2016 Section 5 Green Book

Oakley et al.

TABLE 3. Familial risk of CRSsNP in CRSwNP probands and familial risk of CRSwNP in CRSsNP probands in Utah*

Relatives of probands

Relatives of controls

Relationship

Affected

Unaffected

Affected

Unaffected

HR

95% CI

p

Risk of CRSsNP in relatives of 1638 CRSwNP probands (compared to 8189 controls) First-degree relatives

< 1 × 10 − 16

174

6,149

334

29,585

2.5

2.1–3.0

Second-degree relatives

134

10,161

474

50,275

1.4

1.2–1.7

< 0.001

Third-degree relatives (first cousins)

189

15,081

931

74,235

1.0

0.9–1.2

0.93

Spouses

30

1,216

76

5,574

1.8

1.2–2.8

0.008

Risk of CRSwNP in relatives of 24,200 CRSsNP probands (compared to 121,000 matched controls) First-degree relatives

< 1 × 10 − 14 < 1 × 10 − 4

119

105,910

230

507,619

2.5

2.0–3.2

Second-degree relatives

91

223,198

270

1,071,475

1.6

1.3–2.1

Third-degree (first cousins)

117

266,523

607

1,271,208

0.9

0.7–1.1

0.41

Spouses

27

19,238

60

89,299

2.1

1.3–3.3

0.002

*Cases compared to controls matched 5:1 on sex and birth year. CI = confidence interval; CRSsNP = chronic rhinosinusitis without nasal polyposis; CRSwNP = chronic rhinosinusitis with nasal polyposis; HR = hazard rate ratio from Cox model.

to date. Family relationships have been determined from ge- nealogies and dynamically updated from vital records with- out reliance on self-reported data. There is no other study in the CRS literature that evaluates familial risk beyond first- degree relatives, whereas we have been able to assess risk in the CRSwNP and CRSsNP phenotypes in more distant family members and also in spouses. This affords us the ad- vantage of investigating the familial nature of CRS with or without NP in distant relatives who share genes, but are less likely than close relatives (or spouses) to share in a common environment. According to our findings for CRSsNP, an increased risk was demonstrated in 1stDRs, 2ndDRs, first-cousins, and more distant cousins of case probands, as well as in their spouses, compared to controls. This increased risk supports a multifactorial etiology to this disease; both genetic and environmental. Familial risk can be due to genetic or en- vironmental factors, as the evidence of familiality in our study suggests. First-degree relatives (parents, children, and siblings) who share genetically are more likely to share a common household than more distant family members, and thus may be susceptible to the same environmental influ- ences. On the other hand, second-degree relatives (grand- parents, grandchildren, aunts/uncles, nieces/nephews) share genetically, but are less likely to share a common house- hold. For this reason, familial risk of CRSwNP and CRSsNP may reflect a genetic susceptibility. Relatives of CRSwNP cases appear to have an increased risk of CRS without the presence of polyps, and conversely relatives of

CRSsNP patients may also be at increased risk of nasal polyps. Spouses may share the environmental risk of the proband, but do not share the genetic risk. We observed no risk of CRSwNP in spouses of CRSwNP probands; however, risk of CRSsNP in spouses of CRSsNP cases was nearly as high as in 1stDRs, which supports environmental influ- ences. Given our findings, we conclude that familial risk of CRSwNP may be due more to underlying genetic sus- ceptibility than familial risk of CRSsNP, which may be more environmentally influenced in addition to evidence of a genetic component. However, more research into environ- mental exposures such as tobacco smoke and comorbidities such as asthma and allergies is needed to evaluate familial risk patterns. We acknowledge that the cases and controls linked to UPDB genealogies in order to assess familial risk of CRS may differ from subjects without pedigree information in the UPDB; individuals that link to the genealogies are more likely to be born in Utah, and to relocate outside of Utah less often. Despite this potential bias, our observations of increased risk in 1stDRs and 2ndDRs were highly signifi- cant and unlikely to represent chance findings. In the case of the UPDB, this relatively geographically stable popula- tion leads to more accurate and extensive data on subjects and their various relatives than could be collected other- wise. In addition, Utah has the highest fertility rate in the nation. This increased number of replicates for analysis can better reveal a genetic predisposition when one exists. As

International Forum of Allergy & Rhinology, Vol. 5, No. 4, April 2015

75