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Oakley et al.

review. Of these, 6 did not fulfill the CRS diagnostic criteria by symptoms. Two of these 6 did not have nasal endoscopy or CT evidence of CRS, whereas 4 who did not have qualify- ing symptoms nonetheless had CT evidence of CRS. These 4 patients with “negative” cardinal symptoms but “posi- tive” CTs had the following profiles: 1 had silent sinus syn- drome, 1 had facial pain with no other symptoms, 1 had a history of previous surgery elsewhere for CRS but was asymptomatic at the time of the visit in the database, and 1 had altered mental status due to intracranial complications of rhinosinusitis and symptoms could not be obtained. Of the remaining 73 patients with qualifying symptom pro- files, 2 did not have a confirming endoscopy or CT. This review therefore resulted in 71 of 79 patients meeting the 2007 criteria by Rosenfeld et al. 13 for diagnosis of CRS, with a positive predictive value (PPV) of 90%. The charts were then reviewed for presence/absence of polyps in the clinical record and compared to the coding re- sults in the database for each patient. Of the 79 CRS charts available for review, 62 carried the ICD-9 diagnosis 473.x without 471.x and were considered CRSsNP, whereas 17 carried the ICD-9 diagnosis for CRSwNP, 471.x. Of the 62 putative CRSsNP from diagnosis codes, 48 were confirmed on chart review whereas the remaining 14 were determined to be clinical CRSwNP. Of the 17 putative CRSwNP from diagnosis codes, 8 were confirmed on chart review whereas the remaining 9 patients were determined to be CRSsNP. Thus, the accuracy of using billing codes available in the UPDB to identify CRSsNP or CRSwNP was 71% based on our chart review. Demographic characteristics The characteristics of 1638 CRSwNP and 24,200 CRSsNP adult cases in Utah and 5:1 matched population controls are shown in Table 1. Patients with CRSwNP and CRSsNP were similar in age, with a mean age at diagnosis of 44 years and 43 years, respectively. In contrast, CRSsNP probands were somewhat more likely to be female (52%), whereas the majority of CRSwNP probands were male (55%). This difference in gender percentage between CRSsNP and CR- SwNP was statistically significant ( p < 0.0001, chi-square analysis). Consistent with the Utah population and similar to other regions in the United States, cases and controls in our study were predominantly non-Hispanic Whites; how- ever, the proportion of non-Whites was higher in controls compared to cases. The racial differences between cases and controls, which were solely selected on sex and birth year, were statistically significant for both CRSsNP and CRSwNP (both p < 0.0001, chi-square analysis). Familial risk of CRS The familial risk of CRSwNP and CRSsNP is shown in Ta- ble 2. First-degree relatives of case probands with CRSwNP had a 4.1-fold increased risk (95% confidence interval [CI], 1.8 to 9.4; p < 10 − 3 ) of having the same diagnosis com- pared to population controls. Within this group, parents,

siblings, and children contributed to the overall 1stDRs risk with similar HR estimates (data not shown). Second- degree relatives of CRSwNP probands had a 3.3-fold in- creased risk (95% CI, 1.5 to 7.5; p = 0.004). There was no significantly increased risk beyond 2ndDRs, although the HR in first cousins was suggestive of an increased risk in 3rdDR cases. We observed no increased risk in spouses of CRSwNP probands compared to controls. In the CRSsNP group (Table 2), 1stDRs had a 2.4-fold increased risk (95% CI, 2.2 to 2.6; p < 10 − 15 ) of carrying the same diagnosis compared to controls, 2ndDRs had a 1.4-fold increased risk (95% CI, 1.3 to 1.4; p < 10 − 15 ), whereas 3rdDRs (first cousins) of cases exhibited a modest but significant increased risk at 1.1-fold (95% CI, 1.08 to 1.2; p < 10 − 7 ; and 95%CI, 1.0 to 1.2; p < 0.02). More dis- tant cousins of cases (fourth-degree and fifth-degree) also exhibited a slight increased risk of CRSsNP (HRs = 1.06; 95% CI, 1.03 to 1.08; p < 10 − 12 ). In contrast to CR- SwNP, spouses of CRSsNP probands carried a 2-fold in- creased risk of CRSsNP themselves (95% CI, 1.8 to 2.2; p < 10 − 15 ). We also calculated familial risk of CRSsNP in relatives of CRSwNP case probands, to examine if the risk of a non- polyposis phenotype was also elevated in their family mem- bers (Table 3). In 1stDRs of CRSwNP cases, we observed a 2.5-fold increased risk of CRSsNP (95% CI, 2.1 to 3.0; p < 10 − 15 ), whereas the increased risk of CRSsNP in 2ndDRs of CRSwNP probands was 1.4-fold (95% CI, 1.2 to 1.7; p < 0.001). In the reverse comparison in which familial risk of CRSwNP in CRSsNP probands was calculated, similar risk estimates were observed. Discussion The complex nature of CRS has thus far limited our full un- derstanding of the pathogenesis of this condition, and there- fore our ability to treat it effectively and consistently. Not only is the etiology believed to be multifactorial, with both genetic and environmental influences, but it also presents as an array of various phenotypes or endotypes with associ- ated comorbidities. Prior research into the genetics of CRS has targeted multiple levels of immunologic susceptibility and comorbid links, including multiple human leukocyte antigen (HLA) alleles, bitter taste receptor T2R38, Toll- like receptors (TLRs), and the cystic fibrosis transmem- brane regulator (CFTR) locus. 2,4,14 Although these studies are promising, common limitations among them include small sample sizes, unclear causality, and difficulty repli- cating results. 4 In an effort to take a broader look at the familiality of CRS, this population-based study assessed shared risk of CRSwNP and CRSsNP based on observed familial cluster- ing compared to that expected in the population over a 16- year period. Although there are multiple studies that have analyzed the association between various single nucleotide polymorphisms (SNPs) and CRS in an effort to identify ge- netic links to the condition, 9,15–23 the clinical importance

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