Polygenic Score Pinpoints People Most at Risk of Cirrhosis

By Marilynn Larkin

December 22, 2020

NEW YORK (Reuters Health) - A polygenic score that includes seven newly-identified genetic variants pinpointed individuals at "substantially increased risk" of cirrhosis if they drink to excess or are obese, researchers say.

"Although studies on twin pairs have clearly demonstrated that genetic factors play an important role in susceptibility to cirrhosis, relatively few genetic drivers have been identified as compared to other diseases," Dr. Amit Khera of Massachusetts General Hospital in Boston told Reuters Health by email. "For example, we and others had identified >160 variants linked to heart attack, but <10 for cirrhosis."

In the current study, he said, "using new statistical approaches, we identified 12 variants that impact risk, including seven that had not been previously reported."

For the study, published in Gastroenterology, Dr. Khera and colleagues performed a multi-trait genome-wide association study (GWAS) combining cirrhosis and alanine aminotransferase (ALT) levels from five discovery studies: UK Biobank, Vanderbilt BioVU, the Atherosclerosis Risk in Communities study, and two case-control studies of close to 5,000 individuals with cirrhosis and about 73,000 controls, plus more than 362,000 people with ALT levels.

The team identified risk variants that were replicated in three studies: Partners HealthCare Biobank, FinnGen and Biobank Japan, for a total of 3,554 individuals with cirrhosis and 343,826 controls.

The seven newly-identified and five previously-reported genetic variants were associated with cirrhosis in both the discovery studies' multi-trait GWAS and the replication studies, including a missense variant in the APOE gene and a noncoding variant near EFN1A.

The 12 variants were used to generate a polygenic score, which the team tested in the Partners HealthCare Biobank. A high polygenic score -- defined as the top quintile of the distribution -- was associated with a significantly increased risk of cirrhosis (odds ratio, 2.26) and related comorbidities when compared to the lowest quintile. The risk was even greater among those with extreme polygenic risk (top 1% of the distribution; OR, 3.16).

The clinical impact of extreme polygenic risk was substantially increased in those with greater alcohol consumption or a higher body mass index. Modeled as risk by age 75, the probability of cirrhosis was 13.7%, 20.1%, and 48.2% among individuals with no or modest, moderate, and increased alcohol consumption, respectively.

Similarly, the probability of cirrhosis among those with extreme polygenic risk was 6.5%, 10.3%, and 19.5% among individuals who were of normal weight, overweight, or obese, respectively.

Dr. Khera added, "Among those who reported drinking more than three drinks daily, we estimate a risk of 13% for those with a normal genetic risk versus 48% for those with the highest polygenic score."

Taken together, the results "help explain a commonly observed clinical phenomenon, may destigmatize conditions such as 'alcoholic cirrhosis' in our society, and are likely to prove useful in counseling high-risk patients," he noted.

"Important next steps are to generalize these results to individuals of non-European ancestries, since we know that genetic predisposition can vary by race," he said. "The polygenic score developed here for cirrhosis is not yet available clinically, but a similar score for coronary artery disease is now being offered within the MGH Preventive Genomics Clinic."

SOURCE: https://bit.ly/2KgBCvn Gastroenterology, online December 11, 2020.

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