Examination of the Role of Atrial Natriuretic Peptide Polymorphisms in Allergic Rhinitis and Asthma Severity

Asthma is an inflammatory condition of the airways in the lungs that results in obstruction
of airflow in those with the condition. The disease continues to be a major worldwide health
care problem and its prevalence continues to increase annually. In 2005, 20 million people
were diagnosed with asthma. The disease causes significant morbidity and accounts for 5,000
deaths annually. Between 1980 and 1994 the prevalence of asthma increased 74% in the United
States and, in children under age 5, the prevalence increased by 160%. The allergic etiology
of airway inflammation associated with asthma is established. Bronchial washings of asthmatic
subjects are most often characterized by eosinophils, mast cells, and cytokines that are
associated with the Th2 (allergic) phenotype. Similarly, IgE plays a pivotal role in airway
inflammation of asthmatic subjects when allergens that cross-link IgE bound to mast cells in
the airways cause the release of histamine and other inflammatory mediators. The association
of asthma and the IgE mediated allergic phenotype is well established and up to 70% of
asthmatics also suffer from allergic disease.

Adequately treated asthma often has minimal impact of quality of life but diagnosis and
proper treatment is often delayed, resulting in increased missed school days, emergency room
visits, and otherwise preventable degradation in quality of life. It would therefore be
highly useful to identify a biomarker that can be used to assist in the diagnosis of asthma
or to identify subjects at higher risk of developing allergic disease or asthma in the
future. Efforts at identifying a genetic marker for the early diagnosis of asthma have been
unsuccessful, mainly due to the complexity of the pathogenesis of the disease.

Atrial natriuretic factor is a pro-hormone precursor for 4 natriuretic peptide hormones
including atrial natriuretic peptide (ANP). ANP's effects on the cardiovascular system are
well characterized. Less well understood is the role these hormones play in immune
regulation.

Recent studies have demonstrated a role for ANP in the regulation of immune function: ANP
induces release of histamine from mast cells and macrophages, stimulates migration of
neutrophils, enhances the cytotoxic activity of natural killer (NK) cells, and stimulates
TNF-β production. Human dendritic cells express ANP receptors (GC-a) which polarize CD4+
cells towards a Th2 phenotype.

Since allergic rhinitis and asthma are associated with a Th2 phenotype, it is possible that
elevated levels of ANP can be used to predict asthma severity or to predict future
predilection to atopic disease.

There are a number of ANP gene polymorphisms that have been studied and found to be
associated with renal disease, heart disease, hypertension and diabetes. Several studies have
investigated the potential role of these polymorphisms in cardiovascular disease and have
found association between polymorphisms of the ANP gene and left ventricular remodeling,
hypertension, renal disease, diabetes, and increased risk of ischemic stroke. To our
knowledge, no studies evaluating the role of ANP polymorphisms in allergic disease have been
performed.

The goal of this research proposal is to evaluate whether ANP levels can be utilized to
assist in diagnosis of asthma and in the prediction of asthma severity. Additionally, we will
investigate the potential effect of polymorphisms in the ANP gene on asthma severity and thus
serve as a useful genetic marker to predict future risk of atopy and asthma.