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Reprinted by permission of Int Forum Allergy Rhinol. 2015; 5(4):276-282.

OR I G I NAL ART I CLE

Familial risk of chronic rhinosinusitis with and without nasal polyposis: genetics or environment Gretchen M. Oakley, MD 1 , Karen Curtin, PhD 2,3 , Quinn Orb, BA 1 , Carole Schaefer, BACS 3 , Richard R. Orlandi, MD 1 and Jeremiah A. Alt, MD, PhD 1

Background: Chronic rhinosinusitis (CRS) is a highly preva- lent inflammatory condition, with significant effects onmor- bidity and quality of life, yet li le is known about its patho- genesis. Preliminary evidence suggests there is a heritable component to the multifactorial etiology of CRS; however, our understanding of this genetic susceptibility is limited. Methods: Using an extensive genealogical database linked to medical records, the risk of CRS with nasal polyps (CR- SwNP) and without polyps (CRSsNP) was calculated for relatives and spouses of adult probands (1638 CRSwNP and 24,200 CRSsNP patients diagnosed between 1996 and 2011) and were compared to random population controls matched 5:1 on sex and birth year from Cox regression models. Results: First-degree relatives (1stDRs) of CRSwNP pa- tients demonstrated a 4.1-fold increased risk ( p < 10 − 3 ) of carrying the same diagnosis, whereas second-degree rela- tives (2ndDRs) demonstrated a 3.3-fold increased risk ( p < 0.004), compared to controls. In CRSsNP patients, 1stDRs were at 2.4-fold increased risk ( p < 10 − 15 ), whereas 2nd- DRs were at 1.4-fold increased risk ( p < 10 − 15 ) of the same D espite the enormous impact on personal health and economic productivity of chronic rhinosinusitis (CRS), little is known about the pathophysiologic cause of CRS, limiting our ability to treat it definitively. The various 1 Division of Otolaryngology–Head and Neck Surgery, University of Utah School of Medicine, Salt Lake City, UT; 2 Department of Medicine, University of Utah, Salt Lake City, UT; 3 Pedigree and Population Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT Correspondence to: Jeremiah A. Alt, MD, PhD, University of Utah School of Medicine, Division of Otolaryngology–Head and Neck Surgery, 50 North Medical Drive, Room 3C120, Salt Lake City, UT 84132; e-mail: jeremiah.alt@hsc.utah.edu Potential conflict of interest: None provided. Presented orally at the Annual ARS Meeting on September 20, 2014, Orlando, FL. Received: 22 August 2014; Revised: 23 October 2014; Accepted: 11 November 2014 DOI: 10.1002/alr.21469 View this article online at wileyonlinelibrary.com.

diagnosis. Third-degree relatives (3rdDRs) had a slight in- creased risk at 1.1-fold ( p < 10 − 7 ). Spouses of CRSsNP pa- tients, who likely share environmental circumstances, ex- hibited a 2-fold increased risk ( p < 10 − 15 ). No increased risk was observed in spouses of CRSwNP patients. Conclusion: In the largest population study to date, a sig- nificant familial risk is confirmed in CRSwNP and CRSsNP, which may have a shared genetic and environmental com- ponent. Further understanding of the genetic basis of CRS and its interplay with environment factors could clarify dis- ease etiology and lead to more effective targeted treat- ments. C 2015 ARS-AAOA, LLC. Key Words: chronic rhinosinusitis; CRSwNP; CRSsNP; genetics; famil- iality; environment How to Cite this Article : Oakley GM, Curtin K, Orb Q, Schaefer C, Orlandi RR, Alt JA. Familial risk of chronic rhinosinusitis with and with- out nasal polyposis: genetics or environment. Int Forum Allergy Rhinol. 2015;5:276–282. presentations, associated diseases, and treatment responses of CRS indicate it likely has multiple etiologies. The role of genetics is minimally understood, but is supported by the prevalence of CRS in multiple inherited disorders, such as cystic fibrosis (CF) and Kartagener syndrome, 1,2 as well as its strong association with allergic rhinitis and asthma, both with known heritability. 3,4 Specifically, preliminary studies have reported that up to 14% of patients with CRS with nasal polyposis (CRSwNP) have positive family histories. 5 Furthermore, in a cohort of 174 patients with CRSwNP, 25%had 1 or more first-degree relatives with nasal polyps. 6 An investigation by Adappa et al. 7 demonstrated the asso- ciation between the inheritance of the bitter taste recep- tor and CRS, implicating its potential role in predicting medical and surgical treatment outcomes in patients with CRS. Although a genetic role has been implicated in the patho- genesis of CRSwNP and CRS without nasal polyposis

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