A Genome-Wide Association Study of Basal Transepidermal Water Loss Finds that Variants at 9q34.3 Are Associated with Skin Barrier Function
A Genome-Wide Association Study of Basal Transepidermal Water Loss Finds that Variants at 9q34.3 Are Associated with Skin Barrier Function
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基础经表皮失水的全基因组关联研究发现 9q34.3 的变异与皮肤屏障功能相关
DOI：
10.1016/j.jid.2016.11.030
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发表时间：
2017
影响因子：
6.5
通讯作者：
Wang Sijia
中科院分区：
文献类型：
--
作者：
Zhang Manfei;Li Bingjie;Wu Sijie;Tan Jingze;Yang Yajun;Marini Aless;ra;Vierkotter Andrea;Zhang Juan;Li Hui;Schikowski Tamara;Jin Li;Krutmann Jean;Wang Sijia
表皮动态平衡和屏障通透性是人类皮肤非常重要的特性。透皮失水(TEWL)是指水分从真皮和表皮的水层向水分含量较低的层被动扩散(Nilsson，1977)，已被广泛用于确定表皮的通透性屏障状态(Fluhr et al.，2006)。例如，TEWL测量有助于确定皮肤屏障功能在特应性皮炎(AD)等皮肤病中受到损害(Elias，2008)。同样，它已被成功地用于监测不同治疗方法对皮肤屏障功能恢复的影响(Sextius等人，2010年)。尽管有报道称TEWL受到环境因素的影响，如温度、季节变化、阳光照射和吸烟(Li等人，2014，Liu等人，2010，Xin等人，2016)，但角质层通透性的显著种族差异表明，遗传也在表皮屏障功能中发挥作用(Kompaore和Tsuruta，1993)。然而，据我们所知，还没有基因组研究来探索健康人体皮肤屏障功能的遗传学。为了解决这一问题，我们进行了一项基础TEWL的全基因组关联研究，作为皮肤屏障功能的衡量标准，目的是检测与这一重要皮肤旅行相关的潜在遗传变异。我们从江苏泰州的健康汉人那里收集了611个样本，年龄在31岁到87岁之间。这项研究得到了上海复旦大学伦理委员会中国的正式批准。所有参与者都提供了书面知情同意。TEWL测量是在右脸颊上使用DermaMeter Professional 100(VASEMA GmbH，维也纳，奥地利)进行的(详细信息请参见在线补充材料和补充表S1)。因为获得的TEWL值不服从正态分布(Shapiro-Wilk检验，P<；2.2×10-16)，所以进行了对数变换(参见在线补充图S1)。主成分分析在我们的样本中没有发现显著的人口分层(见在线补充图S2)。与以前的报道基本一致，我们发现长寿与温度(r=0.284，P=9.5 4×10-13)、性别(双尾t检验，P=6.0 6×10-3)和护肤习惯(P=4.74×10-3)显著相关。与环境湿度(P=0.967)、阳光暴露量(P=0.247)和吸烟(P=0.089)无关(见补充资料)。然后我们进行了GWA，根据年龄、性别、体温和护肤习惯进行了调整。在加利福尼亚州圣地亚哥的Illumina人类Omni中华8V1上对个体进行了基因分型。1个芯片，并使用1000基因组计划数据(阶段3)(1000基因组计划联盟等人，2012，Pickrell等人，2009，Kent等人，2002)进行推算。经过质量控制筛选后，对795,279个基因型单核苷酸多态(SNPs)和7,203,134个SNPs(详见补充资料)进行了GWAS分析。我们在染色体带9q34上发现了一个变异。3与TEWL显著相关(rs10858314，β=-0.211±0.038，P=3.11×10-8；见网上补充图S3)。为了验证我们的发现，我们使用相同的表型方法对来自江苏泰兴的366名健康汉族人样本进行了第二次基因分型。在第二次GWA中没有全基因组显著信号，但SNP(Rs10858314)被复制，具有名义意义(β=-0.167±0.065，P=9.96×10-3；见在线补充表S2)。
Epidermal homeostasis and barrier permeability are very important properties of human skin. Transepidermal water loss (TEWL), the passive diffusion of water from the hydrated layers of the dermis and epidermis toward those layers with a lower water content (Nilsson, 1977), has been widely used to determine epidermal permeability barrier status (Fluhr et al., 2006). For example, TEWL measurement helped to establish that skin barrier function is compromised in skin diseases such as atopic dermatitis (AD)(Elias, 2008). Likewise, it has successfully been used to monitor the effects of different treatments on skin barrier function recovery (Sextius et al., 2010). Although TEWL has been reported to be affected by environmental factors such as temperature, seasonal variation, sun exposure, and smoking (Li et al., 2014, Liu et al., 2010, Xin et al., 2016), the presence of significant ethnic differences in stratum corneum permeability suggests that genetics also plays a role in epidermal barrier function (Kompaore and Tsuruta, 1993). However, to our knowledge, no genomic study has been conducted to explore the genetics of barrier function of healthy human skin. To address this, we performed a genome-wide association study (GWAS) of basal TEWL as a measure of the skin barrier function, with the aim of detecting the potential genetic variants associated with this important skin trait.We collected 611 samples from healthy Han Chinese in Taizhou, Jiangsu Province, aged between 31 and 87 years. This research was conducted with official approval from the ethics committee of Fudan University, Shanghai, China. All participants provided written informed consent. TEWL measurement was carried out with a DermaMeter Professional 100 (VASEMA GmbH, Vienna, Austria) on the right cheek (see Supplementary Materials and Supplementary Table S1 online for details). Because the obtained TEWL values did not follow the normal distribution (Shapiro-Wilk test, P< 2.2× 10–16), a logarithmic transformation was performed (see Supplementary Figure S1 online). Principal component analysis found no significant population stratification in our sample (see Supplementary Figure S2 online). Mostly consistent with previous reports, we found TEWL to be significantly correlated with temperature (r= 0.284, P= 9.54× 10–13), sex (two-tailed Student t test, P= 6.06× 10–3), and skincare habits (P= 4.74× 10–3). It was not correlated with humidity of the environment (P= 0.967), sun exposure (P= 0.247), and smoking (P= 0.089)(see Supplementary Materials). We then performed a GWAS, adjusting for age, sex, temperature, and skincare habits. Individuals were genotyped on an Illumina (San Diego, CA) Human Omni Zhonghua 8V1. 1 chip, and imputation was performed using 1000 Genomes Project data (phase 3)(1000 Genomes Project Consortium et al., 2012, Pickrell et al., 2009, Kent et al., 2002). After quality-control filters, the GWAS was carried out on 795,279 genotyped single-nucleotide polymorphisms (SNPs) and 7,203,134 imputed SNPs (see Supplementary Materials for the details). We found a variant on chromosome band 9q34. 3 to be significantly associated with TEWL (rs10858314, β=–0.211±0.038, P= 3.11× 10–8; see Supplementary Figure S3 online). To validate our finding, we performed a second GWAS using the same phenotyping protocol on a replication set including 366 healthy Han Chinese samples from Taixing, Jiangsu Province. There was no genome-wide significant signals in this second GWAS, but the SNP (rs10858314) was replicated with nominal significance (β=–0.167±0.065, P= 9.96× 10–3; see Supplementary Table S2 online).