One of the examples used in the Royal Society Te Apārangi’s discussion paper on “The use of gene editing in healthcare” is somatic inactivation of the PCSK9 gene by gene editing in liver in order to reduce the risk of cardiovascular disease.

This example demonstrates many of the general challenges of gene editing for healthcare when dealing with common and complex diseases like heart disease.

What is PCSK9?

PCSK9 is a gene on human chromosome 1 that encodes a protein in the proprotein convertase subtilisin/kexin family.

PCSK9 loss of function may decrease risk of cardiovascular disease

There is a clear link between decreased PCSK9 expression and decreased LDL-cholesterol levels in plasma. This has created interest in therapies that reduce PCSK9 expression or function so as to reduce LDL levels and consequently reduce cardiovascular disease risk.

What else does PCSK9 do in the body?

Like most, if not all, proteins encoded in the human genome, PCSK9 has multiple roles in human biology in different tissues and different times during development (Norata et al, 2016). It is expressed in

Liver
Vascular walls
Pancreas
Kidneys
Brain

It is proposed to play a role in

Cholesterol homeostasis, by reducing receptors for LDLs and thus increasing LDL-cholesterol levels in plasma.
Triglyceride homeostasis, including limiting peripheral fat accumulation.
Differentiation of cortical neurons (Seidah et al, 2003)
Neurocognitive process

PCSK9 loss of function may increase risk of obesity and diabetes

A recent review of PCSK9 biology (Norata et al, 2016) concludes:

These findings further confirm how the inhibition of PCSK9 will decrease plasma TG levels by increasing catabolism of TG-rich lipoproteins, but as a consequence support the possibility that it might also increase peripheral fat accumulation.

Additionally they point to a report that, in humans, linked PCSK9 LOF to an increased incidence of diabetes (Saavedra et al, 2015).

Evolutionary theory

From an evolutionary perspective if a gene has been maintained in a population for millions of years, as PCSK9 has, then it probably has an important function. Genes that do not provide an advantage will tend not to be conserved and will be gradually lost from the population. Genes that have a net negative effect on fitness will be removed from the population even more rapidly. The proposed “loss-of-function” (LOF) mutations are found naturally in the population but at a very low frequency with 96-99% of individuals in any given population having the standard genetic variant.

So having wild-type PCSK9 is probably net beneficial in almost all genetic backgrounds. How are we meant to understand the potential benefit of “loss-of-function” mutations in this gene then? The most likely scenario is that the perceived benefit of LOF mutation in terms of reduced cardiovascular risk is offset by related costs.

There are at least two candidates for related costs and both could be true, depending on the genetic background:

Deleterious effects of the modified gene on brain development early in life
Increased risk of obesity and type-2 diabetes later in life

Evidence for the first is that PCSK9 is highly expressed in developing brain tissue. Evidence for the second is that experiments show that PCSK9 is involved in limiting peripheral fat accumulation through its regulation of triglyceride.

The fact that a small fraction of apparently normal individuals have PCSK9 LOF substitutions may either be explained by these individuals having some other compensating changes in their genome to allow this change that most people don’t have, or having an increased risk of type-2 diabetes, or a combination of these two. Regardless, there existence does not mean there will be no negative effects to a wild-type individual of gene-editing the LOF mutation into their PCSK9 gene, even when limited to individual tissues.