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- Materials and methods
Background: The interleukin 17A (IL17A) gene, located on chromosome 6p and linked to asthma phenotype, is a highly potential candidate gene conferring asthma susceptibility. The purpose of this study was to investigate the genetic association between single nucleotide polymorphisms (SNPs) of IL17A and asthma in Taiwanese children.
Methods: We selected and performed genotyping on nine SNPs that encompass the genomic region of IL17A in Taiwanese children with or without asthma. A total of 1939 subjects containing 1027 subjects in testing group and 931 subjects in validation group were recruited in this study.
Results: After Bonferroni correction, SNP rs8193036 was found to have a weak association (P = 0.0074 × 9 = 0.066) in genotype frequency test. This association was confirmed by validation group. Logistic regression adjusted allergy comorbidity and gender showed a slightly weaker association.
Conclusions: The results indicated an independent role of IL17A promoter polymorphism rs8193036 in the association with pediatric asthma in Taiwanese population.
Chronic asthma is a complex disease affecting nearly 300 million individuals worldwide (1). The rising incidence of asthma and atopic disorders over the past decades attests to the importance of environmental and lifestyle factors in disease risk assessment (2–4). Strong genetic components associated with asthma were supported by family and twin studies (5, 6), and many genes have been identified or suspected to be involved in the pathogenesis of asthma (7). In Taiwan, there are slight differences in the reported symptoms of allergic diseases; nevertheless, the prevalence of allergic diseases is rising (8–10).
Interleukin 17A (IL17A or known as IL-17), the key cytokine of TH17 cells, is known to induce pro-inflammatory cytokines, the hallmarks of acute inflammatory processes (11). Experimental models suggested that TH17 cells may be important for neutrophilic inflammation in acute airway inflammation (12–14). In obstructive airway diseases, such as bronchial asthma and chronic obstructive pulmonary disease, accumulation of neutrophils in the airways has been a major characteristic (15, 16). Elevation plasma IL17A level associated with asthma severity (17) suggests the potential role in airway remodeling. The accumulated evidence suggests that IL17A may play an important pathologic role in the development of allergies and asthma (18). However, there are no reports on the association of IL17A gene polymorphisms with asthma.
Chromosome 6p of which the genomic region has been reported to be linked to asthma and asthma-related phenotypes in multiple genome scans (19–21). IL17A is located on 6p12.1 the genomic region of which was reported to be associated with different types of asthma (21) but not on 6p21–23 region revealed by linkage studies on asthma (19, 20). Previously, researchers reported that IL17A is a good candidate gene for studying genetic susceptibility of asthma. In our study, we investigated the association between selected single nucleotide polymorphisms (SNPs) of IL17A and asthma and validated the results in another independent subject group. The results strongly indicate that polymorphism in IL17A promoter region is associated with pediatric bronchial asthma in Taiwanese population.
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- Materials and methods
In the current study, we investigated the association between IL17A polymorphisms and pediatric asthma. We found that association between asthma phenotype and IL17A polymorphism rs8193036 was significant before Bonferroni correction in group 1 subjects. After Bonferroni correction, it revealed that rs8193036 is marginally significantly associated with asthma. The association between asthma phenotype and rs8193036 was further validated using group 2 subjects and still showed a significant association. The results of this study indicated a possibility that the polymorphisms of IL17A gene may confer risk for pediatric asthma in Taiwanese population.
The SNP rs8193036 is located at position −692 from the starting site of mRNA and −737 from the start codon of IL17A. Another IL17A promoter SNP rs2275913 is located at position of −197 from the start codon and associated with ulcerative colitis (24). The SNP 3804513, in IL17A intron 2, has been reported to be associated with radiographic progression in Japanese patients with early rheumatoid arthritis (25). No nonsynonymous SNP of IL17A was reported in NCBI SNP database suggesting that regulatory polymorphism(s) of IL17A may play a role in pathophysiological processes of related diseases.
IL17A is significantly expressed in sputum samples from patients with asthma compared with control subjects (17, 26–28) and its level in sputum of patients with asthma correlated negatively with the provocative concentration of methacholine causing a 20% fall in FEV1 (27). IL17A is able to induce the expression of two mucin genes in bronchial epithelial cells (29), and an increased expression of IL17A is associated with enhanced mucin gene expression in vivo (30). The above observations suggest that IL17A expression level and the factors that influence IL17A expression are strong candidates for asthma susceptibility factors.
In group 1, the SNP rs8193036 only showed a marginally significant association with asthma (P = 0.067) after Bonferroni correction. The power to detect significant association was calculated by Power for Association With Errors (PAWE; http://linkage.rockefeller.edu/pawe/) (31, 32). For example, rs8193036 in group 1, given 472 cases and 536 controls, adjust P-value = 0.066 and data without error, the power for genotypic test was 0.65. Under the same condition of ratio and allele frequencies in case and control, 726 case subjects and 820 controls are necessary to detect P = 0.05 and power = 0.8. The SNP rs8193036 in group 2, given 729 cases and 202 controls, P = 0.0253, and data without error, the power for genotypic test was 0.59. The calculation data suggested that our sample size in group 1 and group 2 may not be large enough to detect an association for IL17A effect on asthma. In total subjects including 1201 cases and 738 controls, P < 0.0001, the power for genotypic test was 0.96. The sample size pooling two study groups should be large enough to detect the association for rs8193036 and asthma.
From the results in this study, it may be suggested that IL17A is a candidate gene that confers the genetic susceptibility for pediatric asthma in Taiwanese population. Furthermore, the results provided a genetic basis indicating that the expression regulation was involved in asthma pathological mechanism. To understand further the functions and mechanisms of the associated SNPs in regulating IL17A expression demands further investigations.