LAUSR

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by immune-mediated damage to biliary epithelial cells resulting in inflammation, progressive fibrosis, cirrhosis, and liver failure. While its precise etiopathogenesis remains unclear, the disease is likely to develop in a genetically susceptible host after exposure to an as yet undefined environmental trigger (Fig. 1). The genetic contribution to PBC risk is highlighted by several lines of evidence that demonstrate a high concordance of disease in monozygotic twins, an increased prevalence in first-degree relatives (FDRs) of affected probands, a sibling relative risk (RR) of 10.5, and a high prevalence of disease-specific antimitochondrial antibodies in FDRs of affected relatives compared to population controls. Furthermore, large-scale genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) associated with PBC, though the majority of these SNPs are also associated with other autoimmune diseases. In the current issue of HEPATOLOGY, Ornolfsson et al. use a unique Icelandic database to define the familial risk of PBC beyond FDRs. Applying population-level and otherwise unprecedented genealogical data on all living Icelanders and most of their ancestors since the island’s settlement, the authors report the RR of PBC and the average kinship coefficient in first-degree through fifth-degree relatives of PBC patients compared to age, sex, and number of known relative matched controls. A 9.13-fold (95% confidence interval [CI] 4.17-16.76) increased risk of PBC in FDRs was demonstrated, with a lower but still significantly increased risk also noted among seconddegree and third-degree relatives with RRs of 3.61 (95% CI 1.48-8.92) and 2.59 (95% CI 1.35-4.67), respectively. Among fourth-degree and fifth-degree relatives, the increased risk of PBC trended toward significance with RRs of 1.66 (95% CI 1.00-3.02) and 1.42 (95% CI 0.99-2.20), respectively. The kinship coefficient, defined as the probability that two randomly selected autosomal alleles from two individuals are inherited from the same ancestor, was used as a measure of relatedness of PBC patients compared to the general population. Using this metric, PBC patients were shown to be more genetically related than population controls, even after step-wise exclusion of relatives within one to six meiotic distances. The authors rightfully conclude that their data expand on previous reports by describing familial risk of disease well beyond FDRs. Furthermore, they suggest that these findings emphasize the importance of genetic risk in the pathogenesis of PBC and support future investment in understanding the genetic underpinnings of this disease. Do these data demonstrate that genetic susceptibility is acting alone to cause disease? Not necessarily. As with most autoimmune diseases, PBC is complex; and while genetics are important, it is highly likely that individual alleles are not deterministic but rather act by modifying risk through their effect on disease-specific Abbreviations: CI, confidence interval; FDR, first-degree relative; PBC, primary biliary cholangitis; RR, relative risk; SNPs, singlenucleotide polymorphisms.