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

230 Applying Pharmacogenomics in Therapeutics
salmeterol and fluticasone propionate in a cohort of patients with persistent asthma, 109
the observation of which was also confirmed in a more recent clinical trial. 110
Racial and ethnic disparities in the quality of asthma care have been well documented.
111 In the United States, African Americans (AAs) are disproportionately
affected by asthma. Though socioeconomic factors play a role in this disparity, there
is evidence that genetic factors may also influence the development of asthma and
responses to drug treatments in AA children. Pharmacogenomic studies may identify
genetic variants that contribute to these racial disparities. For example, in a
cohort of 107 AA children with severe asthma, the genotype variation in GSNOR
(encoding glutathione-dependent S-nitrosoglutathione reductase) was found be associated
with a decreased response to albuterol in AA children. 112 Further analysis in
this cohort suggested that a combination of four SNPs within GSNOR, ADRB2, and
CPS1 (encoding carbamoyl phosphate synthetase 1) gave a 70% predictive value for
lack of response to this therapy, indicating that genetic variants could contribute to
the observed population disparities in asthma. 112
Pulmonary Hypertension
Brief Background
Pulmonary hypertension (PH) is a progressive disease characterized by increased
pressure in pulmonary arteries. By definition, PH is characterized by an increase in
mean pulmonary arterial pressure (PAP) to ≥25 mmHg at rest, and a mean primary
capillary wedge pressure of ≤15 mmHg. 113,114 As PH develops, blood flow through
the pulmonary arteries is restricted and the right side of the heart becomes enlarged
due to the increased strain of pumping blood through the lungs, which in turn leads
to common symptoms, such as breathlessness, fatigue, weakness, angina, syncope,
and abdominal distension. 114
PH begins with inflammation and changes in the cells that line the pulmonary
arteries. These changes make it hard for the heart to push blood through the pulmonary
arteries and into the lungs, thus causing increased pressure in arteries. PH is
classified into five groups by the WHO according to the cause of the condition and
treatment options. Pulmonary arterial hypertension (PAH) is the Group 1 PH. In
PAH, the pulmonary arteries constrict abnormally, which forces the heart to work
faster and causes increased blood pressure within the lungs. Group 1 PAH includes
PAH that has no known cause (primary PAH or idiopathic PAH [IPAH]); PAH that
is inherited; PAH that is caused by drugs or toxins; PAH that is caused by conditions
such as connective tissue diseases, liver disease, sickle cell disease, and HIV
infection; and PAH that is caused by conditions that affect the veins and small blood
vessels of the lungs. Group 1 PAH that occurs with a known cause often is called
associated PAH. Groups 2 through 5 are sometimes called secondary PH.
Epidemiologically, IPAH without a known cause is rare, with an estimated 15–50
cases per million. 115 IPAH has an annual incidence of 1–2 cases per million people
in the United States and Europe, but is 2–4 times more common in women than in
men. 116 PH that occurs with another disease or condition is more common. For example,
the prevalence is 0.5% in HIV-infected patients 117 and around 3% in patients
with sickle cell disease. 118,119 PH usually develops between the ages of 20 and 60,