Lazaridis, K.N.

Background: Patients with primary sclerosing cholangitis (PSC) are at risk for developing gallbladder neoplasia (GBN) and biliary neoplasia, including cholangiocarcinoma (CCA), because of chronic inflammation and an underlying field effect. However, the risk of CCA after GBN detection in those with PSC remains poorly understood. We aimed to determine if the incidence of CCA is higher in those with GBN. Methods: We conducted a retrospective review of adult patients with large-duct PSC seen at Mayo Clinic between January 1, 1995, and December 31, 2019. Incidence rates for CCA development were calculated. Cox regression analyses were performed to determine features associated with CCA development beginning at the time of PSC diagnosis. Results: Our study included 1,829 patients with PSC. CCA and GBN developed in 334 (18.26%) and 71 individuals (3.88%), respectively. Among those with GBN, 14 (19.72%) developed CCA. The annual incidence of CCA was nearly twofold higher in patients with GBN (4.34% versus 2.21%). GBN was associated with CCA in an unadjusted analysis (hazard ratio 2.14 [95% CI 1.16–3.94]). When adjusting for other predictors of CCA, an association between GBN and CCA may remain. Conclusions: While few patients with PSC develop GBN, this subgroup is more likely to develop CCA. Consequently, once GBN is detected, clinicians should consider more intensive screening for CCA.

Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non‐European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA‐DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA‐DQB1*06:03. In contrast, only 65% of HLA‐DRB1*13:01 haplotypes in an admixed/non‐European PSC population carried this allele, suggesting that further assessments of the PSC‐associated haplotype HLA‐DRB1*13:01‐DQA1*01:03‐DQB1*06:03 in admixed or multi‐ethnic populations could aid in identifying the causative allele.

Pharmacogenomics, studying genetic variation related to drug response, was established decades ago. Today, performing clinical pharmacogenomics testing has increased, creating great potential to improve patient care. Yet widespread implementation of pharmacogenomics in practice is currently limited, resulting in the “therapeutic odyssey” of patients. Preemptive clinical pharmacogenomics testing prior to the time of prescribing is now emerging as an option that could tailor the pharmacotherapy of patients by increasing drug effectiveness while reducing adverse drug reaction risk.