Can loss-of-function genetic mutations—"human knockouts" that can disrupt both copies of a given gene—give us valuable information about the basic biology and possible therapeutics for major medical disorders? An international collaborative team sequenced the protein-coding regions of 10,503 adults in Pakistan, looking first for insights about cardiovascular and metabolic diseases.

One gene in particular—APOC3, which regulates the metabolism of triglyceride-rich lipoproteins in the blood—was missing in several dozen individuals in a small fishing village on the coast of Pakistan, where first-cousin marriages are culturally prevalent. The team recruited these individuals, who had very low triglyceride levels, and challenged their systems with a high-fat meal.

“These are the world’s first APOC3 human knockouts that have been identified,” said co-first author and principal investigator Danish Saleheen, MD, PhD. “Their genetic makeup has provided unique insights about the biology of APOC3, which may further help in validating APOC3 inhibition as a therapeutic target for cardiometabolic diseases—the leading cause of death globally."  

This is the first major study to be published by an international collaboration led by the Perelman School of Medicine at Penn; the Center For Non-Communicable Diseases (CNCD) in Karachi, Pakistan; the Broad Institute of MIT and Harvard; and the University of Cambridge, UK. Dr. Saleheen has been working for more than a decade in Pakistan, in collaboration with the CNCD, to collect blood samples. The Pakistan-based study already includes more than 70,000 participants, and recruitment is rapidly being expanded to include 200,000. “If we are able to sequence 200,000 participants, we will be able to identify human knockouts for more than 8,000 unique genes,” Saleheen said. “These observations provide us with a roadmap, a systematic way to understand the physiological consequences of complete disruption of genes in humans and to lay the foundation for a ‘human knockout’ program that can yield many benefits for patients in the future.”