Investigative team wins NIDDK grant for Primary Sclerosing Cholangitis research

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Oct 22, 2018 | Konstantinos N. Lazaridis, M.D. | @klazaridis

A Mayo Clinic-led research consortium recently received a significant, five-year grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to study the pathogenesis and outcomes of Primary Sclerosing Cholangitis (PSC), a chronic, progressive liver disease that lacks effective medical therapy. Dr. Konstantinos Lazaridis, a hepatologist and an established clinician investigator from Mayo Clinic in Rochester, Minnesota, is the Principal Investigator of the study.

Investigative teams at four academic medical centers – Mayo Clinic, Emory University, University of Illinois Urbana-Champaign (UIUC), and University of Oslo, Norway – aim to define the gene-environment interactions driving the disease by using artificial intelligence approaches. In so doing, they will identify molecular disease signatures associated with environmental exposures, metabolism-related chemicals and gut bacteria that are unique to PSC patients. Another goal: integrate and share clinical and experimental data as well as biospecimens generated through the grant-funded research with the broader research community by creating the PSC Scientific Community Resource.
“This is the first translational study of PSC in which we aspire to examine how the interaction of genetic risk along with environmental exposures (i.e., the exposome) leads to development of PSC and its outcomes,” Dr. Lazaridis said. “We are thrilled about this scientific opportunity to better understand PSC and believe the discoveries we make will improve the care of our patients. We are indebted to the study participants for their trust to make this research effort possible.”
To conduct the study and generate the proposed Resource, the team will draw on large, active biorepositories, comprised of patient blood and stool samples. Despite PSC’s rarity – one in 10,000 individuals are diagnosed with the disease – approximately five percent of the entire United States PSC patient population has already consented and provided samples for the planned scientific research.

Since genetics alone could not explain why some people develop PSC and others don’t, the thinking is that casting a broader net via “multi-omics” analysis will help to uncover the complex underpinnings of the disease. Simply put, the investigators will examine and incorporate data from several “omics” layers, specifically the genome (genetics), exposome (environment), metabolome (metabolites), methylome (DNA methylation), transcriptome (gene expression), and metagenome (DNA sequencing of bacteria).

To discover changes in patient blood specific to PSC, the team will test for the presence of environmental exposures – pollutants, pesticides, medications, etc. – and the biological responses corresponding to those exposures. Cutting-edge, ultrahigh resolution mass spectroscopy platforms will be used to evaluate the exposome and metabolome in PSC patients as well as healthy- and disease-controls. Preliminary exposome and metabolome profiling has already revealed chemical exposures and corresponding changes in key liver, lipid metabolism and branched chain amino acid pathways in PSC patients not found in controls. By also identifying DNA methylation patterns, which can change the activity of a DNA segment without changing its sequence, and measuring gene expression levels, researchers will assess “the “methylome” and “transcriptome,” in the hope of uncovering other PSC markers.

Investigators also will assess gut microbial diversity, “the metagenome,” given changes in the types and numbers of helpful and harmful bacteria in the gut are associated with diseases including PSC. They will perform DNA sequencing on the microbes found in stool of patients with PSC, other disease states and healthy controls to get a global overview of processes occurring in the gut. This study will also incorporate a novel exposome-level analysis of stool to elucidate links between microbe classification and exposome-metabolome profiles contributing to PSC.

The resulting, omics-specific datasets will be individually analyzed to identify PSC-associated features, accounting for confounders such as age, sex and genetic variation. Systems biology and high-performance computing expertise will then be leveraged to integrate multiple layers of omics data into a meaningful, multi-omics whole. High-resolution clinical data collected from these patients also will be combined with omics data to shed new light on processes underlying PSC variability in regards to disease onset, features, and outcomes. The hope is to improve predictions of which patients will need liver transplantation, identify biomarkers for PSC-associated malignancy, uncover culprits driving the strong relationship between PSC and inflammatory bowel disease (IBD), as well as reveal differences in the development between childhood and adult PSC.
“Having a better understanding of these clinical priorities holds great promise for a more individualized approach to clinical surveillance and therapy of patients with PSC,” Dr. Lazaridis said.
In total, multi-omics assessments will be generated from over 3,600 individuals, including PSC patients, those with other relevant diseases and healthy-controls. Moreover, the approach – broad patient-based studies and centrally-administered resources upon which new hypothesis can be generated and tested – may serve as a model to inspire new lines of investigation and prioritize clinical trials. The datasets will be accessed by a wide range of investigators, given the fact that PSC is highly associated with IBD as well as bile duct and colon cancers.

“The discovered multi-omics signatures of PSC will provide a springboard for development of novel hypotheses regarding pathogenic mechanisms underlying the disease,” Dr. Lazaridis said. “This is a hypothesis generating grant that could lead to innovative lines of research and hopefully new therapies for this devastating disease.”