探討STAT6基因變異點與異位性皮膚炎的易感性

Abstract

背景: 異位性皮膚炎是在孩童及嬰兒間相當常見的慢性、過敏性疾病，而訊息傳遞及轉錄因子6 (STAT6) 蛋白在致敏的機制中扮演重要腳色，其基因多型性會影響其蛋白的功能，可能進而影響疾病，不過STAT6 基因多型性和異位性皮膚炎的關係還是需要進一步進行確認。 方法: 研究對象取自台灣14個鄉鎮的國中小，共收了5,915位學孩童。STAT6基因單一核苷酸多型性(SNP)資料是取自International HapMap Project，以北京漢人及日本人做為分析對象，利用Haploview及連鎖不平衡選取四個tag SNPs，分別是rs703817、 rs324015、rs3024974及SNP rs324011，來探討STAT6基因多型性對孩童異位性皮膚炎的影響。 針對前面流行病學研究中有意義的位點，我們對其前後做細部定序，並對細部定序後所發現的新位點進行第二次相關性研究及in vitro functional assays。 結果: 在分析的四個位點中，rs324011和孩童異位性皮膚炎有顯著相關 (Recessive model: OR=1.6, FDR=0.02; Additive model: OR=1.2, FDR=0.06)。之後，針對 rs324011前後進行細部定序發現五個SNP，分析後發現rs167769 達到邊緣顯著，帶有T對偶基因的孩童有較高的危險，Odds ratio為1.2 (95%信賴區間為1.0-1.5，p值是0.06)，另外在in vitro functional assays中我們也發現，T對偶基因會提高STAT6 基因啟動子的活性。 結論: STAT6 基因上的 rs324011及rs167769 和孩童異位性皮膚炎的易感受有關，帶有T對偶基因的孩童有較高的危險，此外，T對偶基因會提高STAT6 基因啟動子的活性。

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease mainly affecting children and infants. The Signal Transducer and Activator of Transcription 6 (STAT6) genetic variants regulate STAT6 protein which takes roles in allergic pathway. The relationship between STAT6 gene and AD needs further investigation. Methods: This study recruited 5,915 children from public schools in 14 Taiwanese communities. We used Hapmap dataset of Han Chinese to choose four tag SNPs (rs703817, rs324015, rs3024974 and rs324011) by Haploview and investigated the relationship between STAT6 gene and AD. We performed deep sequencing around the variant highly associated with AD and then conducted a second association study in our population. Furthermore, in vitro functional assays were used to verify the significant findings. Results: In our children’s cohort, the variant rs324011 revealed a positive effect on the occurrence of AD (Recessive model: OR=1.6, FDR=0.02; Additive model: OR=1.2, FDR=0.06). After deep sequencing, we identified five new targeted variants around rs324011 (rs167769, rs324012, rs3024948, rs117195019, and rs118014438). Among these variants, rs167769 showed a borderline statistical significance (unadjusted OR=1.21, p=0.07; adjusted OR=1.22, p=0.06). Children with variant rs167769 T allele had a higher risk to suffer from AD. Using in vitro luciferase assay, we also found the polymorphic T allele at rs167769 was associated with higher promoter activity of STAT6 gene. Conclusions: The STAT6 variants rs324011 and rs167769 are associated with AD susceptibility, and the polymorphic T allele at rs167769 would increase promoter activity in vitro.