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Liver Disease Multiomic Analysis Reveals Detection Clues, Points to Treatment Strategies

NEW YORK – Protein profiles in blood plasma samples may help to distinguish between nonalcoholic fatty liver disease (NAFLD) and other forms of liver disease such as cirrhosis, new research suggests, while offering biological clues that may inform future treatment strategies.

"The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options," co-first and co-corresponding author Gardar Sveinbjornsson, a Decode Genetics researcher, and his colleagues wrote in Nature Genetics on Monday.

Through a genome-wide association study that included more than 36,100 individuals with MRI-based proton density fat fraction (PDFF) liver fat quantification measurements — combined with an NAFLD-focused GWAS meta-analysis encompassing nearly 9,500 cases and more than 876,200 unaffected controls — researchers at Amgen subsidiary Decode Genetics, the University of Iceland, and other international centers tracked down 18 NAFLD-associated variants at 17 sites in the genome and four variants linked to liver cirrhosis.

Additional RNA sequencing and blood plasma proteomic profiles, which spanned more than 4,900 blood plasma proteins in nearly 35,600 individuals from Iceland and almost 47,200 UK Biobank participants, pointed to a relatively wide range of proteins that can contribute to NAFLD development or disease features, including coding and regulatory variants contributing to lipid metabolism processes.

With further GWAS and multiomic analyses, the investigators were able to compare and contrast the genetic variants contributing to general PDFF patterns, NAFLD, liver cirrhosis, or hepatocellular carcinoma (HCC), as well as genetic risk variant ties to other traits or conditions.

They also tracked down rare loss-of-function mutations in the mitochondrial enzyme-coding genes MTARC1 and GPAM that appeared to protect against the risk of NAFLD in the Icelandic population.

"We demonstrated the diverse effects of NAFLD risk alleles on other diseases and traits, including blood lipids and proteins, and showed that plasma proteomics has the potential to stage NAFLD," the authors wrote.

In addition, the investigators saw signs that they could distinguish between NAFLD or cirrhosis cases with computational analyses that relied on protein patterns in an individual's blood plasma, liver disease genetic risk scores (GRS), and traits such as sex, age, and body mass index. While individuals with cirrhosis tended to have higher-than-usual levels of the thrombospondin 2 protein THBS2, for example, they linked the aminoacylase-1 enzyme ACY1 to NAFLD.

"We designed models including plasma proteins that outperformed a model trained on liver enzymes and GRSs in discriminating between NAFL and cirrhosis diagnoses," the authors explained, noting that "levels of plasma proteins have the potential to serve as a noninvasive tool for use in the diagnosis and monitoring of disease, whereas GRSs are associated with a lifetime risk of disease."