Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

232 Applying Pharmacogenomics in Therapeutics
capacity, and hemodynamics of PAH patients, 137 acting by increasing the levels of
nitric oxide (NO) and improving pulmonary haemodynamics. 138
Guanylate Cyclase Activators
The NO-soluble guanylate cyclase–cGMP signal-transduction pathway is impaired
in many cardiovascular diseases, including PAH. Riociguat, a guanylate cyclase activator,
which works both in synergy with and independently of NO to increase levels
of cGMP, 139 reduces right ventricular (RV) systolic pressure and RV hypertrophy
(RVH), and improves RV function compared with vehicle. Riociguat has a greater
effect on hemodynamics and RVH than sildenafil. 139
Genetics and Pharmacogenetics of Pulmonary Hypertension
PAH is an uncommon disease in the general population. The prevalence of heritable
PAH remains unknown. The reason for incomplete penetrance of heritable PAH is
not well understood yet. During the past decade, genetic and genomic approaches
have been applied to dissect genetic contributors to PAH, with major discoveries
obtained in the field of hereditary predisposition to PAH. 140 Notably, BMPR2
(encoding bone morphogenetic protein receptor type 2) was identified as the major
predisposing gene, and ACVRL1 (encoding activin A receptor type II-like 1) as
the major gene when PAH is associated with hereditary hemorrhagic telangiectasia.
141 Over 300 independent BMPR2 mutations have been identified, accounting
for approximately 75% of patients with a known family history of PAH, and
up to 25% of apparent sporadic cases have been associated with mutations in this
gene as the major genetic determinant. 142 Taken together, these observations support
a prominent role for TGF-β family members in the development of PAH.
Consequently, a series of candidate gene–based studies have been carried out to
delineate novel genetic variants by examining TGF-β receptors and effectors in
patient cohorts. These studies have implicated genes such as SMAD9 (encoding
SMAD family member 9), SMAD4 (encoding SMAD family member 4), SMAD1
(encoding SMAD family member 1), BMPR1B (encoding bone morphogenetic protein
receptor type IB), and CAV1 (encoding caveolin 1, caveolae protein, 22 kDa) in
PAH. 140 More recently, exome sequencing in a family with multiple affected family
members without identifiable heritable PAH mutations was found to have a heterozygous
novel missense variant in KCNK3 (encoding potassium channel, subfamily
K, member 3). 143 KCNK3 encodes a pH-sensitive potassium channel in the two-pore
domain superfamily, 144 which is sensitive to hypoxia and plays a role in the regulation
of resting membrane potential and pulmonary vascular tone, 145,146 thus potentially
representing a novel target for PAH treatment.
Pharmacogenetics or pharmacogenomics is a tool to better understand the pathways
involved in PH, as well as to improve personalization of drug therapy. Because
of genetic heterogeneity in treatment effects and outcomes across the patients, pharmacogenetics
that will study polymorphisms that modulate the response to treatment
will enable physicians to deliver cost-effective, tailored treatments for all PAH
patients in the future. A patient’s clinical response to disease-specific therapy is
complex, involving the severity of the patient’s disease, other comorbidities, appropriateness
of the prescribed therapy, and patient compliance. 147 However, this is a