Eric D. Larson, Jose Pedrito M. Magno, Matthew J. Steritz, Erasmo Gonzalo d.V. Llanes, Jonathan Cardwell, Melquiadesa Pedro, Tori Bootpetch Roberts, Elisabet Einarsdottir, Rose Anne Q. Rosanes, Christopher Greenlee, Rachel Ann P. Santos, Ayesha Yousaf, Sven-Olrik Streubel, Aileen Trinidad R. Santos, Amanda G. Ruiz, Sheryl Mae Lagrana-Villagracia, Dylan Ray, Talitha Karisse L. Yarza, Melissa A. Scholes, Catherine B. Anderson, Anushree Acharya, Samuel P. Gubbels, Michael J. Bamshad, Stephen P. Cass, Nanette R. Lee, Rehan S. Shaikh, Deborah A. Nickerson, Karen L. Mohlke, Jeremy D. Prager, Teresa Luisa G. Cruz, Patricia J. Yoon, Generoso T. Abes, David A. Schwartz, Abner L. Chan, Todd M. Wine, Eva Maria Cutiongco-de la Paz, Norman Friedman, Katerina Kechris, Juha Kere, Suzanne M. Leal, Ivana V. Yang, Janak A. Patel, Ma. Leah C. Tantoco, Saima Riazuddin, Kenny H. Chan, Petri S. Mattila, Maria Rina T. Reyes-Quintos, Zubair M. Ahmed, Herman A. Jenkins, Tasnee Chonmaitree, Lena Hafrén, Charlotte M. Chiong, Regie Lyn P. Santos-Cortez
A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media. © 2019 Wiley Periodicals, Inc.
Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, United States; Department of Otorhinolaryngology, University of the Philippines Manila College of Medicine - Philippine General Hospital, Manila, Philippines; Philippine National Ear Institute, University of the Philippines Manila – National Institutes of Health, Manila, Philippines; Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States; Folkhälsan Institute of Genetics and Molecular Neurology Research Program, University of Helsinki, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Department of Community Dentistry, College of Dentistry, University of the Philippines Manila, Manila, Philippines; Department of Pediatric Otolaryngology, Children's Hospital Colorado, Aurora, CO, United States; Nordhoff Craniofacial Center, Manila, Philippines; Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Punjab, Pakistan; Newborn Hearing Screening Reference Center, University of the Philippines Manila – National Institutes of Health (NIH), Manila, Philippines; Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States; Department of Genome Sciences, University of Washington, Seattle, WA, United States; USC-Office of Population Studies Foundation, Inc. and Department of Anthropology, Sociology and History, University of San Carlos, Cebu, Philippines; Department of Genetics, University of North Carolina, Chapel Hill, NC, United States; Philippine Genome Center, University of the Philippines, Quezon City, Philippines; University of the Philippines Manila – National Institutes of Health, Manila, Philippines; Department of Biostatistics and Bioinformatics, Colorado School of Public Health, Aurora, CO, United States; Division of Infectious Diseases, Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, United States; Department of Otorhinolaryngology, Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, United States; Department of Otorhinolaryngology, Head & Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Center for Children's Surgery, Children's Hospital Colorado, Aurora, CO, United States
