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HHMI: IN THIS CASE, GENOTYPE SEEMS TO BE ESPECIALLY IMPORTANT?
HHH: These results show how a genotype can provide information that is not captured in phenotype. The PCSK9 genotypes we identified tell us about the level of LDL in the blood over a lifetime rather than at one moment in time. Individuals with mutations in PCSK9 have lower levels of LDL starting at birth so the arteries feeding the heart are exposed to cumulatively fewer LDL particles over time. We have known for years that high levels of LDL are sufficient to cause heart disease, even in the absence of other risk factors. These new data tell us that the reverse is also true; low levels of LDL starting early in life provide protection from heart disease, even in those individuals who have other risk factors.
HHMI: HOW DO MUTATIONS IN PCSK9 CAUSE LOWER LEVELS OF LDL IN THE BLOOD?
HHH: PCSK9 expression causes degradation of LDL receptors, which are proteins on the surfaces of cells that bind and remove LDL from blood. Mutations that interfere with the synthesis of PCSK9 result in an increase in the number of LDL receptors, which leads to lower levels of LDL in the blood.
HHMI: IS THERE MORE TO COME?
HHH: Soon it will be possible to sequence entire genomes of study sujects. A major challenge will be to link the sequence differences identified in genes to traits and diseases. We will need large collections of very carefully phenotyped individuals of different ancestries. The Dallas Heart Study was designed specifically to address this need.
Very few population studies include large numbers of individuals whose ancestors are not from Europe. Genomes differ depending on ancestry. For example, we showed that Hispanics tend to deposit more fat in the liver, which can lead to liver injury and, ultimately, liver failure. In September 2008, we reported that sequence variations in a gene of unknown function called PNPLA3 are responsible for a large fraction of the differences in liver fat between Hispanics and other groups. Now we are exploring whether those sequence variations in PNPLA3 predispose individuals to liver injury after exposure to alcohol, drugs, or infection.
HHMI investigator Helen H. Hobbs is director of the Dallas Heart Study.
Interview by Richard Currey