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Multicenter initiative seeking critical genes in respiratory papillomatosis
Farrel J Buchinsky1, Craig S Derkay, Suzanne M Leal
1Center for Genomic Sciences, Allegheny Singer Research Institute, 320 E. North Avenue, Pittsburgh, PA 15212-4772, USA. fbuchins@wpahs.org
Insights
This study identifies host genes influencing susceptibility to recurrent respiratory papillomatosis (RRP), a disease caused by human papillomavirus (HPV). Understanding these genetic factors enhances knowledge of RRP and host-viral interactions.
Area of Science:
- Genetics
- Immunology
- Virology
Background:
- Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 and 11.
- While many infants are exposed to HPV during birth, only a fraction develop RRP, indicating a role for host genetic susceptibility.
- The variability in disease severity suggests that host genetic factors significantly influence RRP pathogenesis and clinical course.
Purpose of the Study:
- To identify specific host genes that determine an individual's susceptibility to developing RRP.
- To deepen the understanding of host-virus interactions, particularly in the context of HPV infections.
- To explore the genetic underpinnings of RRP to potentially inform future therapeutic strategies.
Main Methods:
- A genome-wide association study (GWAS) was conducted using familial triads (RRP-affected child and parents).
- Transmission disequilibrium test (TDT) was employed to analyze single nucleotide polymorphism (SNP) markers from HapMap data.
- Over- and under-transmitted alleles from parents to affected offspring were identified to pinpoint susceptibility loci.
Main Results:
- Recruitment of approximately 400 patients and their parents has commenced.
- DNA extraction and storage are in progress, with Institutional Review Board approvals secured at multiple hospitals.
- The study is utilizing both genome-wide scans and candidate gene approaches to analyze genetic data.
Conclusions:
- A novel research approach has been developed by integrating a national patient registry with high-resolution human haplotype mapping.
- This strategy aims to uncover the biological mechanisms driving RRP.
- The study will elucidate the genetically determined host-virus interactions contributing to RRP susceptibility.
Objectives:
To determine the host genes that govern susceptibility to recurrent respiratory papillomatosis (RRP). RRP is caused by human papillomavirus (HPV) 6 and 11. Millions of babies are exposed during the birthing process, but relatively few develop the disease and the aggressiveness of the course is highly variable. Genetically encoded host susceptibility is postulated. Determining the host genes that govern susceptibility will enhance our understanding not only of RRP but also of host-viral interaction in general.
Study Design:
A genome-wide association study on familial triads consisting of an RRP-affected child and his or her parents. Using the HapMap data from the human genome project, we will identify those alleles that are over-transmitted by the parents to their affected offspring as compared to those alleles that are under-transmitted.
Methods:
Approximately 400 patients and their parents will be recruited through a collaboration between the Center for Genomic Sciences and the RRP Task Force. DNA will be extracted from blood specimens and viral typing will be performed on biopsy specimens. Patients will be genotyped using single nucleotide polymorphism (SNP) markers and compared to their respective parents' genotype using the transmission disequilibrium test. Both a genome scan and a candidate gene approach will be utilized. RESULTS Institutional Review Board authorization has been obtained at three hospitals and the process is underway at 18 more. Patient and parent recruitment has begun. Specimens have been forwarded to Pittsburgh, Pennsylvania, where the DNA has been extracted and is being stored.
Conclusions:
A novel approach combining a nationwide patient resource and the mapping power of the sub-centimorgan human haplotype map has been developed to elucidate the biological mechanisms of RRP by determining the genetically encoded susceptibilities of host-virus interaction.
