Fight Aging!

It has to be said, it is pretty rare for researchers to find a genetic effect as large as a halving of disease risk in human studies. We'll have to see if this particular case holds up in replication studies, but for the moment researchers are claiming that a mutation in the angiopoietin-like 4 (ANGPTL4) gene reduces risk of heart attack by 50%, and that to initial inspection this mutation doesn't seem to bear any detrimental side-effects. If this is in fact the case, we can add this to the growing list of potentially desirable gene therapies that are now well within the technical capabilities of most laboratories in this new age of CRISPR and low-cost, reliable genetic editing. At this point there are probably a score or more speculative changes that may be worth carrying out on the basis of animal studies or the existence of healthy human mutants, but only two or three, such as myostatin knockout, that are backed by sufficient evidence and experience to seem viable and low risk for immediate clinical translation.

Somewhere out there, right now, people with an interest, people with scientific knowledge, and people with money are exchanging missives and chewing over business plans that involve producing and selling packages of gene therapies for human enhancement. Some of these will include viable compensatory treatments for specific aspects of age-related degeneration; myostatin knockout to reduce loss of muscle mass and strength in aging, for example, or adding lysosomal receptors to increase cellular maintenance and slow loss of organ function. As the cost of gene therapy continues to fall, even as its reliability and capabilities increase by leaps and bounds, we're going to see the same thing happen for this field as happened for stem cell research fifteen years ago. Many groups and clinics will choose to circumvent the more restrictive regulatory systems of the US and Europe. They will offer therapies in other regions based on the technical ability to do so, and where there is a reasonable expectation of success and benefit. My prediction is that this process of commercial and medical exploration will be well underway five years from now.

Mutated gene safeguards against heart attacks

For the large-scale study at hand, the scientists analyzed 13,000 different genes from a pool of 200,000 participants - both heart attack patients and healthy control persons. They were on the lookout for correlations between gene mutations and coronary artery disease. For a number of genes, the researchers registered a correlation, including the ANGPTL4 (angiopoietin-like 4) gene. In addition, subjects with the mutated ANGPTL4 gene had significantly lower triglyceride values in their blood. "The blood fat triglyceride serves as an energy store for the body. However, as with LDL cholesterol, elevated values lead to an increased risk of cardiovascular disease. Low values, by contrast, lower the risk. For most patients the focus still lies on cholesterol. A differentiation is always made between the healthy HDL and the harmful LDL cholesterol variants. However, in the mean time we know that the HDL values always run inversely proportional to those of the triglycerides and that HDL itself actually tends to behave in a neutral manner. The triglycerides, on the other hand, are the second important blood fat, alongside the harmful LDL cholesterol. The only reason HDL blood values are still measured is because, together with HDL and triglyceride values, they can be used to derive the LDL values, which cannot be measured directly."

The current study now shows that the concentration of triglycerides in the blood are influenced not only by nutrition and predisposition, but also by the ANGPTL4 gene. "At the core of our data is the lipoprotein lipase (LPL) enzyme. It causes the decomposition of triglycerides in the blood." Normally, ANGPTL4 hems the LPL enzyme, causing blood fat values to rise. The mutations identified by the researchers disable the function of this gene and thereby ensure that the triglyceride value drops significantly. "At the same time, we discovered that the body does not even need the ANGPTL4 gene and manages wonderfully without it. It seems to be superfluous." Shutting down the gene or inhibiting the LPL enzyme in another manner may ultimately protect against coronary disease. "Based on our results, medications now need to be developed that neutralize the effect of the ANGPTL4 gene, thereby reducing the risk of a heart attack. Other researchers have already done this successfully in animal tests. They drastically reduced the blood fat levels in monkeys that received a neutralizing antibody against ANGPTL4. This feeds the hope that antibody preparations with a similar effect can soon be used successfully in humans."

Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease

Through large-scale exomewide screening, we identified a low-frequency coding variant in ANGPTL4 that was associated with protection against coronary artery disease and a low-frequency coding variant in SVEP1 that was associated with an increased risk of the disease. Moreover, our results highlight LPL as a significant contributor to the risk of coronary artery disease and support the hypothesis that a gain of LPL function or loss of ANGPTL4 inhibition protects against the disease.

ANGPTL4 has previously been found to be involved in cancer pathogenesis and wound healing. Previous functional studies also revealed that ANGPTL4 regulates plasma triglyceride concentration by inhibiting LPL. The minor allele at p.E40K has previously been associated with lower levels of triglycerides and higher levels of HDL cholesterol. We now provide independent confirmation of these lipid effects. In vitro and in vivo experimental evidence suggests that the lysine allele at p.E40K results in destabilization of ANGPTL4 after its secretion from the cell in which it was synthesized. It may be that the p.E40K variant leads to increases in the enzymatic activity of LPL because of this destabilization. Previous, smaller studies produced conflicting results regarding p.E40K and the risk of coronary artery disease; we now provide robust support for an association between p.E40K and a reduced risk of coronary artery disease.

To provide confirmatory orthogonal evidence that a loss of ANGPTL4 function is associated with a decreased risk of coronary artery disease, we searched for loss-of-function mutations in this gene. We found that ANGPTL4 loss-of-function mutations were associated with substantially lower triglyceride levels (35% lower than in persons who were not carriers of a loss-of-function mutation), and we also found that these loss-of-function alleles were associated with a 53% lower risk of coronary artery disease. The identification of additional ANGPTL4 inactivating mutation carriers provides further evidence of the association between a loss of ANGPTL4 function and lower triglyceride levels and a reduced risk of coronary artery disease.