asthma is a chronic lung disease which causes breathing difficulties because of chronic airway inflammation . asthma is a common health problem around the world , and its prevalence also has been increasing in korea . the pathogenesis of asthma is unknown and there are no exact biomarkers to diagnosis asthma . in recent , several candidate genes for susceptibility to asthma were reported using advanced genetic technology and several genetic studies [ 36 ] . however , more candidate genes for asthma will be investigated in the context of personalized medicine . secretoglobin family 3a member 2 ( scgb3a2 ) gene is located on chromosome 5 ( https:/www.ncbi.nlm.nih.gov / gene/117156 ) . previous studies reported that promoter polymorphisms of scgb3a2 gene result in susceptibility to asthma [ 79 ] . scgb3a2 is a small molecular weight secreted protein in airway epithelial cells , which is also referred to as uteroglobin - related protein 1 ( ugrp1 ) . several studies reported that it is involved in lung development   and inflammatory reactions in the respiratory tract [ 8,1416 ] . moreover , scgb3a2 has an anti - inflammatory function , and it is reported to be involved in asthma . development of asthma may involve a series of influences on the individual development [ 1923 ] , and the complex influences may determine scgb3a2 levels . firstly , such effects may result in continued chronic inflammatory cytokine production , and scgb3a2 secretions in airway epithelium may be affected by the cytokines [ 2427 ] . however , scgb3a2 not only act downstream of such inflammation modulators , but also controls the inflammatory pathways [ 2830 ] and other hormones . additionally , polymorphisms in scgb3a2 gene regions have been studied in regard to asthma or allergic diseases by many researchers [ 9,12,3235 ] . 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 . we selected 101 asthma patients ( 34 males , and 67 females ; mean age  standard deviation , years , 47.215.2 ] and 377 control subjects [ 186 males and 191 females ; 49.211.4 ] ) ( table 1 ) . the patients with asthma were recruited from among visitors at the departments of kyung hee university oriental medical center , seoul , korea . patients with asthma were diagnosed according to a clinical history with current clinical symptoms , including episodic wheezing , chest tightness , dyspnea , and 15 or greater reversibility of forced expiratory volume at 1 second ( fev1 ) spontaneously or after treatment with a nebulized beta2-agonist . the exclusion criteria were as follows : ( 1 ) abnormal chest x - ray ; ( 2 ) patients who had tuberculosis ; and ( 3 ) patients who had severe chronic obstructive pulmonary disease ( fev1/fvc < 70% and fev1<50% when using bronchodilator ) . this study was performed in accordance with the guidelines of the helsinki declaration and was approved by the ethics review committee of the medical research institute , kyung hee university medical center ( irb number : 20040915 ) . written informed consent was obtained from each subject . genomic dna samples were extracted using peripheral blood using a commercial dna kit ( roche , indianapolis , in ) . the 3 examined snps were genotyped by direct sequencing after polymerase chain reaction ( pcr ) . pcr was performed with the primers for each snp : rs6882292 in scgb3a2 gene ( forward , 5-aggacttctgctcacaaatgaag-3 ; reverse , 5-cccactcacacatctactatggt-3 ) , rs1368408 ( forward , 5-cttttcaatgttcttccaggag-3 ; reverse , 5-gcaggaagatagttaccagcttc-3 ) , and rs151333009 ( forward , 5-aaagggccagaggtagaagtttt-3 ; reverse , 5-cctgagattccaggatgtgcaa-3 ) ( table 2 ) . final pcr products were sequenced by abi prism 3730xl analyzer ( pe applied biosystems , foster city , ca ) . 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 ) . , chicago , il ) programs were used to analyze genetic data . the linkage disequilibrium ( ld ) block was measured using haploview version 4.2 ( daly lab , cambridge , ma ) . to evaluate relationships , the odds ratio ( or ) , 95% confidence interval ( ci ) , and p value were analyzed using logistic regression method in each model [ dominant ( major homogenotype versus heterogenotype + minor homogenotype ) , recessive ( major homogenotype + heterogenotype versus minor homogenotype ) , and log - additive ( major homogenotype versus heterogenotype versus minor homogenotype ) models ] [ 3739 ] . to perform multiple correction , we selected 101 asthma patients ( 34 males , and 67 females ; mean age  standard deviation , years , 47.215.2 ] and 377 control subjects [ 186 males and 191 females ; 49.211.4 ] ) ( table 1 ) . the patients with asthma were recruited from among visitors at the departments of kyung hee university oriental medical center , seoul , korea . patients with asthma were diagnosed according to a clinical history with current clinical symptoms , including episodic wheezing , chest tightness , dyspnea , and 15 or greater reversibility of forced expiratory volume at 1 second ( fev1 ) spontaneously or after treatment with a nebulized beta2-agonist . the exclusion criteria were as follows : ( 1 ) abnormal chest x - ray ; ( 2 ) patients who had tuberculosis ; and ( 3 ) patients who had severe chronic obstructive pulmonary disease ( fev1/fvc < 70% and fev1<50% when using bronchodilator ) . this study was performed in accordance with the guidelines of the helsinki declaration and was approved by the ethics review committee of the medical research institute , kyung hee university medical center ( irb number : 20040915 ) . written informed consent was obtained from each subject . genomic dna samples were extracted using peripheral blood using a commercial dna kit ( roche , indianapolis , in ) . the 3 examined snps were genotyped by direct sequencing after polymerase chain reaction ( pcr ) . pcr was performed with the primers for each snp : rs6882292 in scgb3a2 gene ( forward , 5-aggacttctgctcacaaatgaag-3 ; reverse , 5-cccactcacacatctactatggt-3 ) , rs1368408 ( forward , 5-cttttcaatgttcttccaggag-3 ; reverse , 5-gcaggaagatagttaccagcttc-3 ) , and rs151333009 ( forward , 5-aaagggccagaggtagaagtttt-3 ; reverse , 5-cctgagattccaggatgtgcaa-3 ) ( table 2 ) . final pcr products were sequenced by abi prism 3730xl analyzer ( pe applied biosystems , foster city , ca ) . 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 ) . , chicago , il ) programs were used to analyze genetic data . the linkage disequilibrium ( ld ) block was measured using haploview version 4.2 ( daly lab , cambridge , ma ) . to evaluate relationships , the odds ratio ( or ) , 95% confidence interval ( ci ) , and p value were analyzed using logistic regression method in each model [ dominant ( major homogenotype versus heterogenotype + minor homogenotype ) , recessive ( major homogenotype + heterogenotype versus minor homogenotype ) , and log - additive ( major homogenotype versus heterogenotype versus minor homogenotype ) models ] [ 3739 ] . to perform multiple correction , 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 ) . the genotype distributions of examined snps in controls were in hwe ( rs6882292 , p=1.00 ; rs1368408 , p=0.061 ; rs151333009 , p=1.00 ) ( data not shown ) . the genotype frequencies ( g / g : g / a : a / a ) of rs6882292 snp of scgb3a2 gene in the control group and in the asthma group were 91.5% : 8.2% : 0.3% and 81.2% : 18.8% : 0.0% . the differences showed significance [ or=2.66 , 95% ci=1.425.01 , p=0.0033 in dominant model ( g / g genotype vs. g / a genotype+a / a genotype ) ; or=2.45 , 95% ci=1.334.54 , p=0.0055 in log - additive model ( g / g vs. g / a vs. a / a ) , respectively ] . the genotype frequencies ( g / g : g / a : a / a ) of rs1368408 snp of scgb3a2 gene in the control group and in the asthma group were 59.1% : the differences also showed significance [ or=1.59 , 95% ci=1.022.49 , p=0.041 in dominant model ( g / g genotype vs. g / a genotype+a / a genotype ) ; or=3.02 , 95% ci=1.157.90 , p=0.03 in recessive model ( g / g genotype+g / a genotype vs. a / a genotype ) ; or=1.63 , 95% ci=1.63 , 95% ci=1.122.37 , p=0.012 in log - additive model ( g / g vs. g / a vs. a / a ) , respectively ] . the minor a allele frequencies rs6882292 and rs1368408 snps of scgb3a2 gene were also associated with asthma ( rs6882292 , p=0.006 , or=2.27 , 95% ci=1.264.08 ; rs1368408 , p=0.021 , or=1.51 , 95% ci=1.072.14 ) . the a allele frequencies rs6882292 and rs1368408 snps of scgb3a2 gene were lower in the control group ( rs6882292 , 4.4% and rs1368408 , 21.9% ) than in the asthma group ( rs6882292 , 9.4% and rs1368408 , 29.7% ) . these results suggest that a allele of rs6882292 and rs1368408 snps of scgb3a2 gene is a risk factor of asthma . previous studies suggested that susceptibility to asthma differs by sex [ 4042 ] . according to sex analysis , there were significant associations between rs6882292 and rs1368408 snps of scgb3a2 gene and male asthma ( table 4 ) . the genotypic frequency of rs6882292 and rs1368408 snps of scgb3a2 gene was associated with male asthma [ rs6882292 , p=0.0011 , or=5.60 , 95% ci=2.0715.15 in dominant model ( g / g genotype vs. g / a genotype ) ; rs1368408 , p=0.026 , or=4.61 , 95% ci=1.2816.57 in a recessive model ( g / g genotype and g / a genotype vs. a / a genotype ) ] . after multiple correction using bonferroni s correction , the significant association remained ( p<0.05 ) . one ld block was made between rs6882292 and rs1368408 in the scgb3a2 gene ( d=1.000 and r=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 ) . scgb3a2 , also referred to as ugrp1 , is one of the susceptibility genes for asthma . in the present study , we evaluated the 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 , 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 . a study of graves disease in the united kingdom also showed that rs1368408 was linked to common disease variation in 5q31 - 33 region . 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 . moreover the rs1368408 snp has been previously studied in regard to asthma in a japanese population . 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 . however , batra et al . found no association in an indian population , and rigoli reported not significant association in sicilian children . among the snps reported that rs7726552 showed significant association with allergic rhinitis ; 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 , resulting in reduced transcriptional activity and ultimately leading to lower expression of scgb3a2 protein . our results suggest that promoter snps ( rs6882292 and rs1368408 ) in scgb3a2 gene may contribute to susceptibility to asthma in a korean population . 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 .
backgroundsecretoglobin family 3a member 2 ( scgb3a2 ) plays an important role in secreting lung surfactant protein , which is a downstream target of thyroid transcription factor.material/methodswe 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.resultsrs151333009 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=1.425.01 , p=0.0033 in dominant model , or=2.45 , 95% ci=1.334.54 , p=0.0055 in log - additive model ; rs1368408 , or=1.59 , 95% ci=1.022.49 , p=0.041 in dominant model , or=3.02 , 95% ci=1.157.90 , p=0.03 in recessive model , or=1.63 , 95% ci=1.63 , 95% ci=1.122.37 , p=0.012 in log - additive model).conclusionsthese results suggest that the promoter snps ( rs6882292 and rs1368408 ) of scgb3a2 gene may contribute to susceptibility to asthma in a korean population .