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In this study, we examined temporal changes in the incidence of primary biliary cirrhosis (PBC) and investigated associations between PBC incidence and sociodemographic factors and spatial clustering. We included 982 patients aged ≥40 years from North East England with incident PBC diagnosed during 1987–2003. Age-standardized incidence rates with 95% confidence intervals were calculated. Negative binomial regression was used to analyze incidence and socioeconomic deprivation. Clustering analysis was performed using point process methods, testing the null hypothesis that disease risk does not vary spatially and that PBC cases occur independently. The age-standardized incidence rate was 53.50 per million persons per year (95% confidence interval: 48.65, 58.35) in 1987–1994 and 45.09 per million persons per year (95% confidence interval: 41.10, 49.07) in 1995–2003. Risk of PBC increased in areas with higher levels of socioeconomic deprivation (P = 0.035). More specifically, risk increased in areas with higher levels of overcrowded homes (P = 0.040), higher levels of households without cars (P < 0.001), and higher levels of non-owner-occupied homes (P < 0.001). Overall, there was evidence of spatial clustering (P = 0.001). The findings confirm that overall incidence of PBC did not rise over time, but sociodemographic variations suggest that certain aspects of deprivation are involved in its etiology. [ABSTRACT FROM PUBLISHER]

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). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10?8) and replicated all previously associated loci. We identified three further new loci in a 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. [ABSTRACT FROM AUTHOR]

The aetiology of primary biliary cirrhosis (PBC) is not well established. Previously we found evidence of space-time clustering and seasonal variation in the date of diagnosis, suggesting a possible role for a transient or seasonally varying environmental factor. We examined whether a temporally varying environmental agent may be involved by analysing population-based PBC data from northeast England over 1987-2003. Using an adaptation of a method proposed by Potthoff and Whittinghill, we found significant temporal variation by date of diagnosis at the level of aggregation of one year. However, there was no evidence for general irregular (non-seasonal) temporal clustering within periods less than a year. These results provide little support for the involvement of agents occurring in geographically widespread mini-epidemics, but--taken together with studies of spatial and spatio-temporal clustering--do not preclude the role of more localised sporadic mini-epidemics. Future research should seek to elicit putative environmental agents., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Unlabelled: The etiology of primary biliary cirrhosis (PBC) is far from clear. Both genetic and environmental factors are likely to be involved. We have previously reported evidence of space-time clustering, suggesting that a transient environmental agent may be involved in etiology. To further examine whether a seasonally varying environmental agent may contribute to the etiology of PBC, we have analyzed seasonal variation with respect to month of diagnosis using population-based data from northeast England over a defined period (1987-2003). Date of diagnosis was defined as the earliest date at which the patient was found to have fulfilled any two of three diagnostic criteria (i.e., antimitochondrial antibody-positive titer ≥1 in 40, cholestatic liver blood tests, diagnostic or compatible liver histology). Monthly expected (E) numbers of cases were calculated under an assumption of a uniform distribution throughout the year. Observed counts (O) were compared with the expected numbers. The chi-squared heterogeneity test was used to test for overall nonuniform variation and also for individual months. Poisson regression analysis was used to fit a sinusoidal (i.e., harmonic) model to the data, using month of diagnosis as a covariate in the model. There was a marked peak for diagnoses in the month of June (O = 115, E = 84.7, O/E = 1.36; P = 0.001). Furthermore, there was evidence of a sinusoidal pattern with a June peak (P = 0.012)., Conclusion: These highly novel results provide further evidence for the involvement of a seasonally varying environmental agent in the etiology of PBC., (Copyright © 2011 American Association for the Study of Liver Diseases.)

The cause of primary biliary cirrhosis (PBC) is unclear. Both genetic and environmental factors are likely to contribute. Some studies have suggested that one or more infectious agents may be involved. To examine whether infections may contribute to the cause of PBC, we have analyzed for space-time clustering using population-based data from northeast England over a defined period (1987-2003). Space-time clustering is observed when excess cases of a disease are found within limited geographical areas at limited periods of time. If present, it is suggestive of the involvement of one or more environmental components in the cause of a disease and is especially supportive of infections. A second-order procedure based on K-functions was used to test for global space-time clustering using residential addresses at the time of diagnosis. The Knox method determined the spatiotemporal range over which global clustering was strongest. K-function tests were repeated using nearest neighbor thresholds to adjust for variations in population density. Individual space-time clusters were identified using Kulldorff's scan statistic. Analysis of 1015 cases showed highly statistically significant space-time clustering (P < 0.001). Clustering was most marked for cases diagnosed within 1-4 months of one another. A number of specific space-time clusters were identified. In conclusion, these novel results suggest that transient environmental agents may play a role in the cause of PBC.