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Genetics of first-cousin marriage families show how some are protected from heart disease

April 12, 2017

PHILADELPHIA - More than 1,800 individuals carrying loss-of-function mutations in both copies of their genes, so-called "human knockouts," are described in the first major study to be published in Nature this week by an international collaboration led by the Perelman School of Medicine at the University of Pennsylvania and colleagues. The program, which has so far sequenced the protein-coding regions of over 10,500 adults living in Pakistan, is illuminating the basic biology and possible therapeutics for several different disorders.

The team has identified more than 1,300 genes completely knocked out in at least one individual. They first turned their attention for deeper analysis to genes involved in 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. These APOC3-knockout individuals had very low triglyceride levels. The researchers challenged their system with a high-fat meal. Compared with family members who were not APOC3 knockouts, the APOC3 knockout family members did not have the usual post-meal rise in plasma triglycerides.

"These are the world's first APOC3 human knockouts that have been identified," said co-first author and the principal investigator of the study, Danish Saleheen, MD, PhD, an assistant professor of Epidemiology and Biostatistics at Penn. "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.

In addition to Penn, the team includes scientists from the Center for Non-Communicable Diseases (CNCD) in Karachi, Pakistan, the Broad Institute of MIT and Harvard, and the University of Cambridge, UK.

Saleheen has been working for over a decade in Pakistan, in collaboration with the CNCD to collect blood samples from all over his country. This Pakistan-based study already includes more than 70,000 participants and the recruitment is rapidly being expanded to include 200,000 people. "We are continuing protein-coding region sequencing studies in the Pakistani population. 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," Saleheen said.

"The Human Genome Project gave us a 'parts' list of 18,000 genes. We are now trying to understand gene function by studying people who naturally lack a 'part,'" said co-senior author Sekar Kathiresan, Director of the Center for Genomic Medicine at Massachusetts General Hospital. "We think that over the next ten to twenty years, with a concerted, systematic effort, it's possible to find humans who naturally lack any one of several thousand genes in the genome and understand what the phenotypic consequences are."

"The project highlights the value of looking at diverse populations, particularly for genetic analyses--you'll find variants in one ethnicity and not another," said co-first author Pradeep Natarajan, an associate scientist at Broad Institute and a postdoctoral research fellow in Kathiresan's lab.

Co-senior author Daniel J. Rader, MD, chair of Genetics at Penn, hopes that future dives into this rich dataset will bring even more novel insights into human biology and point toward new therapeutic targets for treating and preventing disease. "Linking DNA sequencing with deep phenotyping at scale in this population will be an incredible source of new knowledge about how gene alterations influence human health and disease," Rader said. In addition to a continued focus on the biology of heart attacks, type 2 diabetes, and stroke, the team will also be looking for clues for early-onset Parkinson's disease, autism, congenital blindness, and mental retardation, among many other conditions.

Penn scientists are now collaborating with CNCD researchers to conduct deep phenotyping studies in all human knockouts the project identifies. These studies will include detailed physiological and mechanistic studies to understand the biological and pharmacological consequences of both partial and complete disruption of genes in humans.
-end-
This work was funded by National Institutes Health (RC2HL101834 and RC1TW008485) the Fogarty International, the Wellcome Trust, the British Heart Foundation, and Pfizer. Exome sequencing was supported by a grant from the NHGRI (5U54HG003067- 955 11). Fieldwork in the PROMIS study has been supported through funds available to investigators at the Center for Non- Communicable Diseases, Pakistan and the University of Cambridge, UK. Saleheen has received funding from Regeneron Pharmaceuticals, Genentech, Eli Lilly and Pfizer.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.

University of Pennsylvania School of Medicine

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