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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
174
6,149
334
29,585
2.5
2.1–3.0
<
1
×
10
−
16
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
119
105,910
230
507,619
2.5
2.0–3.2
<
1
×
10
−
14
Second-degree relatives
91
223,198
270
1,071,475
1.6
1.3–2.1
<
1
×
10
−
4
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
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