Biomarkers of Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 120

or decreased risk of developing essential hypertension. This is carried out by determining
the presence in the subject of an allele in the promoter region of the tissue kallikrein
gene, which is correlated with an increased or decreased risk of developing essen-
tial hypertension. US Patent No. 6,747,140 describes the susceptibility to develop
hypertension associated with a mutation in the kallikrein gene.
Gene Mutations in Pulmonary Arterial Hypertension
Mutations in bone morphogenetic protein receptor type-2 (BMPR2) are found in
about 50% of patients with familial PAH (Newman et al. 2004 ). Because familial
PAH is highly linked to chromosome 2q33, it is likely that the remaining 50% of
family cases without exonic mutations have either intronic BMPR2 abnormalities
or alterations in the promoter or regulatory genes. Also, only about 10% of patients
with “sporadic” idiopathic PAH have identifiable BMPR2 mutations. Mutations in
BMPR2 confer a 15-20% chance of developing PAH in a carrier's lifetime.
Advances in genetic testing, presymptomatic screening, and biomarkers should
permit early detection of disease in those at risk of PAH and allow trials of preven-
tive therapy in carriers.
Genetic Biomarkers of Early Onset Myocardial Infarction
Two novel genetic biomarkers, SNPs, are associated with an increased risk for MI:
VAMP8, which is involved in platelet degranulation, and HNRPUL1, which
encodes a ribonuclear protein (Shiffman et al. 2006). The retrospective research
study was performed on samples from over 2,000 individuals in three case-control
studies to compare patterns of genetic variation in people with a history of early-
onset MI to those with no history of MI. The results were significant in all three
studies. Large-scale studies like this one, with well-characterized samples from
carefully selected patients allow the identification of genetic markers for risk of
early-onset MI, which could potentially be incorporated into individual risk assess-
ment protocol. The identification of these variants could improve understanding of
disease mechanisms and suggest novel drug targets.
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) that may predispose some people to abnormal heart rhythms, which
leads to sudden cardiac death was identified through a genome-wide association
study (Arking et al. 2006 ). Statistically significant findings were validated in two
independent samples of 2,646 subjects from Germany and 1,805 subjects from the
US Framingham Heart Study. NOS1AP, a regulator of neuronal nitric oxide syn-
thase (nNOS), modulates cardiac repolarization. The gene, not previously discov-
ered by traditional gene-hunting approaches, appears to influence significantly QT
interval length as risk factor for sudden cardiac death. QT interval can be measured