Researchers who study risk factors for cardiovascular disease have long been puzzled by a persistent paradox. African Americans tend to have healthier blood lipid profiles than the general population, but they have higher rates of heart attack and stroke.
This observation has scientists scrambling with the latest genetic tools to find better predictors of cardiovascular disease in blacks to enhance clinical strategies for preventing early death and disability.
A large new study of African Americans confirms that their African ancestry somehow confers the bragging rights for those favorable blood lipids. Other findings in the study complicate the search for predictive genes and their biological meaning in all ethnic groups.
Most strikingly, the blood lipid differences in African Americans cannot be explained by the cardiovascular risk genes discovered and validated in the latest massive genomewide association studies. These same genetic variations, all found in populations of European descent, can have a different effect when parked on a genomic block of recent African origin, the study shows.
“Our results say that your ancestral background may have a significant influence on the effect of a gene variant,” said first author Rahul Deo, who is finishing his cardiology fellowship at Massachusetts General Hospital. “You don’t know the effect of the gene unless you know the ancestral background. Sometimes it might be similar. Sometimes it may not.”
A Benefit of African GenesOn average, about 80 percent of the genome of African Americans has African ancestry and 20 percent has European ancestry, equivalent to three white great-great-grandparents in the family tree.
The study investigated the mixed genomes of nearly 4,500 African Americans from the Jackson Heart Study in Mississippi. In the first step, researchers compared the proportion of the genome of African or European origin with blood lipid levels in each person. Overall, the greater the African ancestry, the higher the high density lipoprotein (HDL) and the lower the unfavorable triglycerides. African Americans with more European ancestry had proportionally lower levels of the good cholesterol and higher triglycerides.
Deo and his co-authors then scanned the genomes looking for major areas that explained the differences in blood lipids. “Unfortunately, we didn’t find any,” he said. “If we had, that would have been our paper.” The culprits, they concluded, must be many gene variants of small effects adding up to these differences between the genomes.
Studies looking for many genes with small effects require at least twice as many people. So the researchers decided to evaluate one of the strongest of the small-effect gene variations previously found and replicated in genomewide association studies in European-ancestor populations.
Known as the S447X mutation at the LPL gene, it has been proposed to be a major factor in healthier triglyceride levels. The protein made by LPL breaks down the circulating fats in the bloodstream. In addition to its dazzling statistical association with lower triglycerides, the mutated gene actually makes a shorter protein. The actions of most gene variations are a mystery, so researchers have placed more credence on known functional mutations.
Surprisingly, this famous variant had no measurable effect when located on a stretch of genome of African origin, but researchers found a new variant in the African genome that may play a role in triglyceride levels.
Gene Story Grows DeeperDeo and his colleagues found a similar pattern for a dozen more genetic risk markers associated with blood lipid levels.
When ensconced within a genome segment of African ancestry, six variants led to more favorable lipid profiles on the African ancestry background and six had more deleterious effects, compared to the European ancestry background.
“Biologically, causal variants should confer the same amount of risk on different backgrounds, said co-author David Reich, whose research group developed the technique used in this study. Called admixture mapping, it can estimate the ancestry of a chunk of genome at any given spot on a chromosome.
“There is something fundamental going on,” said Reich, HMS associate professor of genetics. “The variants people think are causal and quite strong are not the whole story.”
“An important aspect of our work is showing that gene associations identified in populations of European ancestry may not hold up as well in African American–derived populations,” said senior author James Wilson, professor of medicine at the University of Mississippi Medical Center and a former rheumatologist at Brigham and Women’s Hospital. “This also shows how African American populations will help localize true variants as opposed to marker variants.”
Similar studies in blacks will advance the cause for everyone, the authors say. “The only way to know which variants are important in blacks is to do the discovery in blacks,” said co-author Sekar Kathiresan, an HMS assistant professor of medicine and director of preventive cardiology at MGH. In whites, the number of gene loci shown to contribute to unhealthy blood lipids increased to 30 with a report of 11 new variants in the January Nature Genetics by Kathiresan and his co-authors. Now, he and his colleagues are genotyping 8,000 African-American individuals from eight epidemiologic studies, including the Jackson Heart Study, tracking risk factors and heart disease.
Cautionary NoteThe findings address those genes that individually have barely measurable effects on a person’s risk of disease, not the single genetic mutations that by themselves cause devastating disorders or provide dramatic protection in some cases. So far, more than 100 statistically definitive risk genes with biologically modest effects have been identified for diabetes, macular degeneration, prostate cancer, and other diseases by genomewide association studies in mostly European populations.
The current paper, published online Jan. 16 in PLoS Genetics, suggests people need to take extra care in interpreting results of gene association studies. In the new era of genetic-marker tests being marketed directly to consumers, people can misinterpret the presence of these risk genes in their personal genomes as meaningful data about their health risks.
Because of similar concerns about the lack of clinical utility, the Personal Genome Project at HMS has changed its algorithm to exclude most small-effect gene-association annotations when it informs volunteer participants about the details of their fully sequenced genomes, said medical director Joseph Thakuria. Studies of these fully sequenced genomes will provide new answers to questions of genetic risk, he said.
For scientists, the different behavior of the risk genes on an African pedigree may be more evidence that genomewide association studies may have reached certain limits. “We’re finding stuff effectively and efficiently, but on the other hand, we know we’re not finding most of the genetic factors,” Reich said. “People are trying to think about where that dark matter is. What’s causing the genetic effects? It may be a clue to the general architecture of genetic risk.”
Genomewide association studies remain important for discovery of biological pathways and potential drug targets and to develop effective personal disease assessments, the authors say.
Gene-association studies have independent biological value, Deo said. “Every single new gene that comes out of these studies represents a potential pathway to investigate for disease etiology and disease treatment.” For example, as discovered in whites by Kathiresan and co-authors and confirmed in blacks by others, the commonly used lipid-lowering medications—the statins—target genes whose common variants have a very small predictive effect on cholesterol but, nevertheless, a dramatic medical effect.
