Purpose: Reported associations of interleukin-18 (IL-18) single-nucleotide polymorphisms (SNPs) with allergic rhinitis (AR) have been inconsistent, prompting a meta-analysis to obtain more precise estimates. Methods: We synthesized data from 8 articles and examined 3 IL-18 SNPs. Two SNPs (rs360721 and rs187238), in linkage disequilibrium, were combined and termed RS1. The rs1946518 SNP was analyzed separately (termed RS2). The recessive, dominant, and codominant (multiplicative) genetic models were used to estimate ORs and 95% CIs. Subgroup analysis was ethnicity-based. Sources of heterogeneity were investigated with outlier treatment. Sensitivity analysis was used to assess robustness of the associative effects. Multiple comparisons were Holm-Bonferroni corrected. Results: All significant (pa < 0.05) outcomes indicating increased risks were found in the dominant/codominant models in RS1 and RS2. Five aspects of differences marked the significant African (RS1) and overall (RS2) outcomes: (i) magnitude of effect (ORs): greater (3.01–5.15) versus less (1.20–1.47); (ii) precision of -effects (95% CIs): less (1.07–21.52) versus more (1.01–1.89); (iii) outlier treated: no versus yes; (iv) sensitivity outcomes: nonrobust versus robust (dominant model only); and (v) greater evidential strength for RS2 (pa = 0.002) compared to RS1 (pa = 0.02) rendered RS2 our core finding. These levels of statistical significance for RS1/RS2 enabled both to survive the Holm-Bonferroni correction. Conclusions: The core outcome indicating a 1.5-fold increased risk could render the IL-18 polymorphisms useful in the clinical genetics of AR. Future studies that could focus on other IL-18 SNPs may find deeper associations with AR than what we found here.

1.
Pawankar
R
,
Bunnag
C
,
Khaltaev
N
,
Bousquet
J
.
Allergic Rhinitis and Its Impact on Asthma in Asia Pacific and the ARIA Update 2008
.
World Allergy Organ J
.
2012
Apr
;
5
Suppl 3
:
S212
7
.
[PubMed]
1939-4551
2.
Settipane
RA
,
Charnock
DR
.
Epidemiology of rhinitis: allergic and nonallergic
.
Clin Allergy Immunol
.
2007
;
19
:
23
34
.
[PubMed]
1075-7910
3.
Bauchau
V
,
Durham
SR
.
Prevalence and rate of diagnosis of allergic rhinitis in Europe
.
Eur Respir J
.
2004
Nov
;
24
(
5
):
758
64
.
[PubMed]
0903-1936
4.
Dávila
I
,
Mullol
J
,
Ferrer
M
,
Bartra
J
,
del Cuvillo
A
,
Montoro
J
, et al
Genetic aspects of allergic rhinitis
.
J Investig Allergol Clin Immunol
.
2009
;
19
Suppl 1
:
25
31
.
[PubMed]
1018-9068
5.
Feijen
M
,
Gerritsen
J
,
Postma
DS
.
Genetics of allergic disease
.
Br Med Bull
.
2000
;
56
(
4
):
894
907
.
[PubMed]
0007-1420
6.
Steinke
JW
,
Borish
L
,
Rosenwasser
LJ
.
5. Genetics of hypersensitivity
.
J Allergy Clin Immunol
.
2003
Feb
;
111
(
2
Suppl
):
S495
501
.
[PubMed]
0091-6749
7.
Button
KS
,
Ioannidis
JP
,
Mokrysz
C
,
Nosek
BA
,
Flint
J
,
Robinson
ES
, et al
Confidence and precision increase with high statistical power
.
Nat Rev Neurosci
.
2013
Aug
;
14
(
8
):
585
6
.
[PubMed]
1471-003X
8.
Palmer
LJ
,
Cookson
WO
.
Using single nucleotide polymorphisms as a means to understanding the pathophysiology of asthma
.
Respir Res
.
2001
;
2
(
2
):
102
12
.
[PubMed]
1465-9921
9.
Scadding
G
.
Cytokine profiles in allergic rhinitis
.
Curr Allergy Asthma Rep
.
2014
May
;
14
(
5
):
435
.
[PubMed]
1529-7322
10.
Giedraitis
V
,
He
B
,
Huang
WX
,
Hillert
J
.
Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation
.
J Neuroimmunol
.
2001
Jan
;
112
(
1-2
):
146
52
.
[PubMed]
0165-5728
11.
Nakanishi
K
,
Yoshimoto
T
,
Tsutsui
H
,
Okamura
H
.
Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu
.
Cytokine Growth Factor Rev
.
2001
Mar
;
12
(
1
):
53
72
.
[PubMed]
1359-6101
12.
Kalina
U
,
Ballas
K
,
Koyama
N
,
Kauschat
D
,
Miething
C
,
Arnemann
J
, et al
Genomic organization and regulation of the human interleukin-18 gene
.
Scand J Immunol
.
2000
Dec
;
52
(
6
):
525
30
.
[PubMed]
0300-9475
13.
Liang
XH
,
Wai
C
,
Wang
Y
.
Differential and opposed transcriptional effects of interleukin-18 gene polymorphisms (-137, +113, and +127) in human HepG-2, HeLa, U937, and THP-1 cells
.
Med Sci Monit
.
2008
Jan
;
14
(
1
):
BR8
13
.
[PubMed]
1234-1010
14.
Kruse
S
,
Kuehr
J
,
Moseler
M
,
Kopp
MV
,
Kurz
T
,
Deichmann
KA
, et al
Polymorphisms in the IL 18 gene are associated with specific sensitization to common allergens and allergic rhinitis
.
J Allergy Clin Immunol
.
2003
Jan
;
111
(
1
):
117
22
.
[PubMed]
0091-6749
15.
Heinzmann
A
,
Gerhold
K
,
Ganter
K
,
Kurz
T
,
Schuchmann
L
,
Keitzer
R
, et al
Association study of polymorphisms within interleukin-18 in juvenile idiopathic arthritis and bronchial asthma
.
Allergy
.
2004
Aug
;
59
(
8
):
845
9
.
[PubMed]
0105-4538
16.
Li
YR
,
van Setten
J
,
Verma
SS
,
Lu
Y
,
Holmes
MV
,
Gao
H
, et al
Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies
.
Genome Med
.
2015
Oct
;
7
(
1
):
90
.
[PubMed]
1756-994X
17.
Borecki
I
. Linkage and Association Studies. In:
Ltd
JW
, editor
.
Encyclopedia of Life Sciences
.
John Wiley & Sons Ltd
;
2001
.
18.
Lewontin
RC
.
On measures of gametic disequilibrium
.
Genetics
.
1988
Nov
;
120
(
3
):
849
52
.
[PubMed]
0016-6731
19.
Wray
NR
.
Allele frequencies and the r2 measure of linkage disequilibrium: impact on design and interpretation of association studies.
Twin research and human genetics : the official journal of the International Society for Twin Studies.
2005
Apr;8(2):87-94.
20.
Teo
YY
,
Small
KS
,
Fry
AE
,
Wu
Y
,
Kwiatkowski
DP
,
Clark
TG
.
Power consequences of linkage disequilibrium variation between populations
.
Genet Epidemiol
.
2009
Feb
;
33
(
2
):
128
35
.
[PubMed]
0741-0395
21.
Cheng
D
,
Hao
Y
,
Zhou
W
,
Ma
Y
.
The relationship between interleukin-18 polymorphisms and allergic disease: a meta-analysis
.
BioMed Res Int
.
2014
;
2014
:
290687
.
[PubMed]
2314-6133
22.
Faul
F
,
Erdfelder
E
,
Lang
AG
,
Buchner
A
.
G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences
.
Behav Res Methods
.
2007
May
;
39
(
2
):
175
91
.
[PubMed]
1554-351X
23.
Clark
MF
,
Baudouin
SV
.
A systematic review of the quality of genetic association studies in human sepsis
.
Intensive Care Med
.
2006
Nov
;
32
(
11
):
1706
12
.
[PubMed]
0342-4642
24.
Pereira
TV
,
Patsopoulos
NA
,
Pereira
AC
,
Krieger
JE
.
Strategies for genetic model specification in the screening of genome-wide meta-analysis signals for further replication
.
Int J Epidemiol
.
2011
Apr
;
40
(
2
):
457
69
.
[PubMed]
0300-5771
25.
Goodman
SN
.
Toward evidence-based medical statistics. 2: the Bayes factor
.
Ann Intern Med
.
1999
Jun
;
130
(
12
):
1005
13
.
[PubMed]
0003-4819
26.
Goodman
SN
. Introduction to Bayesian methods I: measuring the strength of evidence. Clinical trials.
2005
;2(4):282-90; discussion 301-4, 64-78.
27.
Royall
R
.
Statistical evidence: The likelihood paradigm
.
London
:
Chapman and Hall
;
1997
.
28.
Higgins
JP
.
Commentary: heterogeneity in meta-analysis should be expected and appropriately quantified
.
Int J Epidemiol
.
2008
Oct
;
37
(
5
):
1158
60
.
[PubMed]
0300-5771
29.
Higgins
JP
,
Thompson
SG
,
Deeks
JJ
,
Altman
DG
.
Measuring inconsistency in meta-analyses
.
BMJ
.
2003
Sep
;
327
(
7414
):
557
60
.
[PubMed]
0959-8138
30.
Higgins
JP
,
Thompson
SG
.
Quantifying heterogeneity in a meta-analysis
.
Stat Med
.
2002
Jun
;
21
(
11
):
1539
58
.
[PubMed]
0277-6715
31.
Mantel
N
,
Haenszel
W
.
Statistical aspects of the analysis of data from retrospective studies of disease
.
J Natl Cancer Inst
.
1959
Apr
;
22
(
4
):
719
48
.
[PubMed]
0027-8874
32.
DerSimonian
R
,
Laird
N
.
Meta-analysis in clinical trials
.
Control Clin Trials
.
1986
Sep
;
7
(
3
):
177
88
.
[PubMed]
0197-2456
33.
Galbraith
RF
.
A note on graphical presentation of estimated odds ratios from several clinical trials
.
Stat Med
.
1988
Aug
;
7
(
8
):
889
94
.
[PubMed]
0277-6715
34.
Ioannidis
JP
,
Trikalinos
TA
.
The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey
.
CMAJ
.
2007
Apr
;
176
(
8
):
1091
6
.
[PubMed]
0820-3946
35.
Nieters
A
,
Linseisen
J
,
Becker
N
. Association of polymorphisms in Th1, Th2 cytokine genes with hayfever and atopy in a subsample of EPIC-Heidelberg. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.
2004
Mar;34(3):346-53.
36.
Lee
HM
,
Park
SA
,
Chung
SW
,
Woo
JS
,
Chae
SW
,
Lee
SH
, et al
Interleukin-18/-607 gene polymorphism in allergic rhinitis
.
Int J Pediatr Otorhinolaryngol
.
2006
Jun
;
70
(
6
):
1085
8
.
[PubMed]
0165-5876
37.
Sebelova
S
,
Izakovicova-Holla
L
,
Stejskalova
A
,
Schüller
M
,
Znojil
V
,
Vasku
A
.
Interleukin-18 and its three gene polymorphisms relating to allergic rhinitis
.
J Hum Genet
.
2007
;
52
(
2
):
152
8
.
[PubMed]
1434-5161
38.
Ibrahim
GH
,
ElTabbakh
MT
,
Gomaa
AH
,
Mohamed
EA
.
Interleukin-18 gene polymorphisms in Egyptian patients with allergic diseases
.
Am J Rhinol Allergy
.
2012
Sep-Oct
;
26
(
5
):
385
9
.
[PubMed]
1945-8924
39.
Wu
SQ
,
Liang
W
,
Wang
GL
,
Li
LY
,
Wang
DL
,
Chen
C
.
Polymorphisms of the IL-18 promoter and bronchial asthma
.
Mol Med Rep
.
2012
Dec
;
6
(
6
):
1385
8
.
[PubMed]
1791-2997
40.
Birbian
N
,
Singh
J
,
Jindal
SK
.
Protective role of IL-18 -137G/C polymorphism in a North Indian population with asthma: a pilot study
.
Cytokine
.
2013
Jan
;
61
(
1
):
188
93
.
[PubMed]
1043-4666
41.
Jumpasri
J
,
Tungtrongchitr
A
,
Sookrung
N
,
Tantilipikorn
P
,
Thaipisuttikul
I
,
Chaicumpa
W
. Association of Interleukin 18 (IL-18) /-133(C/G) Polymorphism with Specific IgE Levels to Der p Allergen in Thai Allergic Rhinitis Patients.
Graduate Research Conference
.
Thailand
,
2014
.
42.
Tungtrongchitr
A
,
Jumpasri
J
,
Sookrung
N
,
Visitsunthorn
N
,
Tantilipikorn
P
,
Piboonpocanan
O
, et al
Alteration of -656(G/T) and -607(C/A) polymorphisms in interleukin-18 (IL-18) gene in house dust mite-sensitive allergic rhinitis patients in Thailand. Genetics and molecular research : GMR.
2017
Jul 6;16(3).
43.
Dumas-Mallet
E
,
Button
KS
,
Boraud
T
,
Gonon
F
,
Munafò
MR
.
Low statistical power in biomedical science: a review of three human research domains
.
R Soc Open Sci
.
2017
Feb
;
4
(
2
):
160254
.
[PubMed]
2054-5703
44.
Verhaeghe
B
,
Gevaert
P
,
Holtappels
G
,
Lukat
KF
,
Lange
B
,
Van Cauwenberge
P
, et al
Up-regulation of IL-18 in allergic rhinitis
.
Allergy
.
2002
Sep
;
57
(
9
):
825
30
.
[PubMed]
0105-4538
45.
Ray
A
,
Cohn
L
.
Th2 cells and GATA-3 in asthma: new insights into the regulation of airway inflammation
.
J Clin Invest
.
1999
Oct
;
104
(
8
):
985
93
.
[PubMed]
0021-9738
46.
Hurlé
B
,
Segade
F
,
Rodríguez
R
,
Ramos
S
,
Lazo
PS
.
The mouse tumor necrosis factor receptor 2 gene: genomic structure and characterization of the two transcripts
.
Genomics
.
1998
Aug
;
52
(
1
):
79
89
.
[PubMed]
0888-7543
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