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Association Between Secretoglobin Family 3A Member 2 (SCGB3A2) Gene Polymorphisms and Asthma in a Korean Population

Background Secretoglobin family 3A member 2 (SCGB3A2) plays an important role in secreting lung surfactant protein, which is a downstream target of thyroid transcription factor. Material/Methods We investigated whether single-nucleotide polymorphisms (SNPs) of SCGB3A2 gene contribute to susceptibility to asthma. To explore this possible association, 2 promoter SNPs (rs6882292, 659 G/A and rs1368408, −112 G/A) and missense SNP (rs151333009, stop codon) were tested in SCGB3A2 gene in 101 asthma patients and 377 healthy control subjects. SNPStats was used to obtain odds ratio (OR), 95% confidence intervals (CI), and P value adjusted for age and sex as covariables. Logistic regression method in each model (dominant, recessive, and log-additive) was applied to analyze genetic data. Results rs151333009 SNP showed a monomorphic genotype. Two promoter SNPs (rs6882292, −659 G/A and rs1368408, −112 G/A) showed significant association with asthma (rs6882292, OR=2.66, 95% CI=1.42–5.01, p=0.0033 in dominant model, OR=2.45, 95% CI=1.33–4.54, p=0.0055 in log-additive model; rs1368408, OR=1.59, 95% CI=1.02–2.49, p=0.041 in dominant model, OR=3.02, 95% CI=1.15–7.90, p=0.03 in recessive model, OR=1.63, 95% CI=1.63, 95% CI=1.12–2.37, p=0.012 in log-additive model). Conclusions These results suggest that the promoter SNPs (rs6882292 and rs1368408) of SCGB3A2 gene may contribute to susceptibility to asthma in a Korean population.


Background
Asthma is a chronic lung disease which causes breathing difficulties because of chronic airway inflammation. It results in wheezing, shortness of breath, chest tightness, and cough. Asthma is a common health problem around the world, and its prevalence also has been increasing in Korea [1]. The pathogenesis of asthma is unknown and there are no exact biomarkers to diagnosis asthma [2]. In recent, several candidate genes for susceptibility to asthma were reported using advanced genetic technology and several genetic studies [3][4][5][6]. However, more candidate genes for asthma will be investigated in the context of personalized medicine.
On the basis of this background, the present study was conducted to investigate whether single-nucleotide polymorphisms (SNPs) in SCGB3A2 gene are associated with asthma in a Korean population by case-control comparison of genomic DNA.

Subjects
We selected 101 asthma patients (

Statistics
To determine whether individual SNP was in equilibrium at each locus in the population, we evaluated the Hardy-Weinberg equilibrium (HWE) using SNPStats (http://bioinfo.iconcologia. net/index.php). SNPStats and SPSS 23.0 (SPSS Inc., Chicago, IL) programs were used to analyze genetic data. The linkage disequilibrium (LD) block was measured using Haploview

Results
The genotype and allele frequencies of 2 promoter SNPs (rs6882292, 659 G/A and rs1368408, -112 G/A) and missense SNP (rs151333009, stop codon) were selected in SCGB3A2 in asthma patients and controls (   Table 3. Frequency of the genotype and alleles of tested single nucleotide polymorphisms (SNPs) of secretoglobin family 3A member 2 (SCGB3A2) gene in the control group and the asthma group.
SNP -singe nucleotide polymorphism; OR -odds ratio; CI -confidence interval; n, number of subjects. The P values were calculated using logistic regression analyses, adjusting for the sex and age. Numbers in bold font indicate significant associations.
There were differences between males and females, such as biochemical factors and hormones. Previous studies suggested that susceptibility to asthma differs by sex [40][41][42].
According to sex analysis, there were significant associations between rs6882292 and rs1368408 SNPs of SCGB3A2 gene and male asthma ( LD was evaluated using Haploview version 4.2 (Daly Lab Inc., Cambridge, MA). One LD block was made between rs6882292 and rs1368408 in the SCGB3A2 gene (D'=1.000 and r 2 =0.218) (data not shown). There were 3 haplotypes in the LD block (GG haplotype frequency=0.765, GA haplotype frequency=0.181, and AA haplotype frequency=0.054). We observed differences between the control group and the asthma group in the haplotype analysis (GG haplotype, p=0.02 and AA haplotype, p=0.0051) ( Table 5).

Discussion
SCGB3A2, also referred to as UGRP1, is one of the susceptibility genes for asthma. In the present study, we evaluated the  Table 4. Frequency of the genotype and alleles of tested single nucleotide polymorphisms (SNPs) of secretoglobin family 3A member 2 (SCGB3A2) gene in the control group and the asthma group according to gender.
SNP -singe nucleotide polymorphism; OR -odds ratio; CI -confidence interval; n, number of subjects. The P values were calculated using logistic regression analyses, adjusting for the sex and age. Numbers in bold font indicate significant associations.
relationship between SNPs of SCGB3A2 gene and susceptibility to asthma in a Korean population. Two promoter SNPs (rs6882292, 659 G/A and rs1368408, -112 G/A) showed associations with asthma in allele, genotypic models, and haplotype. The minor allele distributions of rs6882292 and rs1368408 SNPs in the asthma group were higher compared to those of the control group, indicating the minor alleles are risk factor for asthma in a Korean population. In analysis by sex, the association with asthma only showed in the male group, not in the female group.
SCGB3A2 gene was found to be related to thyroid and lung cancer. In a previous study conducted in a Chinese Han population [43], the rs6882292 SNP haplotype was composed of rs1368408 and rs6882292 SNPs, which were reported to be correlated with Graves' disease. The rs1368408 SNP (also known as SCGB3A2, -112G>A promoter polymorphism) showed the strongest association with Graves' disease among chromosome 5q31-33 in a Chinese Han population [43]. A study of Graves' disease in the United Kingdom also showed that rs1368408 was linked to common disease variation in 5q31-33 region [44]. It is downstream-regulated by thyroid transcription factor 1 [TTF-1, also known as NK2 homeobox 1 (NKX2-1)], which also regulates the expression of other thyroid genes and lung surfactant genes [43]. Moreover, TTF-1 may be an immunohistochemical marker of primary lung cancer cells [45]. Higher immunoglobulin E levels of Graves' disease patients were associated with rs1368408 [33].
The rs1368408 SNP has been previously studied in regard to asthma in a Japanese population. Niimi et al. found that the minor A allele of rs1368408 SNP significantly affects asthma development [8]. Individuals with A allele of rs1368408 were about more 4.1 times more likely to have asthma compared to individuals with G/G genotype. Inoue et al. showed that plasma SCGB3A2 levels were associated with the G-112A SCGB3A2 gene promoter polymorphism and the severity of asthma [12]. However, Batra et al. found no association in an Indian population [7], and Rigoli reported not significant association in Sicilian children [34]. Among the SNPs not considered in the present study, Andiappan et al. reported that rs7726552 showed significant association with allergic rhinitis [32]; however, no association was observed between asthma in their study. Regarding the function between the promoter polymorphisms and asthma, A allele of rs1368408 in SCGB3A2 gene promoter decreases the affinity of a particular nuclear protein to the binding site around −112 bp [8], resulting in reduced transcriptional activity and ultimately leading to lower expression of SCGB3A2 protein [8].

Conclusions
Our results suggest that promoter SNPs (rs6882292 and rs1368408) in SCGB3A2 gene may contribute to susceptibility to asthma in a Korean population. Specially, 2 SNPs may be a risk factor for Korean male asthma. However, the present study has some limitations, including sample size and function with asthma. Our results showing an association between the promoter polymorphisms of SCGB3A2 gene and asthma need to be confirmed in studies with larger sample sizes or in other population, and functional studies are also needed.

Conflict of interest
The authors declare no conflict of interest.  Table 5. Frequencies of haplotypes in the control group and asthma.
Haplotypes of the rs6882292 and rs1368408. Numbers in bold font indicate significant correlations.