Research Roundup: Heart disease risk, gene therapy, diabetes, and more

Welcome to the November 15, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

CHIPping away at heart disease risk

The common aging-related blood disorder, CHIP, raises heart disease risk. In work they’re presenting at the 2019 American Heart Association meeting, associate member Pradeep Natarajan, associated scientist Alex Bick, and postdoctoral scholar James Pirruccello in the Program in Medical and Population Genetics analyzed more than 35,000 exomes in the UK Biobank and confirmed that CHIP raises the risk of future cardiovascular events, such as heart attack or stroke. People with large CHIP clones who carry a genetic variant that subdues IL-6 inflammatory signaling are protected from that increased risk, suggesting that targeting inflammation could be a new route to lower heart disease risk in these patients. Read more in Circulation and a Broad news story.

Prevention for all

Type 2 diabetes (T2D) is associated with greater risk of coronary artery disease (CAD). To test whether patients at different genetic risk for CAD benefit similarly from T2D preventive interventions, e.g., exercise, improved diet, or metformin, a team led by the Metabolism Program’s co-director and institute member Jose Florez and postdoctoral scholar Jordi Merino built a CAD polygenic risk score and tested for interaction with diabetes prevention strategies on one-year changes in cardiometabolic risk factors (CRFs), such as obesity and high blood pressure, in 2,658 people in the Diabetes Prevention Program. In Diabetes (article behind paywall), they report that diabetes preventive interventions improve CRFs regardless of CAD genetic risk.

Why did the AAV cross the blood-brain barrier? 

Adeno-associated viruses (AAVs) are the vector of choice for gene therapy, but developing AAVs that can cross the blood-brain barrier has been a challenge. Research scientist Qin Huang, director of vector engineering Ben Deverman, and others at the Stanley Center for Psychiatric Research, including members of the Hail team, studied an AAV variant called AAV-PHP.eB, which can efficiently deliver genes to the mouse brain. To find out how the virus is able to do this, the team looked for genetic variants in mice associated with the ability of the virus to cross the BBB. They found a variant in a receptor called LY6A that the AAV-PHP.B family of viruses binds to, allowing them entry into the mouse brain. See the study in PLoS ONE and more, including images from the paper, in this Instagram post.

Understanding mitochondrial circuitry

Mitochondrial dysfunction is associated with a spectrum of human conditions, ranging from rare metabolism errors to the aging process. But understanding how genetic variations can protect against or contribute to these diverse pathologies is a challenge. To identify the genes and cellular pathways involved, a team led by research scientist Tsz-Leung To, Metabolism Program’s co-director and institute member Vamsi Mootha, and colleagues performed genome-wide CRISPR screening to create a compendium describing the genetic modifiers for different chemically-induced models of mitochondrial dysfunction. Among their results, the team highlights the surprising finding that certain forms of mitochondrial dysfunction may best be buffered with “second site” inhibition to the organelle. Check out their Cell paper for more.

A drop’s props

Lipid droplets (LDs) store lipids for making cellular membranes and for metabolic energy, but it’s unclear exactly how they’re made. A team led by associate members Robert Farese and Tobias Walther, and Jeeyun Chung (HMS/HSPH) discovered that a complex of lipid droplet assembly factor 1 in interaction with seipin, an endoplasmic reticulum (ER) protein, is the core protein machinery that drives the formation of LDs and determines where they form in the ER. Appearing in Developmental Cell, the work could have implications for common metabolic diseases and industrial applications, such as production of biofuels.