484
effect on phenotype. Protein-coding regions of genes in participants of European or
African ancestry in the Exome Sequencing Project were sequenced to determine
whether rare mutations in coding sequence, individually or in aggregate within a
gene, were associated with plasma triglyceride levels (Crosby et al. 2014 ). For
mutations associated with triglyceride levels, the investigators evaluated their asso-
ciation with the risk of CHD. Rare mutations in the gene encoding apolipoprotein
C3 (APOC3) were associated with lower plasma triglyceride levels. Three of the
four mutations that drove this result, were loss-of-function mutations: a nonsense
mutation (R19X) and two splice-site mutations (IVS2 + 1G → A and IVS3 + 1G → T).
The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the
study was a heterozygous carrier of at least one of these four mutations. Triglyceride
levels in the carriers were 39 % lower than levels in noncarriers, and circulating
levels of APOC3 in carriers were 46 % lower than levels in noncarriers. The risk of
CHD among carriers of any rare APOC3 mutation was 40 % lower than the risk
among noncarriers.
Another sequencing study from Denmark found that three rare variants of
APOC3 – R19X, IVS2 + 1G → A, and A43T – are associated with substantially
reduced levels of nonfasting triglycerides and reduced risk of ischemic cardiovas-
cular disease in the general population (Jørgensen et al. 2014 ). One limitation of this
study is that although the risk of ischemic cardiovascular disease is consistently
inversely related to plasma levels of HDL cholesterol in observational studies, clini-
cal trials as well as genetic studies involving mendelian randomization have failed
to establish a causal link between plasma levels of HDL cholesterol and the risk of
ischemic cardiovascular disease. Nevertheless, the fi ndings of this study are of
potential clinical importance, because they suggest that APOC3 is a relevant drug
target for reducing residual cardiovascular risk. Inhibition of APOC3 by antisense
oligonucleotides was shown to reduce plasma levels of APOC3 and triglycerides in
animal models and in a phase I human clinical trial (Graham et al. 2013 ).
Gene Variant as a Risk Factor for Sudden Cardiac Death
Extremes of the electrocardiographic QT interval, a measure of cardiac repolariza-
tion, are associated with increased cardiovascular mortality. A gene called NOS1AP
(CAPON), which may predispose some people to abnormal heart rhythms leading
to sudden cardiac death, was identifi ed through a genome-wide association study
(Arking et al. 2006 ). Statistically signifi cant fi ndings were validated in two indepen-
dent samples of 2,646 subjects from Germany and 1,805 subjects from the US
Framingham Heart Study. NOS1AP, a regulator of neuronal nitric oxide synthase
(nNOS), modulates cardiac repolarization. The gene, not previously discovered by
traditional gene-hunting approaches, appears to infl uence signifi cantly QT interval
length as risk factor for sudden cardiac death. QT interval can be measured non-
invasively with an EKG, and each person’s QT interval, in the absence of a major
cardiovascular event, is stable over time, making it a reliable measure. Approximately
60 % of subjects of European ancestry carry at least one minor allele of the NOS1AP
genetic variant, which explains up to 1.5 % of QT interval variation.
14 Personalized Management of Cardiovascular Disorders