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Understanding RRP a genetic undertaking

Understanding RRP a genetic undertaking. Allegheny General Hospital Pittsburgh, PA. Farrel J. Buchinsky, MD Pediatric Otolaryngologist. Center for Genomic Sciences Allegheny Singer Research Institute. BLUF (bottom line up front). Enrollment tripled since Los Angeles focus meeting

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Understanding RRP a genetic undertaking

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  1. Understanding RRPa genetic undertaking Allegheny General Hospital Pittsburgh, PA Farrel J. Buchinsky, MD Pediatric Otolaryngologist Center for Genomic Sciences Allegheny Singer Research Institute

  2. BLUF (bottom line up front) • Enrollment tripled since Los Angeles focus meeting • Discovered transmission disequilibrium in 2 candidate genes

  3. What is the cause of RRP? HPV 6 & 11 • Necessary • Is it sufficient?

  4. Many exposed • Only few get the disease

  5. Genetic Susceptibility • higher prevalence in relations • But still very rare • HLA DRB1*0301 and DQB1*0201 disproportionately present in RRP • associated with decreased interferon γ expression • Partial reproduc of Gelder • Also assoc in cervical cancer • Epidermodysplasia verruciformis Bonagura; Hum Immunol. 2004 Gelder; J. of Vir. 2003 Madeleine; JID. 2002 Ramoz; Nature G. 2002

  6. Epidermodysplasia Verruciformis • Rare, autosomal recessive, skin disease • Abnormal susceptibility to specific HPVs (5 and 8) • persistent lesions that do not clear virus • 4 specific mutations found in EVER1 Dr. Mark Naylor, Electronic Textbook of Dermatology

  7. More Genetic Evidence • Rabbit papilloma data • HIV/AIDS • 14 AIDS restriction genes explains some of variability rate at which a population progresses from HIV infection to AIDS • Malaria, Otitis Media • Mortality by infectious disease in adoptees more associated with biologic parents than seen for cardiovascular and cancer O'Brien; Nature G. 2004 Sørensen; NEJM. 1988

  8. From who?

  9. So what’s needed 2 specimens 1 mm * 1 mm OR HPV type Specimen of Blood

  10. Acquisition IRB IRB IRB

  11. Enrolment 92 from Patient Support Groups

  12. Recruitment Source

  13. Which gene or genes • 3x109 bases • Candidate Gene Approach • Genomic Scan Approach

  14. Candidates • MHC • Innate Immunity • Toll-like receptors • Cytokines regulating the inflammation • Transcription factors regulating immune response • Known Cell Biology Interactions • E5 inhibits H+ATPase from acidifying vesicles • HPV cell receptor • Other Diseases • Epidermodysplasia Verruciformis • Cervical Cancer

  15. First Candidate Gene Batching • 5 genes • 214 SNPs on Sequenom MassARRAY • 212 cases + relatives

  16. Transmission Disequilibrium Test • Allele 1 = 76%, Allele 2 = 24% • Many trios uninformative • Allele 2 transmitted 16 times, untransmitted 1

  17. TDTae in 2 candidate genes But first... • Quality control scrutiny • Additional SNP genotyping • Sequencing Gordon; Euro J. Hum. Gen. 2004

  18. illumiCode #561 illumiCode #217 illumiCode #1024 /\/\/\/ /\/\/\/ /\/\/\/ /\/\/\/ /\/\/\/ T/T A/T A/A Whole Genome • 96 humans at a time • 300000 SNPs at a time Illumina SNP Assay

  19. CGS Garth Ehrlich, Chris Post Joseph Donfack, Marilyn Smith, Fen Hu Rockefeller University Jurg Ott, Sara Hamon Earliest Collaborators Craig Derkay, RRP Task Force Patient Support Groups Michael Green, Bill Stern Funding NIH – Mentored Clinical Scientist Development Award (Mentored Clinical Scientist Development Award (K08)) RRP ISA – IRB assistant Acknowledgments fjbuch@gmail.com (412) 567-7870 Thank You!

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