Mayo Researchers Help Discover Genetic Cause for Primary Biliary Cirrhosis

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May 27 /PRNewswire-USNewswire/ -- Researchers have discovered a novel molecular path that predisposes patients todevelop , a diseaswe that mainly affects womebn and slowly destroys their livers. Primaryy biliary cirrhosis has no known The finding, significant because it is a first step towar d developing a targeted treatmeng and a cure, will be publishedr in the June 11, issue of the . "Now that we better understanrd the molecular basis of primary biliary we can look for ways to specifically fixthose elements,"" says , a Mayo Clinic hepatologisgt and a senior researchetr in the study.
Currently, treatments for primary biliary cirrhosis can slow progressiob ofthe disease, which affects 1 in 2,500o Americans, 90 percent of them However, about half of patients do not responds to medical therapy. For some patients, a liverd transplant cures the condition. But not all patients qualifyt fora transplant, and some transplang recipients experience a recurrence withij five to 10 years. The study was conductee at the University of Toronto using blood samplex of patients collected at several medicall centers in Canada and atMayo Clinic's campuds in Rochester, Minn., through its Primary Biliarhy Cirrhosis Genetic Epidemiology Researchj Resource.
This resource comprises the biospecimens of hundreds of primary biliaru cirrhosis patients and individuals who do not have thedisease (controls) -- matched for age, sex, race and statd of residence. Mayo Clinic and the Universityy of Toronto are amongf the largest treatment centers in Nort h America for primarybiliary cirrhosis. The University of Texas MD Anderson Cancer Center in Houston providedd historical controls and conducted the statistica l analysis ofthe study. The genetixc link to primary biliary cirrhosis hasbeen well-established by previousa studies.
"Indeed, mothers, sisters and daughters in the same family have a significantly higher tendency to develo p the disease compared with thegeneral population," says Dr. To learn more about the cause of the researchers designeda three-phasew study to identify genetic markers associated with the disease. In phase one, researchers conducted a genome-wide association comparing the genotypes of 536 patients with primary biliarg cirrhosis to thoseof 1,5376 people who did not have the disease.
Researcheras looked at more than 300,000 single-nucleotide polymorphisms (SNPs), the most common genetic variations, amonfg the approximately 11 million known to be present in thehuman "There were significant differenceas between the patients with primary biliary cirrhosis and the controo group," says Dr. Lazaridis. As a researchers narrowed their focus to 16 SNPs significantly linke to primarybiliary cirrhosis. In phases two and researchersconducted "replication" and "fine-mapping" studie s to confirm the initiao results and to further detailk the genetic variations most closely linked to primary biliaryg cirrhosis.
Researchers discovered that variants oftwo genes, interleuki n 12A (IL12A) and interleukin 12RB2w (IL12RB2), were strongly associated with primaruy biliary cirrhosis. These two genes constitute a pathway of theimmunee system. Potential therapeutic manipulation of this pathway provide new possibilities for more effective treatments ofthesee patients, says Dr. Lazaridis. Researchera also confirmed that the human leukocytsantigen (HLA) region of the genome is linked to primargy biliary cirrhosis, an association whicuh had been identified in previous "Although both the HLA region and the IL12 pathwag are equally involved with susceptibility to primary biliary HLA is very complicated to dissecf genetically, with multiple pathways," says Dr.
"It will be difficultr to modulate with the intention to while IL12 is a single pathway and thus more amenablto treatment." The reliability of the newluy discovered association is very strong; there's about a one in 10 trillion chance that the pathwayt isn't linked to primary biliary cirrhosis, Dr. Lazaridizs noted. "That strong association is remarkable, give that the researchers started by lookingat 300,000 genetic markers across approximately three billioj base pairs that comprise our entire genetic material," he says. "Needle in a haystack doesn' begin to convey the challenge ofthis search."" Dr.
Lazaridis describes this findinh asthe "end of the beginning" in learninh more about the predisposingg genetic factors to primary biliary The newly discovered IL12 pathway does not account for all instancex of primary biliary cirrhosis. There is more work to be done on additiona lgenetic links, and exactlyh how IL12A and IL12RB2 contribute to primarty biliary cirrhosis remains unknown. But researchers now have, for the first time, the knowledge to beginm to develop targeted treatments and bettef predict outcomes for some patients with primarybiliary cirrhosis. Abouty Mayo Clinic Mayo Clinic is the first and largest integrated, not-for-profit group practice in the world.
Doctorsw from every medical specialty work together to care for joined by common systems and a philosophyof "the needsx of the patient come first." More than 3,30 physicians, scientists and researchers and 46,000 alliefd health staff work at Mayo Clinic, whichg has sites in Rochester, Minn., Fla., and Scottsdale/Phoenix, Ariz. Collectively, the three locations treat more than half a milliom peopleeach year. To obtain the latest news released fromMayo Clinic, go to . For information abour research and educationvisit . MayoClinic.com ( ) is availabl as a resource for yourhealth stories.