Levy Lab

Hara Levy, MD
Assistant Professor, Pediatrics
Specialization: Pediatrics/Pulmonary
Tel: (414) 266-6730
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Research Interests

Section of Pulmonary and Sleep Medicine

The correlation between CFTR genotype (disease causing gene for cystic fibrosis) and clinical severity is poor with regard to cystic fibrosis (CF) lung disease. Lung disease severity in patients with the same CFTR mutations, even siblings, can differ. This observation had led to the investigation of other genetic influences, considered modifier genes, which impact clinical phenotype.

The overall aim of Dr. Levy’s research is to identify polymorphisms in a gene or genes, which impact pulmonary disease severity. Aim 1 sets to establish and characterize a CF database and define key features of the quantitative and qualitative components of our CF phenotype; relate phenotype to variation in disease severity, as defined by levels of FEV1 adjusted for age and gender in CF patients homozygous for the delta F508 CFTR allele, the most common allele in the Caucasian population. Lung function is the phenotypic marker most commonly used and, as part of Aim 1, we are investigating whether this outcome measure should be the most recent lung function age-correlated or rate of decline and determine over how long a time frame is necessary for validity. Alternative methods being evaluated include stratifying subjects into groups with mild, moderate and severe pulmonary function corrected for age, based on quartiles for lung function. Other phenotypic markers being evaluated include opsonic antibody production to the mucoid strain of Pseudomonas aeruginosa and acquisition of mucoid P. aeruginosa in CF patients. Phenotype definition and recruitment of patients, is critical in determining which candidate modifier gene confers a lung phenotype and provides the basis for Aim 2, which is to genotype single nucleotide polymorphic markers (SNPs) from promising genes based on data from Aim 1, research currently being done in the Children’s Hospital Research Institute as part of a K23 NHLBI grant award using microarray analysis to determine candidate genes, and Aim 3, which is to perform family based association analysis for CF phenotype and pulmonary function and other “intermediate” phenotypes such as presence or absence of opsonic antibodies and/or mucoid Pseudomonas aeruginosa.

Currently, we are in the midst of analyzing whether there are genetic associations between n polymorphisms in genes involved in IL-1 production, signaling and regulation and clinical outcomes in CF. Preliminary analysis would suggest significant polymorphisms in several genes that are associated with better or worse outcomes in CF, and when the data is fully analyzed it appears that this will provide insight into the pathogenesis of CF lung disease. A recent manuscript evaluating IL1 gene polymorphisms in CF patients and correlation of phenotype with genotype was recently published in the June edition of Pediatric Pulmonology (Levy, et al. IL1B polymorphisms modulate cystic fibrosis lung disease. Pediatr Pulmonol. 2009 Jun;44(6):580-93. PMID: 19431193).

These studies have the potential to identify novel interactions that influence CF pathogenesis, thereby allowing for the development of new therapies and intervention strategies. In summary, this research focus involves working at the interface of molecular biology and population genetics, ultimately defining disease-modifying genes and identifying genotype-phenotype correlations in patients with cystic fibrosis (CF). We think that the results of this line of investigation, with properly established data sets, large sample size and appropriate analysis will be of direct relevance to identify the most promising candidate genes modifying CF lung disease. This project could easily be held up as an example of the bench to bedside type of investigation that exemplifies the types of interactions between scientists and clinician researchers that we believe important for advancing medicine.