Two studies, conducted by investigators at the Broad Institute and Massachusetts General Hospital and published in Nature, have identified multiple genetic risk factors and a non-coding gene variant that play major roles in heart disease. In the first of the two investigations, researchers analyzed GWAS of more than 100,000 individuals and found 95 variations across the human genome that contribute to changes in triglyceride and blood cholesterol levels in Western European, African, and Eastern and Southern Asian populations.
Sekar Kathiresan, director of preventive cardiology at MGH and co-senior author on both papers, says that the first study is a good example of the effectiveness of GWAS in gaining real insight into human disease. "The fact that GWAS studies could identify specific sites in the genome responsible for traits has really not been a subject of debate. However, what is a bit more contentious is the question of being able to learn anything useful from that information," Kathiresan says. "For example, when you know that 30 percent at one spot on the genome carries that varied allele that's associated with a lower level of low-density lipoprotein cholesterol, which is really one of the major unanswered questions: Can you then learn something biologically from this stuff?"
In the second study, the team used mouse models, together with small inhibitory RNA and viral-mediated gene transfer, to show how a common change in one genetic letter could create a novel sequence that binds a transcription factor to increase the reading of the SORT1 gene in liver cells. The protein encoded by SORT1 has a direct effect on the level of low-density lipoprotein and very-low-density lipoprotein, both of which control blood lipid levels and are associated with the risk of coronary disease.
Of the second paper, Kathiresan says the team was able to really drill down at the mechanisms, from polymorphism to function, of one genetic locus. "That kind of approach now needs to be applied to each of the other 94 loci," he says. "Some of that effort is ongoing and it's hard work, it could take a couple years, but systematically conducting this kind of effort should lead to even more biological insights."