The Kathiresan laboratory seeks to understand the genetic basis for myocardial infarction (MI) and its risk factors and to exploit these insights to prevent and treat heart disease.
There are three themes to our work: 1) Gene discovery; 2) Functional biology; and 3) Clinical translation.
- What are the genes that cause MI and which, if any, operate outside of known risk factors?
- Beyond LDL cholesterol, are there any lipid pathways that cause MI?
- Can we discover genes where loss-of-function mutations protect against risk for disease?
To address these questions, we utilize a highly collaborative, multidisciplinary approach that combines the new tools of genomics and statistical genetics with classic population science and molecular biology. We have been among the first in the world to perform population-based common variant association studies (CVAS), population-based rare variant association studies (RVAS), and family-based sequencing of all protein-coding regions in the genome (i.e., exome sequencing).
Results from these studies have transformed cardiovascular genetics and more generally, the field of complex trait genetics. The following transformative concepts have emerged from our work:
- There exist many mechanisms to atherosclerosis beyond traditional risk factors.
- Non-coding DNA variation discovered from CVAS can directly contribute to phenotype.
- Common variants in aggregate as a genetic risk score can lead to risk for disease.
- HDL cholesterol is a marker for MI risk rather than a causal factor.
- Outside of LDL cholesterol, the lipoprotein lipase pathway is a major route to MI.
- Loss-of-function mutations that protect against disease can provide breakthrough insight as to which genes are most appropriate to target with therapies for complex disease.