Huffaker Michelle F, Kanchan Kanika, Bahnson Henry T, Ruczinski Ingo, Shankar Gautam, Leung Donald Y M, Baloh Carolyn, Du Toit George, Lack Gideon, Nepom Gerald T, Mathias Rasika A
Immune Tolerance Network, San Francisco, Calif.
Division of Allergy and Clinical Immunology, Department of Medicine, School of Medicine, Baltimore, Md.
J Allergy Clin Immunol. 2023 Apr;151(4):1137-1142.e4. doi: 10.1016/j.jaci.2022.11.008. Epub 2022 Nov 17.
Deleterious variation in the epidermal differentiation complex (EDC) on chromosome 1 is a well-known genetic determinant of atopic dermatitis (AD) and has been associated with risk of peanut allergy (PA) in population-based studies.
Our aim was to determine the effect of genetic variation in the EDC on AD trajectory and risk of PA in early life.
Genome sequencing was used to measure genetic variation in the EDC in the Learning Early about Peanut Allergy (LEAP) study participants. Association tests were done to identify gene- and variant-level predicted deleterious variation associated with AD severity by using the Scoring Atopic Dermatitis (SCORAD) tool (n = 559) at baseline and each follow-up visit, as well as PA and food allergy in peanut avoiders (n = 275). Predicted deleterious variants included missense variants that were frameshift insertions, frameshift deletions, stop-gain mutations, or stop-loss mutations. Associations between variant load, SCORAD score, and PA were tested by using linear and generalized linear regression models.
The genes FLG, FLG2, HRNR, and TCHH1 harbored the most predicted deleterious variation (30, 6, 3, and 1 variant, respectively). FLG variants were associated with SCORAD score at all time points; 4 variants (R1798X, R501X, S126X, and S761fs) drove the association with SCORAD score at each time point, and higher variant load was associated with greater AD severity over time. There was an association between these variants and PA, which remained significant independent of baseline AD severity (odds ratio = 2.63 [95% CI = 1.11-6.01] [P = .02]).
Variation in FLG predicted to be deleterious is associated with AD severity at baseline and longitudinally and has an association with PA independent of baseline severity.
1号染色体上表皮分化复合体（EDC）的有害变异是特应性皮炎（AD）的一个众所周知的遗传决定因素，并且在基于人群的研究中已与花生过敏（PA）风险相关。
我们的目的是确定EDC中的遗传变异对AD病程及生命早期PA风险的影响。
在“早期了解花生过敏”（LEAP）研究参与者中，使用基因组测序来测量EDC中的遗传变异。通过使用“特应性皮炎评分”（SCORAD）工具，在基线及每次随访时进行关联测试，以识别与AD严重程度相关的基因和变异水平的预测有害变异（n = 559），以及花生回避者中的PA和食物过敏（n = 275）。预测的有害变异包括移码插入、移码缺失、无义突变或延长突变的错义变异。通过使用线性和广义线性回归模型测试变异负荷、SCORAD评分和PA之间的关联。
FLG、FLG2、HRNR和TCHH1基因具有最多的预测有害变异（分别为30、6、3和1个变异）。FLG变异在所有时间点均与SCORAD评分相关；4个变异（R1798X、R501X、S126X和S761fs）在每个时间点驱动与SCORAD评分的关联，并且随着时间的推移，更高的变异负荷与更严重的AD相关。这些变异与PA之间存在关联，独立于基线AD严重程度时仍具有显著性（比值比 = 2.63 [95% CI = 1.11 - 6.01] [P = 0.02]）。
预测为有害的FLG变异与基线及纵向的AD严重程度相关，并且与PA存在关联，独立于基线严重程度。
