Polygenic threat ratings from multi-populace information should enhance IBD predictions

Overview

• Post By : Kumar Jeetendra


• Source: Mount Sinai Health System


• Date: 25 Dec,2020

Using genetic data from nearly 30,000 individuals, Mount Sinai researchers have assembled hazard scores from a combination of datasets representing distinct ancestral populations that improve prediction of risk for inflammatory bowel diseases (IBD) including Crohn’s disease and ulcerative colitis. The research was published in Gastroenterology on December 24.

The researchers found that polygenic risk scores, built using association data from several populations in Mount Sinai’s multi-ethnic BioMe Biobank, maximized IBD predictions for each population from the biobank. BioMe is a system-wide attempt at Mount Sinai which is revolutionizing diagnosis and classification of diseases according to the individual’s molecular profile.

The ability to accurately predict genetic disease risk in individuals across ancestries is a critical avenue that may positively affect patient outcomes, as early interventions and even preventive measures are being considered and developed. These findings support a need for greater genetic diversity, including more data on African American populations, to enhance disease risk predictions and reduce health disparities for all populations.”

Judy H. Cho, MD,  Atudy’s Senior Author, Dean of Translational Genetics and Director of The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine, Mount Sinai

The study demonstrated that risk scores calculated from incorporating data significantly improved predictions among people with European, Ashkenazi Jewish, and Hispanic ancestry in BioMe, in addition to European individuals in the UK Biobank, which comprises medical and biological data on half a million people between ages 40 and 69 residing in the UK. Predictive power was lower for patients with African ancestry, probably because of substantially smaller benchmark datasets and substantially greater genetic diversity in populations of African descent.

These polygenic hazard scores–representing an estimate of overall risk based on the amount of a person’s many, largely common, genetic variations –were calculated using IBD association data from cohorts with European, African American, and Ashkenazi Jewish backgrounds.

Additionally, researchers assessed rare variations in genes related to very-early-onset IBD within each population and found that African American carriers of rare LRBA variants showed reduced expression of both proteins LRBA and CTLA-4. LRBA deficiency increases susceptibility to IBD and results in reduced CTLA-4 expression, which is reversed with the commonly prescribed antimalarial drug chloroquine. Future studies by the Cho Laboratory will focus on predicting which subsets of patients may benefit from targeting this pathway.

“Since diminished LRBA and CTLA-4 expression can lead to IBD, it is encouraging that chloroquine can partially recover expression,” says the study’s first author Kyle Gettler, PhD, postdoctoral fellow in the Department of Genetics and Genomic Sciences in the Icahn School of Medicine at Mount Sinai.