Are there any genes that protect people from risk for heart attack?

In one large family, we noticed that low levels of blood lipids (low LDL cholesterol, HDL cholesterol, and triglycerides) was present in several members of the family.  We described this syndrome as ˜familial combined hypolipidemia.  It looked as if a single gene was responsible for the low lipid levels in the family.  To discover the causal gene in the family, we sequenced all of the protein-coding genes in the genome, representing about 30,000,000 of the 3 billion bases in the human genome sequence.  We discovered that loss of function of a gene called angiopoitein-like 3 (ANGPTL3) was responsible for the low lipid levels.  The four people in the family who had the lowest lipid levels had two broken copies of ANGPTL3 (one copy from mom and one copy from dad).  This new observation has immediately suggested ANGPTL3 as a target for medicines.  In addition, we have uncovered an entirely new mechanism for the regulation of LDL cholesterol.  At present, it is unclear if the individuals who have broken copies of ANGPTL3 have lower risk for heart attack (in addition to low lipid levels).  We are in the process to trying to figure this out.

In the population, we recently defined a new protective gene for MI: a triglyceride-regulating protein called apolipoprotein C3 (APOC3).  By studying gene sequences from over 110,000 people, we found that rare, naturally occurring mutations that break one copy of the APOC3 gene lower blood triglycerides and reduce risk of MI by over 40%, without any adverse consequences.


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