Going large with the liver

PHOENIX—In collaboration with the Geisinger Health System, headquartered in Danville, Penn., the Translational Genomics Research Institute (TGen) has conducted what it calls “a groundbreaking study” of nearly 2,300 extremely obese diabetes patients and in the process identified genes associated with unhealthy liver function.

The effort is believed to be the nation's first large-scale genome-wide association study (GWAS) in overweight patients with diabetes. Titled “Genome-wide analysis identifies loci associated with total bilirubin levels, steatosis,” the study looked at how genomic factors affect the development of non-alcoholic fatty liver disease (NAFLD). Specifically, the study identified evidence for association with markers in the neurocan gene on chromosome 19p12 and rs2501843 on chromosome 1.

“These genetic factors could help us identify patients who are most at risk of developing non-alcoholic forms of fatty-liver disease, and which patients may be more likely to progress to severe forms of NAFLD, such as steatohepatitis (NASH),” said Dr. Johanna DiStefano in the news release about the study. She is the study's principal investigator and lead author, as well as director of TGen's Diabetes, Cardiovascular and Metabolic Diseases Division.

NAFLD is the build-up of extra fat in liver cells, not caused by alcohol, and it is one of the most common causes of chronic liver disease. Going along with that is NASH, which is liver inflammation and damage caused by a buildup of fat in the liver, also not caused by alcohol.

“Our results showed evidence for new genetic loci that may play a role in the biological mechanisms of NAFLD and NASH,” said Dr. Glenn S. Gerhard, a faculty member of the Geisinger Obesity Institute and a co-investigator of the study. “We discovered genes that may help identify those patients most at risk for the types of liver disease so severe that they could require transplants.”

Patients included in this study were those with extreme obesity enrolled in a bariatric surgery program. Asked why such a large GWAS like this hadn’t been done before, DiStefano tells DDNews that the patient population was a specific reason for that.

“Doing work like this, we really needed liver biopsy tissue, and as you can imagine, that’s hard to get from most study participants,” DiStefano notes. “But the beauty of this work is that the patients are in a bariatric surgery cohort, and it’s standard protocol to do liver biopsies in such patients.”

Also, using a patient population like this provides a much broader range of patients with non-alcoholic liver disease. Unlike with people at end-stage liver disease, “you get the whole spectrum of disease and different levels of diseased liver tissue,” she says.

The GWAS took DNA from patient blood to correlate with findings from the liver biopsies. DiStefano says the work she and the rest of the research team did will be useful not just to help identify targets for drug discovery but also will be useful for creating earlier diagnostic tools.

“Patients can stay in a relatively benign stage of liver disease or progress to a deadlier form of the disease that would require liver transplant or, in some cases, result in carcinomas,” she says. “I’d like to see these individuals targeted earlier for aggressive preventive therapy.”

Results of the TGen-Geisinger study were presented at the 64th annual meeting of the American Association for the Study of Liver Diseases in Washington, D.C., in early November. The paper was selected for presentation from among a record 3,139 submittals from around the world proposed for what also is known as The Liver Meeting 2013.