Researchers discovered that variants of two genes, interleukin 12A (IL12A) and interleukin 12RB2 (IL12RB2), were strongly associated with primary biliary cirrhosis. These two genes constitute a pathway of the immune system. Potential therapeutic manipulation of this pathway provides new possibilities for more effective treatments of these patients, says Dr. Lazaridis.

Researchers also confirmed that the human leukocyte antigen (HLA) region of the genome is linked to primary biliary cirrhosis, an association which had been identified in previous research. "Although both the HLA region and the IL12 pathway are equally involved with susceptibility to primary biliary cirrhosis, HLA is very complicated to dissect genetically, with multiple pathways," says Dr. Lazaridis. "It will be difficult to modulate with the intention to treat, while IL12 is a single pathway and thus more amenable to treatment."

The reliability of the newly discovered association is very strong; statistically, there's about a one in 10 trillion chance that the pathway isn't linked to primary biliary cirrhosis, Dr. Lazaridis noted.

"That strong association is remarkable, given that the researchers started by looking at 300,000 genetic markers across approximately three billion base pairs that comprise our entire genetic material," he says. "Needle in a haystack doesn't begin to convey the challenge of this search."

Dr. Lazaridis describes this finding as the "end of the beginning" in learning more about the predisposing genetic factors to primary biliary cirrhosis. The newly discovered IL12 pathway does not account for all instances of primary biliary cirrhosis. There is more work to be done on additional genetic links, and exactly how IL12A and IL12RB2 contribute to primary biliary cirrhosis remains unknown. But researchers now have, for the first time, the knowledge to begin to develop targeted treatments and better predict outcomes for some patients with primary biliary cirrhosis.

mayoclinic