Multicenter initiative seeking critical genes in respiratory papillomatosis

Abstract

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.

Fig. 1.

Transmission disequilibrium test If a specific locus neither confers susceptibility to nor protects from recurrent respiratory papillomatosis (RRP), then individuals with the disease whose parents have the genotype depicted would be equally divided among the four genotypes, namely AC, BC, AD, and BD. On the other hand, if the “shaded” allele (B) conferred susceptibility, then the BC and BD individuals would outnumber the AC and AD individuals. By knowing the parents’ genotype, we know what each affected patient’s genotype could have been. We hereby have the basis to compare observed genotype with expected genotype. In this way, we do not have to confront issues such as inappropriate control subjects, and we do not have to be overly concerned with stratification of allele frequencies in various gene pools