Finding rare nonsense variants associated with a “protective” phenotype suggests drugs inhibiting the function of the gene product may be useful therapeutics. One example that has brought this concept to fruition was the association reported in 2006 between nonsense variants in PCSK9 and lower low-density lipoprotein (LDL) as well as protection against coronary artery disease.49 These data suggested inhibition of PCSK9 might be a useful therapeutic strategy in coronary artery disease, and two new drugs with this mechanism of action were approved in 2015.50 Similarly, in an experiment that studied >113,000 subjects drawn from both EHRs and community and prospective cohorts, very rare NPC1L1 loss-of-function variants were found to be less prevalent in cases of coronary artery disease than among controls, supporting suppression of the gene product (an effect of the lipid-lowering agent ezetemibe) as a valid therapeutic strategy.51 A third example is the identification of rare nonsense variants in SLC30A8 as protective against diabetes in the deCODE database as well as community and prospective cohorts.
