponatremic recipients ([Na] Ͻ130 meq/L, n ϭ 541), had a higher risk-adjusted mortality at 3 years (hazard ratio [HR] 1.28; 95% confidence interval [CI], 1.04-1.59; P Ͻ 0.02). The excess mortality was, however, confined to the first 90 days (HR 1.55; 95% CI, 1.18-2.04; P Ͻ 0.002) with no significant difference thereafter. This was also true for hypernatremic recipients ([Na] Ͼ145 meq/L, n ϭ 81), who had an even greater risk-adjusted mortality compared to normonatremic recipients (overall: HR 1.85; 95% CI, 1.25-2.73; P Ͻ 0.002; Յ90 days: HR 2.29; 95% CI, 1.42-3.70; P Ͻ 0.001; Ͼ90 days: HR 1.12; 95% CI, 0.55-2.29; P ϭ 0.8), whereas mildly hyponatremic recipients ([Na] 130-134 meq/L, n ϭ 1,127) had similar risk-adjusted mortality to those with normal [Na] at the same time points. In conclusion, recipient [Na] is an independent predictor of death following liver transplantation. Attempts to correct the [Na] toward the normal reference range are an important aspect of pretransplantation management.