Fatty Liver Disease: Genes Affect Risk

Sept. 26, 2008 -- Newly discovered gene variants explain why Hispanics are most likely -- and African-Americans are least likely -- to have fatty livers.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver ailment in the U.S. and in Europe. It's behind one in 10 liver transplants. About a third of Americans have fatty livers, a step on the path to NAFLD.

As one might think, obesity and the cluster of symptoms known as the metabolic syndrome are linked to NAFLD. Yet some people with these risk factors get the disease while others don't.

A clue comes from the fact that some people are much more prone to liver fat than others. And this predisposition is linked to one's ancestry. Fatty livers occur in 33% of European-Americans, 45% of Hispanic-Americans, and 24% of African-Americans.

Researchers led by Helen H. Hobbs, MD, chief of clinical genetics at the University of Texas Southwestern Medical Center, looked for genetic variations in more than 2,000 participants in the Dallas Heart Study.

The team detected more than 12,000 gene variants. In the end, only one gene was linked to liver fat: a gene with unknown function called PNPLA3.

A variant version of this gene was strongly linked to fatty liver. The variant was seen in 49% of Hispanic-Americans, 23% of European-Americans, and 17% of African-Americans in the study.

Analysis showed that the gene explains 72% of the ancestry-related differences in liver fat. Interestingly, this gene variant was also linked to liver inflammation -- possibly the next step on the way to serious disease.

"Currently, we cannot accurately predict which individuals with fatty liver will develop [serious liver disease] and progress to cirrhosis and liver failure," Hobbs and colleagues note. "This gene variant may confer increased susceptibility to injury."

Apparently, the gene variant linked to liver fat makes the PNPLA3 gene function poorly or not at all.

Another PNPLA3 gene variant -- seen much more often in African-Americans than in Americans of other ancestry -- is linked to lower risk of liver fat. This gene variant appears to make the PNPLA3 gene work better.

The study appears in the Sept. 26 advance online issue of Nature Genetics.