{"doi":"10.1242/dmm.050508","title":"Playing the genetic lottery: an interview with Kiran Musunuru","abstract":"Kiran Musunuru. Photo credit: Peggy Peterson of Peggy Peterson Photography.Professor Kiran Musunuru is a principal expert in genetic research and medicine. As a physician scientist and active cardiologist, his research has been primarily centred on the investigation of cardiovascular diseases. Throughout his career, he has pioneered large-scale human genetic studies and applied emerging gene editing tools to interrogate the mechanisms of disease in model systems, with the ultimate goal of developing innovative gene editing therapies.Kiran did his PhD in biomedical science at The Rockefeller University before studying medicine at Weill Cornell Medical College. He is now based at the University of Pennsylvania, where he is the Director of the Genetic and Epigenetic Origins of Disease Program and the Scientific Director of the Center for Inherited Cardiovascular Disease. He serves on the National Heart, Lung, and Blood Institute Advisory Council of the National Institutes of Health and on the Board of Directors of the American Society of Human Genetics. His ground-breaking research has been widely recognised as he is the recipient of many prestigious awards, including the Presidential Early Career Award for Scientists and Engineers from the White House, the American Heart Association's Award of Meritorious Achievement and Joseph A. Vita Award, the American Philosophical Society's Judson Daland Prize for Outstanding Achievement in Clinical Investigation, and the American Federation for Medical Research's Outstanding Investigator Award. In this interview, we discuss some of his most exciting research, as well as the future of genetic research and gene editing therapies. To begin with, what discovery or research project have you found most exciting in your career?I care a lot about cardiovascular disease, because it is the world's leading cause of death, affecting 18 million people a year worldwide. Even in the poorest countries on Earth, cardiovascular disease has become the leading cause of death, making it the preeminent global health threat of the 21st century. I'm a little biased, because I'm a cardiologist, but nonetheless, I think objectively you can say that's true. I'm particularly excited by an ongoing study that involves individuals who inherited genetic factors that give them very low levels of low-density lipoprotein (LDL) cholesterol and protect them from cardiovascular disease. Before 2009, a family had been identified with very low LDL cholesterol levels, but efforts to identify the causal gene were unproductive, simply because of limitations in the technology. In 2009, exome sequencing changed the game because we could easily sequence all coding regions of the genome. We applied exome sequencing to individuals in the family with the most pronounced phenotype and found that four siblings had two different nonsense mutations in the same gene, causing complete knockout of angiopoietin-like 3 or ANGPTL3 (Musunuru et al., 2010).Around the same time, we were doing a genome-wide association study (GWAS) with 100,000 individuals – I think the biggest that had been done at that time – on blood lipid traits, including LDL cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol (Teslovich et al., 2010). We found 95 loci associated with these traits, and one of these loci was ANGPTL3, which had been robustly associated with LDL cholesterol levels. So, we had two studies with very different approaches that converged on the same target, providing concordant lines of evidence that ANGPTL3 was in fact, an important regulator of LDL cholesterol.Then, the real question was, can we really prove that loss of functional ANGPTL3 not only reduces LDL cholesterol levels, but also protects against cardiovascular disease? The very existence of four healthy siblings who entirely lack ANGPTL3, have lived to an old age, have never had any heart disease or any other serious diseases, and have had children who","journal":"Disease Models & Mechanisms","year":2023,"id":412447,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":258825,"name":"Kiran Musunuru","orcid":"0000-0003-3298-0368","position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":null,"created_at":"2026-07-19T01:21:50.261851Z","pmid":"37814839","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}