Review article
Genetics and epigenetics of chronic
rhinosinusitis
Devyani Lal, MD,a Tripti Brar, MBBS, MD,a Shreya Pusapadi Ramkumar, BS,a,b Jingyun Li, PhD,c,d,e,f,g
Atsushi Kato, PhD,h and Luo Zhang, MD, PhDc,d,e,f,g Phoenix, Ariz; St Louis, Mo; Beijing, China; and Chicago, Ill
Discerning the genetics and epigenetics of chronic rhinosinusitis
(CRS) may optimize outcomes through early diagnostics,
personalized and novel therapeutics, and early prognostication.
CRS associated with cystic fibrosis and primary ciliary
dyskinesia has well-characterized genetic mutations. Most CRS
subjects, however, do not exhibit identifiable monogenic
alterations. Clustering in related individuals is seen in CRS with
nasal polyps. Spouses of subjects with CRS without nasal polyps
also may be at increased risk of the same disease. These
observations generate questions on genetic and environmental
influences in CRS. Genome-wide association studies have
identified variations and polymorphisms between CRS and
control subjects in genes related to innate and adaptive
immunity. Candidate gene and transcriptomics studies have
investigated and identified genetic variations related to
immunity, inflammation, epithelial barrier function, stress–
response, antigen processing, T-cell regulation, and cytokines in
CRS. Epigenetic studies have identified mechanisms through
which environmental factors may affect these gene functions.
However, causality is not determined for most variations.
Inferences drawn from these data must be measured because
most investigations report unreplicated results from small study
populations. Large, replicated studies in tight cohorts across
diverse populations remain a pressing need in studying CRS
genetics. (J Allergy Clin Immunol 2023;nnn:nnn-nnn.)
From athe Department of Otolaryngology Head and Neck Surgery, Mayo Clinic in Ari-
zona, Phoenix; bthe Saint Louis University School of Medicine, St Louis; cthe Depart-
ment of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital
Medical University, Beijing; dBeijing Tongren Hospital, Capital Medical University,
Beijing; ethe Department of Allergy, Beijing Tongren Hospital, Capital Medical Uni-
versity, Beijing; fthe Beijing Laboratory of Allergic Diseases and Beijing Key Labo-
ratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing; gthe
Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese Acad-
emy of Medical Sciences, Beijing; and hthe Division of Allergy and Immunology,
Northwestern University Feinberg School of Medicine, Chicago.
Supported by National Institutes of Health grants R01 AI137174, U19 AI106683, and
P01 AI145818 (to A.K.).
Disclosure of potential conflict of interest: D. Lal reports consultant for GSK and receipt
of consulting fees. A. Kato reports a gift from Lyra Therapeutics for his research. The
rest of the authors declare that they have no relevant conflicts of interest.
Received for publication March 28, 2022; revised January 4, 2023; accepted for publica-
tion January 6, 2023.
Corresponding author: Devyani Lal, MD, FARS, Division of Rhinology, Mayo Clinic in
Arizona, 5777 E Mayo Blvd, Phoenix, AZ 85054. E-mail: lal.devyani@mayo.edu.
0091-6749/$36.00
Ó 2023 American Academy of Allergy, Asthma & Immunology
https://doi.org/10.1016/j.jaci.2023.01.004
Key words: Genetics, genomics, epigenetics, epigenomics, tran-
scriptomics, GWAS, sinusitis, CRS, chronic rhinosinusitis, nasal
polyps, RNA, RNA-Seq, cystic fibrosis, primary ciliary dyskinesia,
review
The study of the genetics of chronic rhinosinusitis (CRS) is
necessary to understand its pathogenesis. Most CRS patients do
not have identifiable monogenic or polygenic alterations, with
the exception of CRS associated with cystic fibrosis (CF) or pri-
mary ciliary dyskinesia (PCD). Understanding CRS genetics,
however, may assist with screening, earlier diagnosis, prognosti-
cation, genotyping, and developing targeted therapeutics, poten-
tially transforming the philosophy of management from treating
symptoms to modulating specific targets.
CRS is a clinical diagnosis characterized by symptomatic local
inflammation of the nose and sinuses that persists for at least 12
weeks.1,2 CRS is best thought of as an umbrella diagnosis encom-
passing many pathogenetic subtypes with differing phenotypic
and endotypic characteristics. However, in clinical practice and
in research studies, CRS is often classified, studied, and treated
according to the presence or absence of nasal polyps (NPs).
The etiology of CRS is poorly understood; pathogenetically,
the syndrome is characterized by mucociliary dysfunction.1,2
Contemporary researchers believe that in the genetically suscep-
tible host, environmental insults that result in mucoepithelial
disruption may trigger a cascade of immunopathologic responses
that become self-perpetuating and result in chronic sinonasal
mucosal inflammation.3 CRS with NP (CRSwNP) patients gener-
ally have more recalcitrant disease than patients with CRS
without NPs (CRSsNP).4-7 At the histopathologic and molecular
levels, CRSwNP is classically characterized by infiltration of eo-
sinophils and TH2 cells that produce IL-5 and other TH2 cyto-
kines, whereas CRSsNP is associated with a predominance of
TH1-mediated inflammation. However, it is now increasingly un-
derstood that CRS phenotypes do not necessarily match these
classic endotypic presumptions, and the underlying pathogenetic
processes in CRS may encompass type 1, type 2, or type 3 inflam-
mation, or a mix.3 CRS may be associated with allergy, atopy to
fungi, aspirin sensitivity (leukotriene dysregulation), asthma, im-
munodeficiency, CF, PCD, vasculitis such as eosinophilic granu-
lomatosis with polyangiitis and granulomatosis with polyangiitis,
or unknown factors.1,2
Causal factors in CRS are not currently detailed, with the
exception of subtypes such as CF and PCD. Familial clustering is
seen in certain subtypes of CRS, especially CRSwNP,8,9 but
spouses of CRS subjects also appear to be at increased relative
risk of developing the disease.9 These reports suggest that familial
1
2 LAL ET AL
Abbreviations used
AERD: Aspirin-exacerbated respiratory disease
CF: Cystic fibrosis
CFTR: CF transmembrane regulator
CGS: Candidate gene studies
CRS: Chronic rhinosinusitis
CRSsNP: CRS without NPs
CRSwNP: CRS with NPs
DC: Dendritic cell
GWAS: Genome-wide association studies
HDAC: Histone deacetylase
MC: Mast cell
miRNA: MicroRNA
mRNA: Messenger RNA
NP: Nasal polyp
PCD: Primary ciliary dyskinesia
RNA-Seq: RNA sequencing
scRNA-Seq: Single-cell RNA-Seq
SNP: Single nucleotide polymorphism
TLR: Toll-like receptor
clustering may be genetic as well as environmental; CRS may be
caused by genetic factors, environmental factors, or both.
We address here the salient pathobiological variations that have
been identified in CRS. We provide a brief overview of CF and
PCD because genetic variations identified in these diseases may
also play a role in CRS overall.
Identification of CRS risk genes
Advances in technology have facilitated the study of genetics
and epigenetics in CRS. Table I provides definitions of types of
genetic studies and genetic terms. Differences between CRS
and controls are investigated through candidate gene studies
(CGS) and genome-wide association studies (GWAS) by investi-
gating variations in DNA and RNA sequences through techniques
such as single nucleotide polymorphism (SNP) and RNA
sequencing (RNA-Seq). Epigenetic studies investigate the effect
of human behavior, diet, and environment on gene transcription
by investigating variations in DNA methylation, histone modifi-
cations, noncoding RNAs,10,11 and alternative polyadenylation.12
Bridging the gap between genetic variations, epigenetic modifica-
tions, and pathogenetic mechanisms is the science of transcrip-
tomics, which analyzes RNA transcripts produced by the
genotype at a given time (the transcriptome). Transcriptomics
links the genome and the proteome (proteins expressed in a tissue
at a given time), and by measuring the transcriptome in different
tissues or at various time points, the relationship between gene
regulation and cellular molecular mechanisms can be studied.
Heritability of CRS
The heritability of CRS has not yet been defined. The genetic
contribution to asthma predisposition (heritability) is estimated to
be 55% to 74% heritability in adults and almost 90% in children.13
The heritability of allergic rhinitis is about 33% to 90%.13,14 In
CRS, like most airway pathologies, genetic susceptibility may
be one of several factors that result in airway disease. Familial
clustering has long been reported in CRS.8,9 In a large
population-based study, 1,638 CRSwNP and 24,200 CRSsNP
J ALLERGY CLIN IMMUNOL
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subjects were matched to random controls. First- and second-
degree relatives were found to have a 4.1-fold and 3.3-fold
elevated risk for CRSwNP, respectively. For CRSsNP patients,
first- and second-degree relatives had a 2.4-fold and 1.4-fold
risk of developing CRSsNP, respectively.9 Additionally, spouses
of CRSsNP patients were also at a 2-fold increased risk of the dis-
ease.9 In Sweden, Bohman et al8 found that the relative risk of
CRSwNP in first-degree relatives was 4.9; the prevalence of
CRSwNP in relatives was 13.4%, versus 2.7% in the control pop-
ulation. However, whether familial clustering results from germ-
line changes or the impact of shared environments remains
unclear15 and needs further investigation in CRS. Additionally,
historical data for familial clustering in aspirin-exacerbated respi-
ratory disease (AERD) are also not well supported.16
Genetic architecture of CRS disease risk
The genetic architecture of CRS risk has not yet been detailed.
CRS is thought to be a polygenic disorder that develops as a result
of complex interactions between multiple genes and environ-
mental factors. How these genes interact with each other and with
the environment to produce CRS is still poorly understood. Only a
very small percentage of CRS is due to monogenic causes (as in
CF), where mutations in a single gene of high penetrance results
in disease.
Most studies in CRS genetics have been performed in patients
identified with NPs. Martin et al10 published a systematic review
of the genetics and epigenetics of nasal polyposis. Of 179 articles
that underwent full-text review, 20 articles considered CRS pa-
tients as a whole (without differentiating between those with
and those without NPs). They reported 99 genes and over 150
SNPs and genetic variants were identified as being related to
NPs. The main biological functions related to these variations
included the cytokine-mediated signaling pathway, defense
response, inflammatory response, response to cytokines, immune
response, stress response, response to chemical stimulus, and
signal transcription.10
Candidate gene studies
Studies in CRS genetics have mostly studied NP. However, it is
now increasingly evident that the classic linkage between the
phenotype of CRSwNP with type 2 inflammation and CRSsNP
with type 1 inflammation is not always valid. Therefore, in
contrast to the review provided in this journal by Hsu et al in
2013,17 we will focus on variations identified by targeted candi-
date gene investigations and those identified on association
studies without a priori assumptions. The implications of these
genes on major biological pathways are also presented.
Genes and pathways already suspected of playing a pathoge-
netic role in CRS have been studied through focused sequencing.
Several CGSs have investigated a variety of associations with
CRS, including CRSwNP, asthma, and total serum IgE levels.18-23
CGS have also investigated specific subtypes of CRS to study var-
iations associated with allergic fungal rhinosinusitis, AERD,
presence of coexistent sinonasal bacterial infection, deployment
of surgical intervention, and differences in patient outcomes
(see Table E1 in the Online Repository available at www.
jacionline.org). Nonetheless, the relatively small sample sizes
of these studies, compounded by the lack of replication of the sig-
nificant variants in larger cohorts with different ethnic
J ALLERGY CLIN IMMUNOL LAL ET AL 3
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TABLE I. Glossary of genetic nomenclature

Allele Variant of a gene present at a specific locus on a chromosome.
Locus, loci Physical region or regions on a chromosome that may contain 1 or multiple genes.
Polymorphism Gene state in which more than 1 allele variant occupies that gene’s locus. To be considered a
polymorphism, each allele must also occur in the population at a frequency of >
_1% of the population.
Candidate gene studies (CGS) Study of select genes and their variants based on an a priori hypothesis about their function or role in a
disease.
Single nucleotide polymorphism (SNP) Common type of genetic variation in which a single nucleotide is substituted with another at a specific
position in the genome. Approximately 4-5 million SNPs are present in a human’s genome, at a
frequency of about 1 in every 1000 nucleotides. For example, the nucleotide guanine (G) may be
substituted with the nucleotide cytosine (C) for a specific location, leading to 2 possible nucleotide
variations, G or C, referred to as alleles. To be classified as an SNP, a variant has to be present in >
_1%
of the population. SNPs that occur more frequently in people with certain traits or pathology compared
to controls are considered to be associated with the trait and/or disease.
Genome-wide association studies (GWAS) Study of the entire genome of a large population to identify SNPs. GWAS analyze thousands of SNPs in
a single analysis. Identification of large numbers of SNPs across the genome helps with disease
identification (biomarker), prognostication, and prediction.
Heritability Statistic that measures the fraction of an observed phenotype variability (eg, disease) that can be
attributed to genetic variation after nongenetic attributions (environment, chance) have been accounted
for. Any disease can be modeled as the sum of genetic (genotype) and environmental effects. If the
heritability of a trait is stated to be 0.8, then 80% of that trait is related to variations in the genome and
cannot be explained by environmental factors or chance (not that 80% is inherited from parents).
Heritability can be estimated by studying phenotypic variation among related individuals in a
population or through GWAS by measuring associations between individual phenotype and genotype
data.
Transcriptomics Analysis of the RNA transcripts produced by the genotype at a given time (aka the transcriptome).
Transcriptomics provides the link between the genome and the proteome (proteins expressed in a
tissue at a given time). By measuring the transcriptome in different tissues or at various time points,
the relationship between gene regulation and cellular molecular mechanisms in any disease can
studied.
Single-cell RNA sequencing (scRNA-Seq) Analysis of RNA sequences from individual cell types in an organ or tissue to examine cell-level
differences that are masked by bulk tissue RNA studies. scRNA-Seq protocols involve isolating single
cells and their RNA and offer information on the function of that individual cell in the context of its
microenvironment during health and diseased states.
Epigenetics Branch of genetics that focuses on the impact of the environment, human behavior, habits, diet, etc, on
gene function. These changes do not change the germline DNA sequencing but rather influence gene
transcription through mechanisms like DNA methylation, histone modifications, and noncoding RNA
such as microRNAs. These mechanisms can cause upregulation or silencing of genes. Epigenetic
changes are reversible but are also heritable.
More information is available at Medline’s ‘‘Help Me Understand Genetics’’ (medlineplus.gov/genetics/understanding/).

populations, may affect these studies’ reliability. Henmyr et al24
aimed to replicate 53 SNPs reported to be associated with CRS
by previous CGS in a White population of European origin; how-
ever, the investigators only found 7 variants in 7 genes that were
significantly associated with CRS susceptibility. Of these, only
some SNPs in PARS2, TGFB1, and NOS1 reached the significant
threshold after multiple testing. Table E1 outlines the candidate
genes investigated and implicated in the pathogenesis of CRS.
These include genetic variations in antigen presentation, proin-
flammatory response, type 2 inflammation, innate immunity, tis-
sue remodeling, cellular responses to stress, membrane receptors,
and ion channels. In addition, Table E1 provides information on
whether SNPs susceptible to CRS were replicated in the study
of Henmyr et al or of others. Table II summarizes the pathobio-
logic implications of the genetic variations identified.25-93
A prospective study on children found that a variant
(rs6967330-A) in CDHR3 that has been previously identified as
an asthma risk allele94 was also associated with a higher incidence
of rhinovirus type C infection.95 A retrospective study on CRS
(n 5 343) versus controls (n 5 389) that sought to see if individ-
uals with CRS had this allele also identified the odds of CRS to be
higher in those individuals with the CDHR3 allele rs6967330,
even after eliminating asthma as a confounding factor.96 Thus,
it is plausible that CRS occurred as a result of childhood viral in-
fections due to certain genetic variations. In addition, the same
group also identified the GSDMB rs7216389 SNP to be higher
in CRS patients,97 and this SNP has been previously identified
in childhood-onset asthma and increased susceptibility to rhino-
virus infections.98
Genome-wide association study
Three recent pooling-based GWAS assessing separate pools of
DNA from CRS patients and control subjects found novel genetic
variants in several innate immunity-related genes involved in the
pathogenesis of CRS.99-101
Kristjansson et al27 reported their large GWAS meta-analysis
on NP and CRS to date from the United Kingdom and Iceland
on 5,608 CRS subjects, 4,366 NP subjects, and over 700,000 con-
trols. The findings from these studies are summarized in Table E1
and Table II. The authors showed that 10 loci (HLA-DQA1, IL33,
TSLP, ALOX15, 10p14, FOXP1, CYP2S1, IL18R1, SLC22A4, and
MYRF) were significantly associated with NP and 2 variants
4 LAL ET AL J ALLERGY CLIN IMMUNOL
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TABLE II. Genes identified in CRS, association with major biological pathways, and disease processes
Gene/loci Function Regulation Population Disease Study

Innate immunity:
Genes encoding
HLA-MHC
class I
A1/B8 Antigen [ Associated White Asthma, NP Moloney 198025
presentation
A74 Associated European CRSwNP Luxenberger 200026
Cw*04 Cw*12, Associated Turkish NP Keles 200818
A*24 B*07, B*57
Innate immunity:
Genes encoding
HLA-MHC
class II
DRB1*04 Antigen Associated Turkish Asthma, AIA Keles 200818
presentation
DQA1 rs1391371 Associated European Genome-wide Kristjansson 201927
NP, CRS
DRA rs2395190 Associated East Asian Genome-wide Sakaue 202128
CRS
rs9268644 Korean CRSwNP Kim 201219
rs3129878
rs3129881
rs2239805
DQB1*03 Associated American Allergic fungal Schubert 200429
sinusitis and
hypertrophic
sinus disease
DR16, DQ8, DQ 9 Associated Chinese CRSwNP Zhai 200730
DRB1*03, DRB1*04 Associated Mestizo Mexican CRSwNP Jaqueline 200631
DRB1*08
Innate immunity:
Toll like
receptors (TLR)
TLR2 rs3804099 Member of TLR Associated Korean CRS Park 201132
family that with [ risk
plays a
fundamental role
in pathogen
recognition
and activation
of innate
immunity
7 other No association Canadian CRS Tewfik 200833
variations
TLR2 TLR4 3 SNPs TLR2 (2258A>G) Turkish CRSwNP Kesici 202134
and TLR4
(1196C>T)
associated
TL2, TLR4, mRNA levels Associated Korean Biofilms of Sun 201235
NF-kappaB CRS
patients
Innate immunity:
Bitter taste
receptors
TAS2R13 rs1015443 Mediates taste Associated with Canadian CRS Mfuna Endam 201436
detection
TASR249 rs12226920
TAS2R49 rs12226919
TAS2R38 rs10246939 Mediates capability Associated with United States CRSwNP and Adappa 201437; Mfuna
to taste bitter Canadian refractory Endam 201436
compounds CRS patients
Associated Polish CRS Dzaman 201637
homozygous AVI
genotype had higher
computed tomography
scores than homozygous
PAV genotypes

(Continued)
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TABLE II. (Continued)

Gene/loci Function Regulation Population Disease Study
Nonfunctional phenotype Italian CRSwNP Cantone 201838
more common
in CRS patients
compared to controls
and gram-negative
biofilms in CRS
more likely to occur
in those with
nonfunctional haplotype
Innate immunity:
NO generation
NOS1 rs1483757 NO synthase Protective effect Canadian CRS Zhang 201139
rs9658281
rs1483757 Associated White CRS Henmyr 201424
NOS1AP rs4657164 Encodes accessory Associated White CRS Henmyr 201424
protein for
NO synthase
type 1 gene
NOS2 rs2779248 Inducible Associated Turkish Eosinophilic Akyigit 201740
NO synthase CRSwNP
that synthesizes
NO
CAT rs7943316 Antioxidant enzyme Associated
that protects
cells against
oxidative stress
Other innate
immunity genes
MET rs38850 Proto-oncogene that Role in CRS development Canadian CRS Castano 201041
encodes a member
of receptor
tyrosine kinase
family of proteins
is involved in
cellular survival,
migration,
and invasion
[ United States CRSwNP Stankovic 200842
SERPINA1 rs1243168 Encodes inhibitor Homozygous patients Canadian CRS Kilty 201043
of serine had increased
protease and probability of
targets elastase, having CRS;
plasmin, thrombin, associated with
trypsin, chymotrypsin, clinically severe CRS
and plasminogen
LTF Involved in regulation Associated Polish CRSwNP with or Zielinska-Blizniewska
of iron without asthma 201244; Liu 200445
homeostasis and allergy
TNF-a rs1800629 Responsible for Pathogenesis association Turkish American CRSwNP Batikham 201046;
recruitment European Bernstein 200947;
of eosinophils Erbek 200748
and cascade
development
[ Chinese Qing 202149
IL1B rs16944 Member of IL-1 Increases IL-8 expression Turkish CRSwNP Erbek 200748
involved in alongside CpG3
various immune methylation
responses reduction
IL18R1 rs6543124 Cytokine receptor Associated with European NP genome-wide Kristjansson 201927
involved in
IL-18–mediated
IFN-g synthesis
in TH1 cells
CXCL5, CCL20 CXCL9, TH1 chemokines; [ East Asian Noneosinophilic Wang 201650;
CXCL10 CXCL11 mediate immune CRSwNP Okada 201851
response through
activation and
recruitment
of cells

(Continued)
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TABLE II. (Continued)

Gene/loci Function Regulation Population Disease Study

SAA1 Acute phase Y

reactant
CHI3L1 Regulates [
morphology of
vascular
endothelial cells
lactoferrin Iron binding protein Y NP Liu 200445;
Stankovic 200842
DMBT1 Unclear
PIP Regulates water
transport
STATH Maintains high
calcium level
in saliva
CYP2S1 rs338598 Cytochrome P450 Associated European Genome-wide Kristjansson 201927
monooxygenase NP
ANKS1A rs36110421 Regulator of Associated East Asian Genome-wide Sakaue 202128
different CRS
signaling
pathways
FAM71D rs192465115 Unclear
WSB2 rs11068795 Proteasomal Associated European CRS Soliai 202152
degradation American
of target
proteins and
acts as a negative
regulator of
IL-21R; involved
in ‘‘localized
opacification’’
class phenotype
CYLC2 rs10820254 Part of cytoskeletal Associated European CRS Soliai 202152
calyx of mammalian American
sperm heads;
associated with
‘‘diffuse
opacification’’
class phenotype
BCAP29, TAX1BP1, Many different 39 UTR length shift Chinese Noneosinophilic Tian 201253;
DEDD, MAP3K1, functions associated NP Tian 201454
NET1, RNF144B, development
SGPL1, SOD1,
SOD2, YARS,
UBA52, UBE4B,
GRB2, CD163
Genes encoding
structural
proteins
KRT19 Structural integrity Hypomethylation of Korean CRSwNP Kim 201855
of epithelial promoters
cells
COLI81 Provides instructions Increased gene Chinese Zheng 201556
for collagen methylation
synthesis
FUT2 rs11665674 Golgi stack membrane [ East Asian Genome-wide Sakaue 202128
protein CRS
TP73 rs3765731 Member of p53 Associated Canadian CRS Tournas 201057
family involved
in cellular responses
to stress and
development
Genes involved
in adaptive
immunity: TH2
inflammation
IL13 Growth promoting [ Associated CRSwNP Milonski 201558
cytokine

(Continued)
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TABLE II. (Continued)

Gene/loci Function Regulation Population Disease Study
IL4 rs2243250 Cytokine produced C-590T polymorphism Korean CRSwNP Yea 200659
by activated associated with
T cells with protection
many functions
[ Associated Milonski 201558
IL6 rs1800796 Involved in Associated Chinese CRS Zhang 201260
maturation of
B cells
rs13447445 Polymorphisms White CRSwNP Bernstein 200947
contribute to
association in
this region
Periostin rs3829365 Type 2–associated [ CRSwNP and Milonski 201558;
(POSTN) gene in asthma ASA Stankovic 200842
and other type 2
inflammatory
diseases
[ East Asian Noneosinophilic Okada 201851;
CRSwNP Wang 201650
[ European Aspirin-sensitive Plager 201061
CRSwNP
IL10 rs1800896 Immune regulatory Polymorphisms Korean AIA and Kim 200962
cytokine contribute to CRSwNP
with anti- development of AIA
inflammatory with rhinosinusitis
function through gene–gene
interaction with
TGFB1;
hypomethylation
of gene
miR-19a expression NP Luo 201763
suppresses
IL-10 in peripheral
DCs, which
may target immune
therapy for NPs
CCL26, POSTN, Involved in Basal, differentiating, NP Ordovas-Montanes
CST1 inflammation and secretory 201864;
epithelial cells Jackson 202065
received signals
from IL-4 and/or IL-13
based on
responsive genes
CST1, CCR3 , CCL13 Involved in [ European Asthmatic Plager 201061;
CCL26 (eotaxin-3), accumulation of CRSwNP, Okada 201851;
CLC, CCL18 leukocytes in eosinophilic Wang 201650
(PARC), F13A1, allergic NP
IL1RL1, CPA3 inflammation
CCL18 lncRNA Involved in Associated Chinese CRSwNP Liu 201966
XLOC_010280 accumulation
upregulates of leukocytes
CCL18
IL5RA Member of IL-5 Hypermethylation Korean CRSwNP with Cheong 201167
pathway AIA
Analyzed B cell lineage AERD NP Buchheit 202068
and found that IgG41 compared
and IgE1 antibody to CRSwNP
secreting cells NP
were elevated
TSLP rs13156068 Initiates DC-mediated Associated in female Chinese CRSwNP Zhang 201369
rs764917 TH2 immune subjects
rs6886755 response in
allergic cascade
rs764917 Associated in male
subjects
rs764917_CC Protective role
rs764917_CA Risk factor
Hypermethylation CRSwNP Li 201970

(Continued)
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TABLE II. (Continued)

Gene/loci Function Regulation Population Disease Study

rs1837253 Associated European Genome-wide NP Kristjansson 201927

IL33 rs3939286 Enhances Pathogenesis Belgium CRSwNP Buysschaert 201071
rs1420101 production association.
of TH2
cytokines
rs1888909 Associated European Genome-wide NP Kristjansson 201927
ILIRl1 rs10204137 Receptor for IL-33 Protective effect Canadian CRS Castano 200972
rs10208293
rs13431828
rs2160203
rs4988957
FCER1A rs2427827 Receptor for IgE Associated Indian CRSwNP Dar 201823
PLAT Involved in conversion Hypermethylation; NP Kidoguchi 201873
of plasminogen downregulated PLAT
to plasmin may promote NPs
IL8 IL-1b and TNF-a Recruitment of Hypomethylation in Chinese CRSwNP Li 201974
increase IL-8 neutrophils and CRSwNP; [
expression immune cells on ELISA
miR-125b Enhances type I [ Associated Chinese Eosinophilic Zhang 201275
interferon CRSwNP
expression; RNA
silencing and
posttranscriptional
regulation
AHR miR-124 Critical in development miR124 decreased in CRSwNP Liu 201876
of inflammatory NP and negatively
response; RNA correlated with AHR
silencing and
posttranscriptional
regulation
Five upregulated miRNA RNA silencing and Mucin-type O-glycan Chinese CRSwNP Xuan 201977; Yu
and 19 downregulated posttranscriptional synthesis path 201878
miRNAs’ regulation was significantly
enriched in upregulated
miRNAs. TGFB, TRP
channels, and MAPK
signaling
pathway were
significantly linked to
downregulated
miRNAs
miRNAs belonging Related to ciliogenesis Significantly impaired CRSwNP Callejas-Diaz 202079
to mir-34 and and ciliary function during epithelium
mi-449 families differentiation from
altered miRNA
expression
10p14 rs1444782 Near GATA3, a master Associated European Genome-wide Kristjansson 201927
regulator NP
in TH2 response
Genes involved in
tissue remodeling
TGFB1 rs1800469 Regulates cell Associated White CRS Henmyr 201424
proliferation,
differentiation,
and growth;
can be inhibited by
HDAC inhibitors
Polymorphisms have CRS, AIA Kim 200962
gene–gene
interaction with
IL-10 contributing
to pathogenesis
rs11466315 Suppression may be Korean NP Cho 201280
involved in inhibition
of NP growth
(Continued)
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TABLE II. (Continued)

Gene/loci Function Regulation Population Disease Study

TSA contributes to Korean NP Cho 201381

reversal of
TGFB1-induced
ECM synthesis
that leads to polyp
development
[ Contributes to down Chinese NP Yu 201878
regulation
of miR-663 that may
have regulatory
effects in NP
Associated with change Chinese Xuan 201977
in miRNA level
MMP1 rs1799750 Involved in breakdown Associated with Polish CRSwNP Molga 201682
of extracellular
matrix
MMP2 Helps cleave type No association Chinese CRSwNP Wang 201083
4 collagen
MMP9 rs3918242 Degrades type 4 and Associated with Turkish CRSwNP with Erbek 200984
5 collagen AIA
rs3918242 Associated with Chinese CRSwNP Wang 201083
rs2274756
SERPINE1PAI1 Involved in normal No association NP De Alarcon 200685
blood clotting
(homeostasis)
ADAMTS1 Involved in growth, Hypomethylation Korean NP Kim 201855
fertility, and of promotor
organ function
Genes involved
in arachidonic
acid metabolism
COX2 rs20417 Component of Associated with [ risk Polish CRSwNP Sitarek 201286
respiratory chain
ALOX15 Codes for [ AERD NP; Stevens 202187;
arachidonate correlated with Jackson 202065
15-lipoxygenase eosinophils
enzyme;
lipoxygenase is
activated
by IL-13 and
promotes
eotaxin-3
expression,
involved in type
2 helper
T-cell inflammation
and tissue
eosinophilia
rs34210653 Polymorphism associated European; loss-of- Genome-wide Kristjansson 201927
with protective effect; function NP and CRS
disruption of variant carried by 1
hydrogen bone in
in enzyme active 20 Europeans
site leads to notable
reduction in enzymatic
activity
ALOX5 rs3780894 Member of Associated Canadian CRS Al-Shemari 200888
lipoxygenase
family involved
in synthesis
of leukotrienes
from arachidonic
acid
ALOX5AP rs17612127 Involved in synthesis Associated Canadian CRS Al-Shemari 200888
of leukotrienes
from arachidonic
acid

(Continued)
10 LAL ET AL J ALLERGY CLIN IMMUNOL
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TABLE II. (Continued)

Gene/loci Function Regulation Population Disease Study
rs17238773 Protein that transfers Hypomethylated Korean CRSwNP with Cheong 201167
of arachidonic AIA
acid to ALOX5
CYSLTR1 rs321090 Mediates Associated Canadian CRS Al-Shemari 200888
bronchoconstriction
PGDS, LTB4R Leukotrienes and Hypomethylated Korean CRSwNP with Cheong 201167
prostaglandins AIA
PTGES Enzyme of PGE2 Hypermethylated
biosynthetic
pathway
Genes involved in
transcription/
transcription
factors/translation
EGR2 Binds regulatory Involved in Chinese CRS blood DC Ma 201889
domains pathogenesis
critical for
myelin formation
and maintenance
LINC02106 05:50254705:C:T Noncoding RNA Associated East Asian Genome-wide Sakaue 202128
CRS
NR2F2 Transcription factor Hypomethylation Korean NP Kim 201855
of promotor
PARS2 rs2873551 Involved in protein Associated White CRS Henmyr 201424
biosynthesis
charging transfer
RNAs
FOXP1 rs17718444 Transcriptional Associated European NP in genome- Kristjansson 201927
repressor of wide
T follicular significance
helper cell
differentiation
MYRF rs174535 Transcription factor Associated
involved
in central
nervous system
Genes involved
in ion transport
CFTR locus on Mutations of CFTR Heterozygotes have White Asthma, CRS, Meth 200990;
7q31.1-7q32.1 present on higher risk and/or NP Pinto 200891;
long arm of Raman 200292;
chromosome Wang 200593
7 can result in
CF, which is
associated with CRS
SLC22A4 rs1050152 Sodium ion–dependent Associated European Genome-wide NP Kristjansson 201927
carnitine transporter

AIA, Aspirin-intolerant asthma; ASA, aspirin sensitive asthma; ECM, extracellular matrix; lncRNA, long noncoding RNA; NO, nitric oxide; PGE2, prostaglandin E2; TSA, Trichostatin
A; UTR, untranslated region. [; Upregulated; Y, downregulated; Y, downregulated but mixed study results.

(HLA-DQA1 and ALOX15) associated with CRS. The loss-
of-function variant rs34210653 (Thr560Met) in the ALOX15
gene, carried by 1 in 20 Europeans, appears to protects against
NP and CRS.27 The ALOX15 gene codes for arachidonate 15-
lipoxygenase enzyme. Arachidonate 15-lipoxygenase is activated
by IL-13 and promotes eotaxin-3 expression, which is involved in
TH2 cells, tissue eosinophilia, and type 2 inflammation in
CRSwNP.102,103
Review of the 1000 Genomes Project database revealed that
this variant rs34210653 exhibits common allele frequency
(0.066) in admixed American populations and intermediate
frequency in European populations (0.011), but has extremely
low frequency or is nonpolymorphic in other populations (Afri-
can, 0.002; East Asian, 0; South Asian, 0.003). This suggests that
the association of CRS and NP with the rs34210653 in ALOX15
may also be ethnic specific. (The 1000 Genomes Project, archived
online at www.genome.gov/27528684/1000-genomes-project,
was a collaboration among research groups in the United States,
the United Kingdom, China, and Germany to produce an exten-
sive catalog of human genetic variation.)
Kristjansson et al27 assessed the NP associations of variants re-
ported to associate with eosinophil count. Of the 210 eosinophil
variants, 24 associate significantly with NP in the combined Ice-
land and United Kingdom data set. Of those, 7 were highly corre-
lated with 1 of the 10 signals (HLA-DQA1, IL33, TSLP, ALOX15,
10p14, FOXP1, CYP2S1, IL18R1, SLC22A4, and MYRF) detected
in NP. The remaining variants represent 17 novel NP-associated
variants. Further analysis of the 17 NP-associated signals demon-
strated that 7 were NP-associated variants associated with CRS
and 13 NP-associated variants associated with asthma. All of
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FIG 1. Shared susceptible genes/loci among NPs, allergy and blood eosinophil count, as per GWAS in
European populations (visualized using PhenoGram).
the variants have effects in the same direction for both NP and
eosinophil count. Fig 1 presents the data from previous GWAS
in European populations to determine the overlapping suscepti-
bility loci of CRS,27 allergy (combined phenotype of asthma,
hay fever, and eczema),104 and blood eosinophil count.105 The re-
sults of this analysis suggest that increased circulating eosinophil
count may be a major common event in CRS and allergy.
A recently published GWAS of 220 disorders/traits conducted
using Biobank Japan28 provided an atlas of genetic architectures in
non-European populations. Five loci (LINC02106, HLA-DRA,
ANKS1A, FAM71D, and FUT2) exhibited the genome-wide signif-
icance for CRS in 4617 participants from East Asian populations.
However, likely as a result of the small sample size for NP (n 5
160), no associated loci were reported. Soliai et al52 published the
first GWAS of CRS and its subphenotypes in the United States in
a study of a European American population with 483 CRS and
2057 control subjects. Analysis of genotypes of all CRS subjects re-
vealed 82 significant SNPs at 6 loci, but the authors could not vali-
date either of the 2 SNPs associated with CRS and NP in the study
by Kristjansson et al.27 The investigators next studied CRS subphe-
notypes in 646 subjects with sinus computed tomographic scans,
172 of which were part of the GWAS. The investigators validated
2 loci that were associated with CRS in first-stage GWAS. The
SNP (rs11068795) associated with expression of the WSB2 gene
LAL ET AL 11
in skin is also associated with ‘‘localized opacification’’ on
computed tomographic scans. Another SNP (rs10820254, located
close to the CYLC2 gene) is associated with the ‘‘diffuse opacifica-
tion’’ class phenotype. Because WSB2 functions as a negative regu-
lator of the IL-21 receptor (IL-21R, a molecule associated with
microbe-related epithelial conditions such as inflammatory bowel
disease and Helicobacter pylori infection), the authors reported a
critical role of mucosal immunity in CRS pathogenesis,52 noting
that IL-21R expression is also upregulated in atopic dermatitis pa-
tients who experience Staphylococcus aureus colonization barrier
dysfunction.
Mapping of major biologic connections of genetic
variations associated with CRS
To characterize the main biological connections and identify
the functional pathways and networks associated with CRS
susceptibility, all associated genes reported from CGS and
GWAS were integrated and analyzed. Plausible genes were
prioritized by the functional mapping and annotation GWAS
platform as well as the Data-Driven Expression Prioritized
Integration for Complex Traits (DEPCIT) package according to
the CGS and GWAS data sets. To characterize the main biological
connections and networks associated with CRS susceptibility,
12 LAL ET AL J ALLERGY CLIN IMMUNOL
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FIG 2. Biologic connections and functional networks for prioritized plausible genes of CRS. Networks of
enriched gene ontology/pathway terms were constructed using Metascape. Each term is presented as a
circle node. Circle size represents the number of genes enriched; circle color represents cluster identity.
Terms with similarity score > 0.3 are linked by an edge. The shade of edge represents the degree of
correlation.

enriched ontology clusters from plausible genes were assessed
(Fig 2). Some of the enriched pathways, such as cytokine produc-
tion, leukocyte activation involved in immune response, and
cytokine-mediated signaling pathways, were assembled together
and exhibited high connectivity. Additionally, the enriched
pathway related to inflammatory bowel disease was also assem-
bled at the core, probably conferring pleiotropic effects or shared
genetic architecture across different inflammatory traits. Investi-
gation of these networks could help develop a comprehensive un-
derstanding of CRS.
seem to have higher ratios of the eosinophilic endotype than
Asian populations.106 In line with this, one study reported that
numerous second-generation Asian patients with CRSwNP
residing in the United States had the same noneosinophilic in-
flammatory characteristic as native-born patients from Asian
countries,107 in concordance with the findings of the above 2
GWAS, according to which the significant genes/loci are not
shared between European and East Asian populations. It is likely
that these differences relate to genetic heterogeneity among
ethnic groups.

Limitations of CGS and GWAS EPIGENETIC STUDIES

Inconsistent findings between studies of CRS as well as lack of
evidence of precise biological function are major limitations of
GWAS. Ethnic heterogeneity and admixed CRS phenotypes
could partially explain these divergences. In addition, differences
in techniques to detect the genetic markers, as well as other
confounding factors such as sex, age, and environmental expo-
sure, also influence the reproducibility of the data. Inflammatory
features of CRS also differ across ancestry and geographic
populations. For example, European and American populations
Epigenetic changes can persist in the genes for an individual’s
lifetime, and they can be passed on to progeny for 2 or 3
generations.108 Table E2 in the Online Repository available at
www.jacionline.org summarizes epigenetic studies in CRS along
with associated major biologic pathways.
Most epigenetic CGS have also focused on CRSwNP. In NP,
higher methylation levels were associated with plasminogen
activator, tissue type (plasminogen activator, PLAT) gene,73 and
thymic stromal lymphopoietin (TSLP) gene.70 Downregulated
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PLAT with excessive fibrin deposition by aberrant coagulation
cascade may promote NP. Methylation of CpG sites 1, 2, and 3
in IL8 proximal promoter was significantly decreased in
CRSwNP versus CRSsNP.74 DNA methylation of the CpG3 site
correlated negatively with tissue eosinophil cationic protein and
myeloperoxidase. IL-1b and TNF-a significantly increased IL-
8 expression alongside CpG3 methylation reduction.74
Differences in microRNA (miRNA) levels involved in type I
interferon pathway,75 transcription factor aryl hydrocarbon recep-
tor (AHR),76 transforming growth factor beta 1 (TGFB1),77,78
mucin-type O-glycan biosynthesis, and ciliogenesis and ciliary
function were also reported in NP tissue.77,79 NP tissue was
also noted to have increased expression of IL-874 and TNF-a
signaling49 as well as decreased expression of IL-10 in peripheral
dendritic cells (DCs).63 Expression of miR-150-5p and its target
gene, EGR2 (early growth response 2), are upregulated in CRS
blood DCs.89 Two studies investigated and reported that
TGFB1 proliferation of NP fibroblasts could be inhibited by his-
tone deacetylase (HDAC) inhibitors.80,81 miR-19a (but not the
other miR-17-92) was higher in DC of CRSwNP.63 Recombinant
IL-4 suppressed IL-10 expression in DC, which was abolished by
blocking HDAC-11 or knocking down the miR-19a gene in DC.63
Both histone acetylation studies were in vitro studies investigating
effect of HDAC inhibitors.80,81
An early genome-wide DNA methylation assay studied blood
and polyp tissue from subjects with and without aspirin hyper-
sensitivity (no controls).67 In NP of patients with aspirin-
intolerant asthma, hypermethylation was detected at 332 loci in
296 genes, and hypomethylation at 158 loci in 141 genes. In the
arachidonate pathway, PGDS, ALOX5AP, and LTB4R were hypo-
methylated, whereas PTGES was hypermethylated.67 More
recently, Kim et al55 compared NP with uncinate process tissue
in Korean patients. Compared to healthy controls, 397 and 387
genes were hypermethylated in eosinophilic CRSwNP and non-
eosinophilic CRSwNP, respectively, and 399 and 208 genes
were hypomethylated. Genes involved in cancer pathways,
KRT19 (keratin 19), NR2F2 (nuclear receptor subfamily 2 group
F member 2), and ADAMTS1 (ADAM metallopeptidase with
thrombospondin type 1 motif 1) were among the top genes whose
promoters were significantly hypomethylated in NP.
In the Chinese population, NP was associated with down-
regulated miRNAs in TGFB signaling pathway,77 enriched
messenger RNAs (mRNAs) in CCL-18 (C-C motif chemokine
ligand), impaired ciliogenesis, and ciliary function.79 Increased
expression of enhanced type I interferon was seen in eosinophilic
CRSwNP.109 Higher methylation of the COL181 gene, which co-
des for a subtype of collagen,56 and upregulated miRNAs in
mucin-type O-glycan biosynthesis77,66 were also reported. In 2
studies investigating alternative polyadenylation in the 39 un-
translated region in eosinophilic CRSwNP tissue versus uncinate
tissue, the authors found several different pathways, including
Wnt signaling (an important pathway for immune cell mainte-
nance and renewal), transcription, nucleolus, transcription regula-
tion, apoptosis, protein targeting and transport, RNA splicing,
protein localization, and mRNA processing; the studies had no
healthy controls.53,54
The greatest challenge in epigenetic data is interpreting
whether identified differences play a causal role in pathogenesis,
occur as a result of the disease,110,111 or are just noise. Epigenetic
studies investigating the specific influence of environmental aller-
gens, smoking, diet, and other factors have not yet been conducted
LAL ET AL 13
in CRS. Most studies were conducted in small samples (ranging in
size from 2 to 187 subjects) in Asian populations. Only 2 studies
were replicated with a larger sample size by the same investi-
gator.80,53 Most studies were conducted on NP tissue, with the
exception of 2 studies that included sinonasal tissue as well as pe-
ripheral blood,78,67 and 2 miRNA studies were done exclusively
on DC of peripheral blood.63,89
TRANSCRIPTOMICS
Bulk transcriptome analysis in whole tissue
In the 2000s, several investigators started to report microarray
findings in CRS, including gene expression profiles in NP45,112
and AERD,42 and the effect of glucocorticoid treatment in
NP.113 Table E3 in the Online Repository available at www.
jacionline.org summarizes salient studies in CRS transcriptomics.
Although initial studies identified novel molecules, results were
inconsistent. Liu et al45 found upregulation of prolactin-
inducible protein, statherin, lactoferrin, and DMBT1 (deleted in
malignant brain tumors 1) in NP, while Stankovic et al42 reported
downregulation of them in NP. These inconsistent results may be
related to small sample sizes and differences in specimen samples.
Liu et al used sphenoid and ethmoid tissues, whereas Stankovic
et al used inferior turbinate and ethmoid tissue in controls. There
are regional differences in the expression of many genes, including
lactoferrin in sinonasal mucosa. Because gene expression in con-
trol tissue influences outcomes in NP-associated genes, investiga-
tors have to pay attention to the control tissue in each study.
Because the more recent transcriptomic analyses used inferior
turbinate, uncinate, or ethmoid tissue in controls, results from
these studies were similar to findings by Stankovic et al.42 Stan-
kovic et al also reported the first observation of upregulation of
POSTN (periostin), which is now a well-known type 2–associated
gene in asthma and other type 2 inflammatory diseases,114,115
such as CRSwNP and AERD. After this, many investigators iden-
tified upregulation of POSTN in NP from patients with asthmatic
or eosinophilic CRSwNP by microarray and RNA-Seq.50,51,61 In
addition to POSTN, Plager et al61 also showed the upregulation of
many type 2–associated genes in NP from asthmatic CRSwNP
including CLC (Charcot-Leyden crystal), CCR3, CCL13 (MCP-
4), CCL18 (PARC), CCL26 (eotaxin-3), F13A1, IL1RL1, CPA3
(carboxypeptidase A3), and CST1 (cystatin SN). This implies
accumulation of eosinophils, M2 macrophages, TH2 cells, group
2 innate lymphoid cells, mast cells (MCs), and elevation of type 2
cytokines including IL-4 and IL-13 in NP.
In East Asia, the prevalence of eosinophilic NP is lower than in
Western countries, allowing investigators to directly compare
eosinophilic and noneosinophilic NP by transcriptome analysis.
One study used RNA-Seq to identify upregulated genes in NP
compared to control tissue and found 1058 and 647 upregulated
genes in eosinophilic and noneosinophilic NP, respectively.50
Another study used microarray techniques and found 1449 and
880 upregulated genes in eosinophilic and noneosinophilic NP,
respectively.51 The studies, both from Asia, also identified differ-
entially expressed genes between eosinophilic and noneosino-
philic NPs. Importantly, eosinophilic NP-specific genes
included many of the previously identified upregulated genes in
NP in the United States such as CLC, CCL26, CST1, and
POSTIN.42,50,51,61 Nakayama et al106 directly compared Asian
(residing in Japan) NP with White (residing in the United States)
NP by RNA-Seq and found that the gene expression profile in
14 LAL ET AL
eosinophilic NP strongly overlapped between the 2 populations.
Noneosinophilic NP-specific genes including IFN-g–induced
TH1 chemokines (CXCL9, CXCL10, and CXCL11), IL-17–
induced chemokines (CXCL5 and CCL20 [LARC]), and innate
molecules such as SAA1 (serum amyloid A1) and CHI3L1 (chiti-
nase-3–like protein 1) were similarly elevated in both Asian
studies.50,51 This suggests that a mixed type 1 and type 3 endotype
may be the dominant endotype in noneosinophilic NP in Asia.
These studies also used gene enrichment analyses such as gene
ontology and pathway analyses in dysregulated genes to predict
molecular mechanisms and pathogenesis of CRSwNP. Although
pathogenesis and dysregulated genes in CRSsNP were unclear
for a longer period as a result of the heterogeneity of endotypes,
Klingler et al116 was recently able to identify type 1, 2, and 3
endotype–specific genes in CRSsNP by microarray and predict
molecular mechanisms in each endotype in CRSsNP by gene
enrichment analysis. Overall, these results suggest that current
microarray and RNA-Seq analyses provide reproducible tran-
scriptomic results if investigators focus on the same control tissue
and endotypic inflamed tissue.
Single-cell transcriptome analysis
Although bulk RNA-Seq provides overall transcriptional
changes in target tissues, investigators have yet to study the
sources of these altered genes in separate assays. Single-cell
RNA-Seq (scRNA-Seq) technology is able to fill this gap by
detecting the whole transcriptome profile of individual cells.
Ordovas-Montanes et al64 provided the first evidence of scRNA-
Seq analysis in CRS and found transcriptional changes in many
structural and inflammatory cell types in NP. This study mainly
focused on epithelial cell components and found that NP are char-
acterized by basal cell hyperplasia, reduction of glandular cells,
and an aberrant basal progenitor differentiation compared to non-
polypoid mucosa.64 Furthermore, they clearly showed that basal,
differentiating, and secretory epithelial cells received signals
from IL-4 and/or IL-13 in NP, a finding based on the elevation
of canonical IL-4/IL-13 responsive genes including CST1,
CCL26, and POSTN.64 Stevens et al87 performed scRNA-Seq in
whole NP tissues from patients with CRSwNP and AERD and
found that ALOX15 (15-lipooxygenase) was significantly
elevated in apical and ciliated epithelial cells from AERD NP
and that the level of ALOX15 correlated with eosinophils in NP.
Both bulk and single-cell transcriptome studies help us to identify
and confirm the direct roles of type 2 cytokines in epithelial cells.
For example, Jackson et al65 used airway epithelial cells differen-
tiated by air–liquid interface culture and performed scRNA-Seq
in control and IL-13–stimulated epithelial cells, finding a dra-
matic change of secretory cell phenotype and also confirming
the findings of Ordovas-Montanes et al64 and Stevens et al87
that IL-13 induced CST1, CCL26, POSTN, and ALOX15 in secre-
tory and ciliated epithelial cells. Other studies have focused on
specific cell types. Ma et al117 focused on CD41 T cells in NP
and found that TH2 cells can be classified into 2 main subpopula-
tions, pathogenic TH2 cells and CD1091CRTH22 TH2 cells,
which produce both type 2 cytokines and immunosuppressive
IL-10. Buchheit et al68 analyzed B-linage cells and found that
IgG41 and IgE1 antibody secreting cells were elevated in
AERD NP compared to CRSwNP NP and control tissue. They
also found that IL5RA was expressed in a subset of plasma cells
in AERD NP. Dwyer et al118 investigated MCs and found that
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MCs in NP can be classified into 4 subtypes, MCT (tryptase1),
MCTC (tryptase1chymase1), intermediate MC, and proliferative
MC; they also found that MCTC and intermediate MC play proin-
flammatory roles in eosinophilic NP. Finally, Nakayama et al106
used scRNA-Seq to identify the original source of elevated genes
in NP found by bulk RNA-Seq. Overall, scRNA-Seq reveals the
heterogeneity and novel cell populations in each cell type, detects
molecular mechanisms at the cellular level, and provides new in-
sights into the pathogenesis of CRS.
Limitations of transcriptomic studies
Although scRNA-Seq provides comprehensive information
and is a useful tool to study disease pathogenesis, there are
some limitations. Although up to 30% to 60% of CD451 cells in
NP are neutrophils and eosinophils, they were almost absent in
earlier scRNA-Seq studies in NP.64,87 This weakness raises the
concern that the frequency of cell types discovered by scRNA-
Seq may not be accurate enough. To fill this gap, several investi-
gators performed bulk RNA-Seq in purified eosinophils and
neutrophils from NP and peripheral blood and identified NP-
specific genes in each granulocyte.119,120 Bulk RNA-Seq is not,
however, able to identify the heterogeneity found in other immune
cells, including T cells, B cells, and MCs. In addition, Poposki
et al120 noted that less than 1% contaminating cells influences
the result of transcriptome analysis if these genes are highly ex-
pressed in the contaminating cells but not in target cells. Future
studies will require optimizing scRNA-Seq technology for gran-
ulocytes. Finally, RNA expression is frequently transient and
may not be directly correlated with protein level. This influences
both in vivo tissue samples as well as in vitro culture studies. In-
vestigators need to keep this in mind when making research plans
and analyzing data.
PATHOBIOLOGIC FUNCTIONS OF GENES
ASSOCIATED WITH CRS
Table II summarizes the biologic pathways related to key ge-
netic variations and details the study population and disease asso-
ciation in CRS.
Innate immunity
Innate immunity plays a first-line role in the detection of
pathogens. HLA haplotype variations have importance in antigen
processing and presentation (Table II). HLA genes may be asso-
ciated with immune response, cell surface receptor signaling
pathway, immune system processes, and antigen processing and
presentation.10 Toll-like receptors (TLRs) recognize pathogens
like bacteria, viruses, and fungi and subsequently lead to inflam-
matory processes involving adaptive immunity. TLR2 has been
recognized as the main receptor for Staphylococcus aureus.
Although different polymorphisms in TLR have been reported
in various ethnic populations in CRS compared to controls,32
these have not been replicated.32,33 Recently, bitter taste receptors
have been identified to play a role in the upper airway innate im-
mune response. CRS associated with certain genotypes has been
reported to be associated with worse surgical outcomes or the
need to undergo a surgical treatment, while patients homozygous
for the TAS2R38 allele (PAV) were less likely to require surgical
treatment for CRS.121 An Italian study found that the
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nonfunctional phenotype was more common in CRS patients
compared to controls, and gram-negative biofilms in CRS patients
were more likely to occur in those with the nonfunctional haplo-
type.38 A Polish study reported similar findings: the homozygous
AVI genotype had higher computed tomographic scores than the
homozygous PAV genotypes, and TAS2R38 polymorphisms may
result in susceptibility to CRS.37 A replication study by Mfuna
Endam et al36 identified an SNP in TAS2R38 (rs10246939) in Ca-
nadian patients with CRSwNP and refractory CRS as well as 3
novel SNPs associated with CRS.
The NOS family of genes encodes for enzymes involved in gen-
eration of nitric oxide, a reactive free radical involved in innate
immunity. In small and diverse populations, SNPs for NOS1
and NOS2 have been differentially associated with CRS,24,39
CRSwNP patients40 and CAT, the gene for catalase, was reported
to be more active in eosinophilic CRSwNP patients.40 Other
genes involved in innate immunity have been investigated.
MET, a proto-oncogene that encodes a member of the receptor
tyrosine kinase family of proteins, is involved in cellular survival,
migration, and invasion. In a Canadian population, MET
(rs38850) was found to be associated with CRS.41 SNP in SER-
PINA1 (Serpin family A member 1; rs1243168), a gene that en-
codes the inhibitor of serine protease and targets elastase,
plasmin, thrombin, trypsin, chymotrypsin, and plasminogen,
has also found to be associated with CRS unresponsive to medical
therapy in a Canadian population.43 This gene is deficient in
alpha-1-antitrypsin, an inherited condition that causes severe
lung and liver disease. LTF, the gene for lactoferrin, which plays
an important role in first-line defense, has also been shown to have
associations with CRSwNP in a Polish population, especially
those with asthma or allergy.44
Acquired immunity
SNPs in proinflammatory genes are detailed in Table II, as are
significant variations in genes related to type 2 inflammation.
Additionally, polymorphisms in the IL4 gene (rs2243250) were
found to be associated with CRSwNP in Koreans.59 Milonski
et al58 also found the tissue mRNA levels of IL4, 1L13, and
POSTN to be higher in CRS versus controls. In a Chinese popu-
lation, TSLP polymorphisms were higher in CRSwNP,69 and in
a Belgian population, IL33 polymorphisms were higher in
CRSwNP versus controls.71 ILIRL1, which serves as the receptor
for IL-33, has been associated with several polymorphisms
(rs10204137, rs10208293, rs13431828, rs2160203, and
rs4988957) in a Canadian population with CRS.72 FCER1A, a re-
ceptor for IgE, had polymorphisms (rs2427827) in CRSwNP in an
Indian population.23
Genes involved in tissue remodeling
Aberrant tissue remodeling has been implicated as one of the
pathophysiologic mechanisms in CRS. Polymorphisms in TGFB1
in CRS (rs11466315 in Korean and rs1800469 in White popula-
tions) have been reported.24,62 Polymorphisms in matrix metallo-
protein MMP9 (rs3918242) have been identified in CRSwNP with
aspirin-intolerant asthma in Turkish48 and CRSwNP in Chinese83
populations. In addition, rs2274756 in MMP9 has been identified
in Chinese subjects with CRSwNP83 and MMP1 (rs1799750) in
CRSwNP in a Polish population.82 Studies undertaken to find as-
sociations between MMP283 and SERPINE1 (PAI1)85 have not
shown any significant associations.
LAL ET AL 15
Genes in arachidonic acid metabolism and aspirin-
exacerbated respiratory disease
Altered arachidonic metabolism has been implicated in aspirin-
exacerbated respiratory disease (AERD), which is associated with a
triad of CRSwNP, asthma, and aspirin sensitivity. However,
CRSwNP, even in the absence of AERD, has shown to be associated
with polymorphisms in certain genes involved in arachidonic acid
metabolism. The rs20417 variant of COX2 was found in Polish in-
dividuals with CRSwNP.86 The rs3780894 variant of ALOX5 and
rs17612127 in ALOX5AP were found in CRS in a Canadian popu-
lation.88 Additionally, rs17238773 in ALOX5AP was found in a
replication study in Whites.24 The rs321090 variant in CYSLTR1
(receptor for cysteinyl leukotriene involved in mediating broncho-
constriction) was also found in the same Canadian population in
CRS that found SNPs in ALOX5 and ALOX5AP.88 Familial clus-
tering of AERD is not strongly supported in the literature.16
CRS and the CFTR gene
Several studies have found higher prevalence of CFTR muta-
tions in non-CF CRS patients.90-92,122,123 However, most studies
are limited in studying only the known CFTR variants, and it is
likely that several unknown variants have been missed, unless
gene sequencing technology is used to study these associations
in CRS.
CRS ASSOCIATED WITH CHARACTERIZED
GENETIC DEFECTS
Cystic fibrosis
CF is a life-shortening, autosomal recessive disorder associated
with mutations of the CF CFTR (transmembrane conductance
regulator) gene, which is present on the long arm of chromosome
7 (7q).124 In the United States, CF is a common genetic disease,
occurring in 1 in 2,500 to 3,500 White newborns and carried by
1 in 27 individuals in North America. CF also affects people of
all races, including African American (1 in 15,000), Hispanic
American (1 in 13,500), and Asian American (1 in 35,000).125
The frequency of CF, however, appears to be decreasing, and
the longevity of subjects has greatly improved.126 The CFTR
gene codes for the CFTR protein, which is a chloride and bicar-
bonate channel in exocrine glands. CFTR mutations can lead to
increased mucus viscosity, leading to associations with CRS,
bronchiectasis, pancreatic insufficiency, and liver disease.124
Phe508 is the most common mutation, seen in up to 90 percent
of CF patients in the United States.127,128 Compared to controls,
genetic mutations in the CFTR gene are more commonly seen
in CRS patients without diagnosed CF,123 and CFTR heterozy-
gotes have a higher risk of developing CRS.129 In addition,
CFTR dysfunction may occur as a result of smoking, infection,
or hypoxia.129 In a systematic review and meta-analysis of 6
studies from the United States and Europe, Yong et al123 found
that the pooled prevalence of CFTR mutations in patients with
CRS was 5.65% and that of the Phe508 mutation was 4.22%.
These rates were significantly higher than the estimated preva-
lence of CFTR carrier status of 3% to 4% in the general popula-
tion, raising the possibility that these mutations may confer
susceptibility to CRS. However, overall, the study was limited
by the lack of stringent inclusion criteria for CRS.
An international web consortium, CFTR2 (cftr2.org/), devoted
to the collection of mutations in the CFTR gene, has identified over
16 LAL ET AL
TABLE III. Classification of mutations associated with the CFTR gene
Class Mutation
I No functional CFTR protein created due to premature
stop codons from nonsense, frameshift mutations causing
premature termination of mRNA and defective protein production
II Abnormal CFTR protein processing leading to intracellular
protein degradation
III Gating mutations causing defective chloride channel opening
IV Altered conductance of chloride channel
V Reduced quantity of CFTR channels at cell surface
VI Unstable CFTR protein
Data are from published sources.124,130-133
2000 CFTR mutations, with at least 300 variants now known to be
disease causing. CFTR mutations are grouped into 6 major classes
according to their effect on CFTR protein synthesis and function
(Table III).124,127,130-133 Although some mutations fall clearly
into one class, others lead to several functional defects—for
example, the CFTR mutation Phe508del, which is the archetypal
misfolding class II mutation, also affects gating and stability.
The class of mutation, the presence of modifier genes, as well as
the presence of complex alleles (ie, 2 or more mutations on the
same allele that interact to modify protein quantity or function)
impact disease severity. Therefore, even in Phe508del homozy-
gotes, additional CFTR mutations in promoter, intronic, and
exonic regions are associated with disease severity, which also
might affect responsiveness to new CFTR modulators.124
Some studies have found that the genotype of CF has a
relationship with the presence or absence of polyps. Of 45
patients, 62.5% Phe508 homozygotes had NPs, versus 42.1% of
heterozygotes. However, there was no association of genotype
with severity of CF.134 Another study did not find high-risk geno-
types to be associated with more severe sinonasal disease.135
Similarly, Weinstock et al136 did not find an association of high-
and low-risk genotypes with the presence of nasal polyposis,
extent of sinus surgery, or recurrence. It has been shown that
IFRD1 gene polymorphisms affect lung disease severity in CF,
as well as increase the risk of developing nasal polyposis.137
Why some CF patients develop CRSwNP while others develop
CRSsNP needs to be further studied; the genetic underpinnings
of CRS in CF are not completely understood.
CFTR modulators are compounds that can target CFTR protein
dysfunction.124,128 Ivacaftor is a CFTR potentiator that increases
the probability of the chloride channel remaining in an open state.
Lumacaftor is a corrector that improves availability of the CFTR
protein at the cell membrane and is especially useful in Phe508
mutations. Triple modulator combinations (ivacaftor combined
with 2 corrector compounds with different mechanisms of action)
significantly restored Phe508del CFTR function on Phe508del
homozygotes as well as those with a single copy of Phe508del
combined with nonmodulable mutations in clinical trials.124
The understanding of genetics of CF have allowed for the use of
gene editing to potentially treat CF patients.138 Without a clear
understanding of the genetic basis of CRS, however, the ability
to create such precision approaches may not be possible.
Primary ciliary dyskinesia
PCD is a rare syndrome affecting 1:10,000 to 15,000 Euro-
peans. Consanguinity and closed genetic pool populations, such
as Arabs, have higher prevalence of PCD.139,140 In contrast to CF,
J ALLERGY CLIN IMMUNOL
nnn 2023
Prevalence Targeted drugs
22%
88% VX-809 corrector (lumacaftor) or VX-661 correctors
(tezacaftor, elexacaftor)
6% VX-770 potentiator (ivacaftor)
6%
5%
5%
which is a monogenic disorder, PCD can result from mutations in
1 or more of over 40 genes (Table IV). These mutations ultimately
result in structural abnormalities and dysfunction of the motile
cilia with hallmark ultrastructural defect (absence of the outer
or inner dynein arm with microtubular disorganization).140 Unex-
pected neonatal respiratory distress in full-term infants, persistent
wet cough from early infancy, bronchiectasis, CRS, and middle
ear effusion with conductive hearing impairment should raise
concern for PCD. Fifty percent of PCD patients have situs inver-
sus and are commonly infertile.140 Mutations in the DNAH5 gene
are the most frequently reported, followed by DNAI1. Different
mutations are associated with variable phenotypes. A biallelic
pathogenic mutation or hemizygous X-linked mutation in a
known PCD gene can confirm PCD diagnosis.141,142 Most PCD
is inherited in an autosomal recessive fashion, although rare
X-linked (PIH1D3 and OFD1 gene mutations) and autosomal
dominant (FOXJ1 mutations) inheritances are also known.140
The top 5 implicated genes for PCD differ by ethnicity.139 Addi-
tionally, about 30% to 35% of patients with PCD have no identifi-
able genetic mutations. Genes related to PCD are large and
therefore can have several mutations, all of which are not patho-
genic. These factors, along with the lack of a comprehensive data-
base of all genetic mutations that can cause PCD, limit the
sensitivity of genetic testing. There is no clear correlation be-
tween severity of CRS and the type of ciliary abnormality in
PCD, and no studies have been undertaken to correlate type and
severity of CRS and PCD genotype. Additionally, PCD genotype
has not been found to be a predictor for endoscopic sinus surgery
in a retrospective study including 54 pediatric PCD subjects.143
Recently, polymorphisms in the taste receptor TAS2R38 have
been implicated in susceptibility to respiratory infections in
PCD.144 The genomics of PCD is still poorly characterized, and
personalized therapy in PCD is not yet on the horizon.
Limitations of genetic studies
While studying the role of genomics and epigenomics in CRS
is progressing rapidly, interpretation of data remains a challenge,
and each type of genetic study has its limitations. Further, CRS
demonstrates high heterogeneity in clinical features, diversity of
immunologic profiles, and significant influence from ancestry and
current environments. Contemporary data suggest that individual
patients may have highly heterogenous inflammatory profiles
with varying admixtures of type 1, type 2, and type 3 responses.1,2
Given this background, interpretation of CRS genetic studies
must be nuanced through our contemporary understanding of
CRS heterogeneity. Comparing CRS with controls and defining
each study group and phenotype precisely are imperative to
J ALLERGY CLIN IMMUNOL LAL ET AL 17
VOLUME nnn, NUMBER nn

TABLE IV. Genetic mutations in PCD and association with situs inversus
Type of defect Genes involved in mutation Situs inversus

Defects of outer dynein arm composure Heavy chains DNAH5 and DNAH11, intermediate chains Yes
DNAI1 and DNAI2, light chains DNAL1 and NME8 result in
dysfunction of outer dynein arms
Defects in outer dynein arm docking complexes (ODA-DC) and CCDC114, 1472 ARMC4, 73 CCDC151, TTC25 Yes
targeting
Abnormal cytoplasmic dynein preassembly factors (dynein DNAAF1, DNAAF2, DNAAF3, DNAAF4 (DYX1C1), DNAAF5 Yes
axonemal assembly factors [DNAAFs]) (HEATR2), LRRC6, ZMYND10, SPAG1, C21ORF59,
DNAAF6 (PIH1D3), CFAP300 cause PCD with combined
outer and inner dynein arm defects
Tubular disorganization CCDC39, CCDC40 Yes
Defects in radial spoke components RSPH1, RSPH4A, RSPH9, RSPH3, DNAJB13 No
Defects in central pair associated proteins HYDIN100, STK36 No
Isolated nexin link defects DRC1, CCDC65,GAS8 No
Reduced generation of multiple motile cilia (respiratory cells MCIDAS (major regulator of ciliogenesis in multiciliated cells; No
usually lack any motile cilia or show only very few motile respiratory cells usually lack any motile cilia or show only
cilia) very few motile cilia), CCNO (mutations result in a very low
number of cilia covering the airway cells; cilia can still have
normal cilia motility)
Motile ciliopathies with subtle or no respiratory disease MNS1, DNAH9, CFAP53, ENKUR Maybe

The following genes are autosomal recessive: ARMC4, C21orf59, CCDC103, CCDC114, CCDC151, CCDC39, CCDC40, CCDC65, CCNO, CFAP221, CFAP298, CFAP300,
DNAAF1, DNAAF2, DNAAF3, DNAAF4, DNAAF5, DNAAF11 (LRRC6) DNAH11, DNAH5 (most common), DNAH8, DNAH9, DNAH11, DNAI1 (second most common), DNAI2,
DNAJB13, DNAL1, DRC1, GAS8, GAS2L2, HYDIN, LRRC56, MCIDAS, NME8, ODAD1, ODAD2, ODAD3 (CCDC151), RSPH1, RSPH3, RSPH4A, RSPH9, SPAG1, SPEF2,
STK36, TTC25, ZMYND10. The following genes are X-linked recessive: OFD1, PIH1D3, RPGR. The following gene is autosomal dominant: OFD1.

TABLE V. Research needs and future directions for genetic studies in CRS
d Development of large biobanking alliances nationally and internationally with well-characterized cohorts that are based on histology, inflammation, and
molecular-driven endotyping of CRS.
d Identification of CFTR gene variations in non-CF CRS.
d Identification of PCD genotypes in non-PCD CRS.
d Further study of genetic diseases, such as AAT deficiency, that have not been adequately studied in CRS and need attention. AAT is characterized by mu-
tations in the SERPINA1 gene. In homozygotes, mutations are known to lead to early-onset panacinar emphysema and chronic obstructive pulmonary
disease. AAT belongs to the serine protease inhibitor group that critically regulate various inflammatory cascades, with a major role in the neutralization of
neutrophil proteases, in particular neutrophil elastase.157
d Machine learning applications for studying large populations, association of comorbid conditions, and identification of theratypes and integrated multio-
mics.158
d Multiomics study with application of machine learning for calculating heritability and developing a polygenic risk score to make risk predictions and prog-
nostications for disease onset, severity, and therapeutic responsiveness.158,159
d Optimizing scRNA-Seq technology. Although up to 30% to 60% of CD451 cells in NP are neutrophils and eosinophils, they were almost absent in earlier
scRNA-Seq studies in NP.64,87 Future studies will require optimizing the technology for granulocytes.

AAT, Alpha-1-antitrypsin.

genetic studies.145 In the absence of clear cutoffs between normal
and disease states, genetic studies may yield results that may not
be relevant.
Another major drawback is the cross-sectional nature of
genetic studies, which can only offer input on association, not
causation. Indeed, most studies in the literature, with notable
exceptions, offer a genetic snapshot in time and may not account
for certain individuals who are normal at the time of study and
may miss individuals who are predisposed and progress to
develop CRS over the course of their lives. Prospective studies
in the literature are rare. Chang et al146 studied early-life risk fac-
tors for CRS. They created a longitudinal birth cohort study that
enrolled over 1000 individuals at birth and followed them into
adulthood. The investigators found that the strongest risk factor
of having adult ‘‘sinusitis’’ was physician-diagnosed sinusitis at
age 6. The group with early-onset CRS (childhood sinusitis
with development of adult CRS) differed from those without
sinusitis in that they were more likely to have maternal history
of asthma, to be skin test positive to Alternaria, and to report
eczema, allergic rhinitis, wheeze, asthma, a higher number of
colds during childhood, and increased total serum IgE levels at
9 months of age. In those with late-onset adult sinusitis, there
were no significant differences in these characteristics compared
to those without sinusitis. However, the diagnosis of adult sinus-
itis in this study was made according to a history of whether or not
the patient had undergone a sinus x-ray, as advised by a commu-
nity physician.146 Additionally, in a retrospective review, Chang
et al96 found CRS to be higher in those individuals with
CDHR3 allele rs6967330 (previously identified by Bønnelykke
et al94 in a pediatric study to be associated with higher incidence
of asthma and rhinovirus type C infection95). Thus, childhood
viral infections may predispose people to development of CRS
as a result of certain genetic variations. Longitudinal studies
may be far more valuable at understanding the causation and
18 LAL ET AL
pathophysiology of CRS than most cross-sectional studies, which
at best imply association. This also implies that longitudinal
studies may be critical to further understanding CRS
pathogenesis.
Reproducibility remains a concern for GWAS of CRS.52 Of
note, the finding by Kristjansson et al27 of only 2 genome-wide
significant loci despite genotyping approximately 10,000 cases
suggests that substantial clinical heterogeneity could have
masked other risk loci, as use of diagnosis codes for inclusion
may have captured a range of conditions with overlapping symp-
toms. Use of phenotypic classifications that are based on the pres-
ence or absence of NPs to study genetics must be supplanted by
use of biomarkers to subtype disease and study genetic profiles.
For example, eosinophilic CRSwNP and noneosinophilic
CRSwNP have distinct mRNA and miRNA profiles.50,51,147,148
Most candidate gene and epigenetic studies reported in CRS
are nonreplicated and have been primarily conducted on small
populations in Asia, where the population may have genetic and
environmental influences distinct from other global populations.
Ideally, longitudinal replication studies involving repeated ob-
servations, as well as replication across different study designs
and well-characterized cohorts in large populations, should be
performed to validate results.149 Additionally, a multiomics
approach that includes genetic, transcriptomic, and epigenetic an-
alyses will lend further reliability to genetics studies in CRS.
FUTURE DIRECTIONS
Sophisticated genotyping will eventually supersede phenotyp-
ing and clarify whether subtypes of recalcitrant CRS represent the
most severe continuum of a disease process or distinct geno-
pathotypes. Such genotyping can help identify potential super-
responders to targeted therapies, like recently approved biological
drugs that target specific molecules and their receptors, such as
IL-5,150 IgE,151 and IL-4–IL-13 receptors,152 regardless of NPs.
Identification of genotypes also potentially opens up possibil-
ities for gene therapy130 and gene-editing technology for specific
types of CRS.153 For example, CRISPR-Cas9 machine technol-
ogy can potentially be applied for precise epigenome editing in
the future.154 Additionally, trials of novel drugs targeting canon-
ical epigenetic pathways,155,156 such as DNA methyltransferase
inhibitors, HDAC inhibitors, and miRNA based therapeutics,
could potentially also be undertaken in CRS. Development of
CFTR modulators targeted to alleviate specific defects128 exem-
plify development of precision medicine through study of ge-
netics and provide a model for identification and development
of theratypes and personalized therapy for recalcitrant CRS. Phar-
macotherapeutics and novel gene therapies currently being tested
for CF and PCD offer future directions for development of thera-
peutics for CRS. Pressing needs that require investigations are
proposed in Table V.157-159
SUMMARY
Despite many studies, monogenic or polygenic variations have
yet to be identified for most CRS patients. It is likely that variations
of multiple genes may have small but incremental effects in CRS
pathogenesis. When broadly put together, the body of literature
identifies variations in genes related to immunity, epithelial
integrity, and barrier as well as cytokine signaling, tissue remodel-
ing, regulation of cytokine production, and inflammatory responses
J ALLERGY CLIN IMMUNOL
nnn 2023
in CRS. However, causality is not determined for most of these
reported variations. Inferences from these data must be measured
because most investigations report unreplicated results from small
study populations. Large, replicated studies in tight cohorts across
diverse ethnic and geographical populations is a pressing need in
studying CRS genetics. With the exception of some GWAS,
genetic studies have mostly been conducted in Asia. Given the
variabilities in genetic composition and the environmental insults
across the globe, broad generalization to other populations should
await confirmation through large population-based replication
studies. Future investigations into specific genetic biomarkers
will also clarify the heritability of CRS. As the physiologic and
pathobiological roles of these genes become better understood,
novel diagnostic and therapeutic tools will become available for
risk prediction as well as novel and targeted drug therapy; further,
we will gain the ability to alter the risk of CRS by using gene-based
therapy or epigenetic reprogramming.
We thank Angela Donaldson (Mayo Clinic, Jacksonville, Fla) for review of
the report.
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