Human knock-outs

In my view one of the most interesting and astonishing finding of large-scale exome-sequencing studies is the identification of a substantial number of loss-of-function (LOF) mutations in every human. These disabling mutations of single genes can even point to new drugs.

On average, everyone is heterozygous carrier of 200 inactivating mutations and even homozygous for 20 LOF mutations. However, these LOF mutations in any particular gene are rare, so very large populations are needed to study their effects.

Until now, LOF mutations have long been implicated in certain diseases, such as hypertrophic cardiomyopathy, dilated cardiomyopathy, just to name a few. Most, however, seem to be harmless — and some are even beneficial to the persons carrying them as described below.

It is known that Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann–Pick C1-like 1 (NPC1L1) protein which is important for intestinal cholesterol absorption.
However, until a few weeks ago no clinical trial had shown that Ezetimibe actually reduces heart attack, stroke, or death.

And here genetics steps in: in a recent study published in the NEJM we  identified naturally occurring LOF mutations that disrupt the function of NPC1L1 gene encoding the Niemann–Pick C1-like 1 protein.

We actually found these LOF mutations to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease.

Hence, our study shows that human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug.
And, surprise, surprise, the IMPROVE-IT study, published just a few days after publication of our NEJM paper, demonstrated a real although modest clinical benefit for Ezetimibe.
Other examples of human knock-outs and their relevance for medicine is described in a featured story from MIT technology review which can be found here.