Scanning the genomes of more than 100,000 people from all over the world, scientists report the largest set of genes discovered underlying high cholesterol and high triglycerides - the major risk factors for coronary heart disease, the nation's number one killer. Taken together, the gene variants explain between a quarter and a third of the inherited portions of cholesterol and triglyceride measured in the blood. The research, representing scientists from 17 countries, appears in two papers in the August 5 issue of Nature.

The National Institutes of Health's National Heart, Lung, and Blood Institute (NHLBI) is the lead funder of the research, with additional support from the National Human Genome Research Institute (NHGRI), the National Institute on Aging (NIA), and several other NIH components.

Genome-wide association studies, or GWAS, analyze DNA across populations to pinpoint hard-to-find genetic hotspots for common diseases that are thought to have many causes, both genetic and environmental. Previous gene-scanning approaches have turned up hints about the nature of inherited heart disease risk. The new results take science well beyond what was previously known, and pinpoint research directions to elucidate the molecular and cellular mechanisms by which genetic variants contribute to disease.

"Genetic studies that survey a wide variety of human populations are a powerful tool for identifying hereditary factors in health and disease," said study co-author and NIH Director Francis S. Collins, M.D., Ph.D. "These results help refine our course for preventing and treating heart disease, a health problem that affects millions of Americans and many more people worldwide."

The research team found 95 genetic variants - arrangements of the nucleic acids in DNA that differ among people - which contribute to changes in blood cholesterol and triglyceride levels in women and men of many ethnic backgrounds. Abnormal levels of blood cholesterol and of triglycerides are powerful risk factors for heart disease. Because high blood cholesterol on its own does not cause symptoms, doctors routinely do blood tests to assess individual risk, but they do not know how much risk of developing cardiovascular disease is inherited.

Of the genetic variants, 59 had not been known and thus provide new clues for developing effective medicines to combat heart disease.

A significant insight from this research is that many of the variants show up in the DNA of people of widely diverse backgrounds. That is because the scientists scoured the DNA from people participating in large, population-based heart disease studies, reflecting people of European, Eastern and Southern Asian, and African-American descent.

Together, research participants from NHLBI study populations contributed about half of the 100,000 genomes scanned. Among the NIH population-based studies involved in the research were the Framingham Heart Study; the Atherosclerosis Risk in Communities Study; the Cardiovascular Health Study; the SardiNIA Study; the Ages, Gene, Environment Study; the InCHIANTI Study; the Family Heart Study; the NHLBI Candidate Gene Association Resource Program; the NIH Pharmacogenetics Research Network; the deCODE MI Study; and the Women's Genome Health Study.

"The NHLBI is a leader in supporting long-term studies, including the decades-long Framingham Heart Study, that carefully track the health outcomes of large groups of people and generations of families." said NHLBI Acting Director Susan B. Shurin, M.D. "This genome-wide association study successfully demonstrates how cutting-edge genomics research can be leveraged by our past and current research investment in population-based studies assessing long-term health and disease."

The research team's other study probed deeply into one of the genetic variants identified in the accompanying GWAS analysis.

In the group's second study, the scientists had an unusual opportunity to follow up on the findings of the GWAS to determining how one unusual gene variant trips up cholesterol and triglyceride metabolism in mice. Previous studies had identified the same genetic variant in humans who were prone to deadly heart attacks: The variant is common in people of African American, Hispanic, Asian Indian, and Chinese ancestries. Having a genetically identical mouse model enables researchers to look further into the contribution of a particular genetic variant to inherited heart disease risk.

"The new findings point us to specific genetic signposts that allow us to understand more fully why many people from all walks of life have abnormal levels of cholesterol and other blood lipids that lead to heart disease," said Christopher J. O'Donnell, M.D., associate director of the Framingham Heart Study and senior advisor for genomics to the NHLBI acting director. "What's really exciting about this work is that we are moving from discovery to understanding brand-new information about how genes alter the lipids that contribute to heart disease."

In addition to the NHLBI, the NIA and the NHGRI, other NIH funding sources include the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, the National Cancer Institute, the National Institute of General Medical Sciences, the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Center for Research Resources.