Association Between 17q12-21 Variants and Asthma in Japanese Women: rs11650680 Polymorphism as Potential Genetic Marker for Asthma

Abstract

Epidemiological evidence on the relationship between single-nucleotide polymorphisms (SNPs) rs7216389 and rs11650680 on chromosome 17q12-21 and asthma is inconsistent. We examined this issue in young adult Japanese women. Case subjects were 202 women who had been diagnosed with asthma by a doctor, while 1290 women without doctor-diagnosed asthma served as control subjects. Adjustments were made for age and the presence of older siblings. There were no significant associations between SNP rs7216389 and asthma. Compared with the CC genotype of SNP rs11650680, the CT genotype, but not the TT genotype, was significantly inversely associated with asthma: the adjusted odds ratio for the CT genotype was 0.67 (95% confidence interval: 0.46–0.96). This inverse relationship was significant in women with late-onset asthma, but not in those with early-onset asthma. Under the dominant model, a significant inverse association was found between rs11650680 and asthma in women without older siblings, but not in those with older siblings; the interaction, however, was not significant. This is the first study to show that the CT genotype of SNP rs11650680 was significantly inversely associated with asthma, especially adult-onset asthma. We could not find evidence for interactions between rs11650680 and older siblings affecting asthma.

Introduction

In 2007, a genome-wide association study of 994 cases and 1243 controls from the United Kingdom and Germany observed strong relationships between multiple single-nucleotide polymorphisms (SNPs) on chromosome 17q21 and childhood asthma in family and case-referent panels (Moffatt et al., 2007). Among the indentified SNPs, SNP rs7216389, which is located in an intron of the GSDMB gene in the 17q12 region, was most strongly associated with both childhood asthma and transcription levels of the nearby ORMDL3 gene in the 17q12 region (Moffatt et al., 2007). Significant positive relationships between the TT genotype or the T allele of SNP rs7216389 and asthma were shown in the above-mentioned genome-wide association study (Moffatt et al., 2007) as well as in several genetic association studies among Japanese individuals (Hirota et al., 2008), UK children (Tavendale et al., 2008), Danish children (Bisgaard et al., 2009), individuals from Iceland, Australia, The Netherlands, Germany, the United Kingdom, and Korea (Halapi et al., 2010), French children (Smit et al., 2010), Korean children (Yu et al., 2011), UK adults (Binia et al., 2011; Marinho et al., 2012), Chinese adults in Hong Kong (Sy et al., 2012), Chinese children (Yang et al., 2012), and US children (Çalışkan et al., 2013). In contrast, in two studies on white US children (Sleiman et al., 2008) and Chinese adults (Fang et al., 2011), a significant positive relationship between the C allele of SNP rs7216389 and asthma was observed. A study of Chinese children in Hong Kong found that, compared with the TT genotype of rs7216389, the TC genotype, but not the CC genotype, was significantly inversely associated with asthma and that rs7216389 was not related to atopy or total plasma IgE levels (Leung et al., 2009). In a study of Korean children, a significant inverse association was found between the combination of TC and CC genotypes of rs7216389 and asthma in comparison with the TT genotype (Kang et al., 2012). No significant association was found between SNP rs7216389 and asthma in two studies of African Americans (Galanter et al., 2008; Sleiman et al., 2008).

SNP rs11650680 is located in the promoter region of TOP2A in the 17q21.2 region. The above-mentioned genome-wide association study also found that SNPs rs7216389 and rs11650680 were independently strongly associated with asthma (Moffatt et al., 2007). The C allele of rs11650680 was significantly inversely related to asthma in a case–control study of African Americans (Galanter et al., 2008). Significant inverse associations were found between the TT genotype of rs11650680 and asthma, atopy, and total plasma IgE levels in a study of Chinese children in Hong Kong (Leung et al., 2009). In a cross-sectional study of Korean children, compared with the CC genotype of rs11650680, the CT and TT genotypes combined were significantly inversely related to asthma, although no significant association was observed between rs11650680 and asthma in an independent case–control study (Kang et al., 2012). There was no relationship between SNP rs11650680 and asthma in three studies of UK adults (Marinho et al., 2012), Chinese children (Yang et al., 2012), and Chinese individuals (Li et al., 2012).

In this study, we investigated the associations between SNPs rs7216389 and rs11650680 and asthma in young adult Japanese women using data from the Kyushu Okinawa Maternal and Child Health Study (KOMCHS). In addition, we performed a haplotype analysis and examined the possibility of an interaction between the SNPs and the presence of older siblings.

Materials and Methods

Study population

The KOMCHS is a prospective prebirth cohort study. Details of the baseline survey of the KOMCHS have been described elsewhere (Miyake et al., 2013). Eligible women were those who became pregnant while living in one of the seven prefectures on Kyushu Island in southern Japan, with a total population of ∼13.26 million, or in the Okinawa Prefecture, an island chain in the southwest of Japan, with a total population of nearly 1.37 million. Between April 2007 and March 2008, we requested that 423 obstetric hospitals in the above-mentioned eight prefectures provide as many pregnant women as possible with a set of leaflets explaining the KOMCHS, an application form to participate in the study, and a self-addressed and stamped return envelope. Pregnant women who were willing to participate in the study returned the application form to the data management center. In total, 1757 pregnant women between the 5th and 39th week of pregnancy provided their written informed consent to participate in the KOMCHS and completed the baseline survey. Around 4 months after delivery, 1492 women provided informed consent to genotyping. The ethics committee of the Faculty of Medicine, Fukuoka University approved the KOMCHS.

Selection of cases and control subjects

In the baseline survey, each participant filled out a self-administered questionnaire and mailed the completed questionnaire to the data management center. Research technicians completed missing or illogical data by telephone interview. The questionnaire included questions on age, presence of older siblings, and asthma.

Among the 1492 women whose DNA samples were available, 202 cases were those who had answered yes to the question: “Have you ever been diagnosed by a physician as having asthma?” The remaining 1290 women served as control subjects.

DNA extraction and genotyping

Genomic DNA from buccal specimens collected with BuccalAmp swabs (Epicenter BioTechnologies, Madison, WI) was extracted using a QIAmp DNA mini kit (Qiagen, Inc., Valencia, CA). Genotyping of SNPs rs7216389 and rs11650680 was performed using TaqMan SNP Genotyping Assays on the StepOnePlus machine (Applied Biosystems, Foster City, CA), according to the manufacturer's instructions.

Statistical analysis

SNPs under study were tested for deviation from a Hardy–Weinberg equilibrium using the chi-square test. Linkage disequilibrium was examined using Haploview software version 4.2 (Broad Institute, Cambridge, MA) (Barrett et al., 2005). Logistic regression analysis was performed to estimate the crude odds ratios (ORs) and 95% confidence intervals (CIs) for asthma relative to the SNPs under investigation, with the reference category being the homozygote of the major allele. Multiple logistic regression analysis was used to adjust for age and the presence of older siblings. The statistical power calculation was performed using QUANTO version 1.2 (Gauderman, 2002). Haplotypes and their frequencies were inferred according to the expectation maximization algorithm. For differences in haplotype frequency between the cases and control groups, crude ORs and 95% CIs were estimated based on the frequency of each haplotype relative to all other haplotypes combined. The interaction was tested using a term of the product of two variables in a multiple logistic regression model. Excluding the calculation of linkage disequilibrium and statistical power calculation, all statistical analyses were carried out using STATA/SE software version 12.0 (StataCorp, College Station, TX).

Results

Women with asthma were more likely to be older than the control subjects (Table 1). There was no difference between case subjects and control subjects with regard to the presence of one or more older siblings.

Table 1.

Characteristics of the Study Population

Variable	Cases (n=202)	Controls (n=1290)	p-Value ^a
Age, years, mean±SD	31.5±4.2	30.6±4.2	0.008
Presence of one or more older siblings, n (%)	99 (49.0)	675 (52.3)	0.38

Chi-square test or t-test.

The distributions of SNPs rs7216389 and rs11650680 were in the Hardy–Weinberg equilibrium in the cases (p=0.85 and 0.12, respectively) and in the control subjects (p=0.26 and 0.14, respectively). SNPs rs7216389 and rs11650680 were not in linkage disequilibrium.

Compared with a reference group of women with the CC genotype of SNP rs11650680, those with the CT genotype had a significantly reduced risk of asthma, while the TT genotype was not related to asthma according to our crude analysis (Table 2). Adjustment for age and the presence of older siblings did not appreciably alter the results: the adjusted OR for the CT genotype was 0.67 (95% CI: 0.46–0.96, p=0.029). This inverse association fell just short of the significance level under the dominant model (p=0.059). No significant relationships were observed between SNP rs11650680 and asthma under the additive or recessive model. There were no significant associations between SNP rs7216389 and asthma in any genetic model. With regard to the relationship between SNP rs7216389 and asthma under the additive model (the adjusted OR: 0.84 [95% CI: 0.66–1.08, p=0.17]), the statistical power calculation revealed that, using our sample size, we could detect the gene–disease association for an OR of 0.703 with an accuracy of more than 80% at a significance level of 0.05 with a two-sided alternative hypothesis under the log-additive model.

Table 2.

ORs and 95% CIs for Asthma in Relation to SNPs rs7216389 and rs11650680 in Japanese Women

			n (%)
SNP	Model	Genotype	Cases (n=202)	Controls (n=1290)	Crude OR (95% CI)	Adjusted OR (95% CI) ^a
rs7216389	Codominant	TT	115 (56.9)	675 (52.3)	1.00	1.00
		TC	76 (37.6)	528 (40.9)	0.84 (0.62–1.15)	0.84 (0.61–1.14)
		CC	11 (5.5)	87 (6.7)	0.74 (0.38–1.43)	0.71 (0.37–1.38)
	Additive				0.85 (0.67–1.09)	0.84 (0.66–1.08)
	Dominant				0.83 (0.62–1.12)	0.82 (0.61–1.10)
	Recessive				0.80 (0.42–1.52)	0.77 (0.40–1.47)
rs11650680	Codominant	CC	155 (76.7)	907 (70.3)	1.00	1.00
		CT	41 (20.3)	358 (27.8)	0.67 (0.47–0.97)	0.67 (0.46–0.96)
		TT	6 (3.0)	25 (1.9)	1.40 (0.57–3.48)	1.45 (0.58–3.60)
	Additive				0.80 (0.59–1.09)	0.80 (0.58–1.09)
	Dominant				0.72 (0.51–1.02)	0.71 (0.50–1.01)
	Recessive				1.55 (0.63–3.82)	1.60 (0.64–3.96)

Adjusted for age and presence of older siblings.

CI, confidence interval; OR, odds ratio; SNP, single-nucleotide polymorphism.

Four haplotypes were constructed, but none of these were significantly associated with asthma (Table 3).

Table 3.

Haplotype Analysis of SNPs rs7216389 and rs11650680 in Relation to Asthma in Japanese Women

	n (%)
Haplotype ^a	Cases (2n=404)	Controls (2n=2580)	Crude OR (95% CI) ^b
TC	265 (65.6)	1584 (61.4)	1.20 (0.96–1.51)
TT	41 (10.1)	294 (11.4)	0.88 (0.61–1.25)
CC	86 (21.3)	588 (22.8)	0.92 (0.70–1.19)
CT	12 (3.0)	114 (4.4)	0.66 (0.33–1.22)

Haplotype order is rs7216389 and rs11650680.

Crude OR for each haplotype is relative to all other haplotypes combined.

There was one case with missing data on age at onset of asthma. Under the codominant model, an inverse relationship between the CT genotype of SNP rs11650680 and asthma was statistically significant in women who had developed asthma at the age of 18 or older (n=72), but not in those who had developed asthma at the age of 17 or younger (n=129): the adjusted ORs were 0.53 (95% CI: 0.28–0.997, p=0.049) and 0.76 (95% CI: 0.49–1.17, p=0.21), respectively.

Under the dominant model, a significant inverse association was found between SNP rs11650680 and asthma in women without older siblings, but not in those with one or more older siblings; the interaction, however, was not significant (Table 4). There was no interaction between SNP rs7216389 and the presence of older siblings.

Table 4.

Association Between SNPs rs7216389 and rs11650680 and Asthma, Stratified by Presence of Older Siblings in Japanese Women

		Presence of older siblings
		No		Yes
SNP	Genotype	No. of cases/controls	Adjusted OR (95% CI) ^a	No. of cases/controls	Adjusted OR (95% CI) ^a	p-Value for interaction
rs7216389	TT	59/302	1.00	56/373	1.00
	TC+CC	44/313	0.71 (0.46–1.08)	43/302	0.95 (0.62–1.45)	0.35
rs11650680	CC	81/419	1.00	74/488	1.00
	CT+TT	22/196	0.59 (0.36–0.97)	25/187	0.87 (0.54–1.42)	0.27

Adjusted for age.

Discussion

To our knowledge, the current study is the first to show that, compared with the CC genotype of SNP rs11650680, the CT genotype, but not the TT genotype, was significantly associated with a reduced risk of asthma, especially adult-onset asthma. On the other hand, the present study failed to detect a significant association between SNP rs7216389 and asthma. Our results concerning SNP rs11650680 are not consistent with those of three case–control studies of Chinese children (152 cases and 190 controls) (Yang et al., 2012), Chinese individuals (241 cases [11–80 years] and 212 controls [18–89 years]) (Li et al., 2012), and Korean children (931 cases and 480 controls) (Kang et al., 2012) or with those of a cross-sectional study of 983 UK adults (Marinho et al., 2012) showing the null relationship between this SNP and asthma, those of a study of Chinese children in Hong Kong that showed a significant inverse association between the TT genotype, but not the CT genotype, and asthma (315 cases and 192 controls) (Leung et al., 2009), and those of a study of African Americans showing a significant inverse relationship between the C allele and asthma (261 cases [12–24 years] and 176 controls [8–40 years]) (Galanter et al., 2008), but are partially consistent with those of a cross-sectional study of 1797 Korean children (including 162 children who had been diagnosed by a physician as having asthma) that showed a significant inverse association between the combination of the CT and TT genotypes and asthma (Kang et al., 2012). The present results concerning SNP rs7216389 are in agreement with those of the above-mentioned study of African Americans (Galanter et al., 2008) and those of another case–control study of African American children (Sleiman et al., 2008), which found a lack of association between this SNP and asthma, but are not consistent with those of several studies showing significant associations. The inconsistency of our findings with those of other studies may be, at least partly, explained by the differences in the genetic backgrounds of the populations examined, definitions of asthma, and statistical power.

We are unable to explain why we observed a significant inverse association between the CT genotype of SNP rs11650680 and asthma. Kang et al. (2012) demonstrated that atopic asthmatic Korean children with the CT or TT genotype of rs11650680 showed lower eosinophil cationic protein levels than did those with the CC genotype, and that nonatopic asthmatic children with the CT or TT genotype of rs11650680 showed higher methacholine provocation test values than did those with the CC genotype. SNP rs11650680 might be related to eosinophilic inflammation and bronchial hyperresponsiveness. In the present study, an inverse relationship between the CT genotype of SNP rs11650680 and asthma was stronger in women with late-onset asthma than in those with early-onset asthma. This SNP might have more of an impact on nonatopic asthma than on atopic asthma; however, we were not able to distinguish atopic from nonatopic asthma because neither data on serum IgE levels nor skin prick test results were available in the current study.

SNP rs7216389 is associated with the expression levels of GSDMB and ORMDL3 genes in white blood cells (Halapi et al., 2010). There are also significant positive associations between the number of T alleles of rs7216389 and the expression levels of GSDMB and ORMDL3 in human rhinovirus-stimulated peripheral blood mononuclear cells from adults (Çalışkan et al., 2013). In cord blood mononuclear cells, compared with the CC genotype of SNP rs7216389, the TT genotype was significantly associated with increased Der p 1-activated ORMDL3 gene expression and with increased Der p 1-induced and phytohemagglutinin-induced GSDMA gene expression; moreover, the TT genotype showed significantly increased IL-17 secretion in unstimulated and phytohemagglutinin-stimulated cord blood (Lluis et al., 2011). Given these findings, as well as those of previous epidemiological studies showing significant relationships between SNP rs7216389 and asthma, the lack of significant inverse association between this SNP and asthma in the present study might be due to insufficient statistical power.

Although the interaction between SNP rs11650680 and the presence of older siblings affecting asthma was not significant, the inverse association between the combination of the CT and TT genotypes and asthma was significant only in women without older siblings. Given that the presence of older siblings is a factor in the hygiene hypothesis, there might be an interaction between this SNP and some types of environmental factors related to the hygiene hypothesis with respect to asthma.

Certain methodological weaknesses of the current study should be borne in mind. In the baseline survey, the participation rate must have been fairly low, and our subjects were probably not representative of Japanese women in the general population. Nevertheless, the distribution of the two SNPs under investigation was consistent with the Hardy–Weinberg equilibrium, and any selection bias based on genotype distribution is expected to be negligible. The outcome in the present study was self-reported, doctor-diagnosed asthma. The possibility of nondifferential outcome misclassification would introduce a bias toward the null.

Conclusion

The current study showed that the CT genotype of TOP2A SNP rs11650680 was significantly inversely associated with asthma in comparison with the CC genotype, while the GSDMB SNP rs7216389 was not related to asthma in young adult Japanese women. There were no significant interactions between these SNPs and the presence of older siblings affecting asthma. We acknowledge that the present results need to be confirmed by both larger case–control studies with smaller likelihoods of selection bias and functional studies.

Footnotes

Acknowledgments

This study was supported by the KAKENHI Grants (19590606, 20791654, 21590673, 22592355, 24390158, 25463275, and 25670305); by the Health and Labour Sciences Research Grants for Research on Allergic Disease and Immunology and Health Research on Children, Youth and Families from the Ministry of Health, Labour and Welfare, Japan; by the Central Research Institute of Fukuoka University, and by the Takeda Science Foundation. The authors would like to acknowledge the Kyushu Branch of the Japan Allergy Foundation, the Fukuoka Association of Obstetricians & Gynecologists, the Okinawa Association of Obstetricians & Gynecologists, the Miyazaki Association of Obstetricians & Gynecologists, the Oita Association of Obstetricians & Gynecologists, the Kumamoto Association of Obstetricians & Gynecologists, the Nagasaki Association of Obstetricians & Gynecologists, the Kagoshima Association of Obstetricians & Gynecologists, the Saga Association of Obstetricians & Gynecologists, the Fukuoka Society of Obstetrics and Gynecology, the Okinawa Society of Obstetrics and Gynecology, the Fukuoka Dental Hygienists' Association, the Okinawa Dental Hygienists' Association, the Miyazaki Dental Hygienists' Association, the Oita Dental Hygienists' Association, the Kumamoto Dental Hygienists' Association, the Nagasaki Dental Hygienists' Association, the Kagoshima Dental Hygienists' Association, the Saga Dental Hygienists' Association, the Fukuoka City Government, and the Fukuoka City Medical Association for their valuable support, as well as Mrs. Yukari Hayashi for her technical assistance.

Disclosure Statement

No competing financial interests exist.

References

Barrett

J.C.

, Fry

, Maller

, and Daly

M.J.

(2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics, 21, 263–265.

Binia

, Khorasani

, Bhavsar

P.K.

, Adcock

, Brightling

C.E.

, Chung

K.F.

, Cookson

W.O.

, and Moffatt

M.F.

(2011). Chromosome 17q21 SNP and severe asthma. J Hum Genet, 56, 97–98.

Bisgaard

, Bønnelykke

, Sleiman

P.M.

, Brasholt

, Chawes

, Kreiner-Møller

, Stage

, Kim

, Tavendale

, Baty

, Pipper

C.B.

, Palmer

C.N.

, and Hakonarsson

(2009). Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. Am J Respir Crit Care Med, 179, 179–185.

Çalışkan

, Bochkov

Y.A.

, Kreiner-Møller

, Bønnelykke

, Stein

M.M.

, Du

, Bisgaard

, Jackson

D.J.

, Gern

J.E.

, Lemanske

R.F.

Jr. , Nicolae

D.L.

, and Ober

(2013). Rhinovirus wheezing illness and genetic risk of childhood-onset asthma. N Engl J Med, 368, 1398–1407.

Fang

, Zhao

, Wang

, Gong

, and Liu

(2011). Association of genetic variants in chromosome 17q21 and adult-onset asthma in a Chinese Han population. BMC Med Genet, 12, 133.

Galanter

, Choudhry

, Eng

, Nazario

, Rodríguez-Santana

J.R.

, Casal

, Torres-Palacios

, Salas

, Chapela

, Watson

H.G.

, Meade

, LeNoir

, Rodríguez-Cintrón

, Avila

P.C.

, and Burchard

E.G.

(2008). ORMDL3 gene is associated with asthma in three ethnically diverse populations. Am J Respir Crit Care Med, 177, 1194–1200.

Gauderman

W.J.

(2002). Sample size requirements for matched case-control studies of gene-environment interaction. Stat Med, 21, 35–50.

Halapi

, Gudbjartsson

D.F.

, Jonsdottir

G.M.

, Bjornsdottir

U.S.

, Thorleifsson

, Helgadottir

, Williams

, Koppelman

G.H.

, Heinzmann

, Boezen

H.M.

, Jonasdottir

, Blondal

, Gudjonsson

S.A.

, Jonasdottir

, Thorlacius

, Henry

A.P.

, Altmueller

, Krueger

, Shin

H.D.

, Uh

S.T.

, Cheong

H.S.

, Jonsdottir

, Ludviksson

B.R.

, Ludviksdottir

, Gislason

, Park

C.S.

, Deichmann

, Thompson

P.J.

, Wjst

, Hall

I.P.

, Postma

D.S.

, Gislason

, Kong

, Jonsdottir

, Thorsteinsdottir

, and Stefansson

(2010). A sequence variant on 17q21 is associated with age at onset and severity of asthma. Eur J Hum Genet, 18, 902–908.

Hirota

, Harada

, Sakashita

, Doi

, Miyatake

, Fujita

, Enomoto

, Ebisawa

, Yoshihara

, Noguchi

, Saito

, Nakamura

, and Tamari

(2008). Genetic polymorphism regulating ORM1-like 3 (Saccharomyces cerevisiae) expression is associated with childhood atopic asthma in a Japanese population. J Allergy Clin Immunol, 121, 769–770.

10.

Kang

M.J.

, Yu

H.S.

, Seo

J.H.

, Kim

H.Y.

, Jung

Y.H.

, Kim

Y.J.

, Kim

H.J.

, Lee

S.Y.

, and Hong

S.J.

(2012). GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness. Hum Immunol, 73, 954–959.

11.

Leung

T.F.

, Sy

H.Y.

, Ng

M.C.

, Chan

I.H.

, Wong

G.W.

, Tang

N.L.

, Waye

M.M.

, and Lam

C.W.

(2009). Asthma and atopy are associated with chromosome 17q21 markers in Chinese children. Allergy, 64, 621–628.

12.

F.X.

, Tan

J.Y.

, Yang

X.X.

, Wu

Y.S.

, Wu

, and Li

(2012). Genetic variants on 17q21 are associated with asthma in a Han Chinese population. Genet Mol Res, 11, 340–347.

13.

Lluis

, Schedel

, Liu

, Illi

, Depner

, von Mutius

, Kabesch

, and Schaub

(2011). Asthma-associated polymorphisms in 17q21 influence cord blood ORMDL3 and GSDMA gene expression and IL-17 secretion. J Allergy Clin Immunol, 127, 1587–1594.e6.

14.

Marinho

, Custovic

, Marsden

, Smith

J.A.

, and Simpson

(2012). 17q12-21 variants are associated with asthma and interact with active smoking in an adult population from the United Kingdom. Ann Allergy Asthma Immunol, 108, 402–411.e9.

15.

Miyake

, Tanaka

, Okubo

, Sasaki

, and Arakawa

(2013). Fish and fat intake and prevalence of depressive symptoms during pregnancy in Japan: baseline data from the Kyushu Okinawa Maternal and Child Health Study. J Psychiatr Res, 47, 572–578.

16.

Moffatt

M.F.

, Kabesch

, Liang

, Dixon

A.L.

, Strachan

, Heath

, Depner

, von Berg

, Bufe

, Rietschel

, Heinzmann

, Simma

, Frischer

, Willis-Owen

S.A.

, Wong

K.C.

, Illig

, Vogelberg

, Weiland

S.K.

, von Mutius

, Abecasis

G.R.

, Farrall

, Gut

I.G.

, Lathrop

G.M.

, and Cookson

W.O.

(2007). Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature, 448, 470–473.

17.

Sleiman

P.M.

, Annaiah

, Imielinski

, Bradfield

J.P.

, Kim

C.E.

, Frackelton

E.C.

, Glessner

J.T.

, Eckert

A.W.

, Otieno

F.G.

, Santa

, Thomas

, Smith

R.M.

, Glaberson

, Garris

, Gunnlaugsson

, Chiavacci

R.M.

, Allen

, Spergel

, Grundmeier

, Grunstein

M.M.

, Magnusson

, Bisgaard

, Grant

S.F.

, and Hakonarson

(2008). ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry. J Allergy Clin Immunol, 122, 1225–1227.

18.

Smit

L.A.

, Bouzigon

, Pin

, Siroux

, Monier

, Aschard

, Bousquet

, Gormand

, Just

, Le Moual

, Nadif

, Scheinmann

, Vervloet

, Lathrop

, Demenais

, Kauffmann

, and the EGEA Cooperative Group. (2010). 17q21 variants modify the association between early respiratory infections and asthma. Eur Respir J, 36, 57–64.

19.

H.Y.

, Ko

F.W.

, Chu

H.Y.

, Chan

I.H.

, Wong

G.W.

, Hui

D.S.

, and Leung

T.F.

(2012). Asthma and bronchodilator responsiveness are associated with polymorphic markers of ARG1, CRHR2 and chromosome 17q21. Pharmacogenet Genomics, 22, 517–524.

20.

Tavendale

, Macgregor

D.F.

, Mukhopadhyay

, and Palmer

C.N.

(2008). A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications. J Allergy Clin Immunol, 121, 860–863.

21.

Yang

F.F.

, Huang

, Li

Q.B.

, Dai

J.H.

, and Fu

(2012). Single nucleotide polymorphisms in the ORM1-like 3 gene associated with childhood asthma in a Chinese population. Genet Mol Res, 11, 4646–4653.

22.

, Kang

M.J.

, Kim

B.J.

, Kwon

J.W.

, Song

Y.H.

, Choi

W.A.

, Shin

Y.J.

, and Hong

S.J.

(2011). Polymorphisms in GSDMA and GSDMB are associated with asthma susceptibility, atopy and BHR. Pediatr Pulmonol, 46, 701–708.