锌指蛋白33B在儿童哮喘中的与特应性相关标志物的性相互作用
2022/08/19
摘要
背景：与免疫反应相关的性别差异可影响儿童哮喘的特应性表现。虽然全基因组关联研究调查了免疫反应的性别特异性遗传结构，但儿童哮喘中性互作基因特应性相关标志物，包括过敏皮肤试验、免疫球蛋白E和嗜酸性粒细胞，尚未被广泛分析。
方法：本研究基于来自哥斯达黎加哮喘遗传流行病学研究（GACRS）的889个三组和来自儿童哮喘管理计划（CAMP）的284个三组的全基因组测序数据，对特应性相关标记物进行了全基因组的性互作基因分析。我们还对英国Biobank参与者进行了自我报告的儿童哮喘研究。此外，GACRS的下游分析整合了基因表达来解开观察到的关联。
结果：在10q11.21处的SNP rs1255383证明了特应性（阳性皮肤试验）的全基因组显著性基因间相互作用（P相互作用=9.08×10-10），女性和男性之间的作用方向相反。在有儿童哮喘病史的英国Biobank参与者中，高嗜酸性粒细胞计数的性别特异性效应方向一致（P相互作用=0.0058）。位于10q11.21的ZNF33B（锌指蛋白33B）基因表达与女孩的特应性中度相关，但与男孩无关。
结论：我们报告了锌指基因中/附近的SNP作为特应性相关标记的新的性别差异位点，在女性和男性中具有相反的作用方向。ZNF33B作为儿童哮喘特应性反应性别差异特征的重要驱动因素，其潜在作用有待进一步研究。
Zinc finger protein 33B demonstrates sex-interaction with atopy-related markers in childhood asthma
Sanghun Lee, Dmitry Prokopenko, Rachel S Kelly, Sharon Lutz, Jessica Ann Lasky-Su, Michael H Cho, Cecelia Laurie, Juan C Celedón, Christoph Lange, Scott T Weiss, Julian Hecker, Dawn L DeMeo
Abstract
Background: Sex differences related to immune responses can influence atopic manifestations in childhood asthma. While genome-wide association studies have investigated a sex-specific genetic architecture of the immune response, gene-by-sex interactions have not extensively been analyzed for atopy-related markers including allergy skin tests, immunoglobulin E, and eosinophils in child asthmatics.
Methods: We performed a genome-wide gene-by-sex interaction analysis for atopy-related markers using whole genome sequencing data based on 889 trios from the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) and 284 trios from the Childhood Asthma Management Program (CAMP). We also tested the findings in UK Biobank participants with self-reported childhood asthma. Furthermore, downstream analyses in GACRS integrated gene expression to disentangle observed associations.
Results: SNP rs1255383 at 10q11.21 demonstrated a genome-wide significant gene-by-sex interaction (P interaction=9.08×10-10) for atopy (positive skin test) with opposite direction of effects between females and males. In the UK Biobank participants with a history of childhood asthma, the signal was consistently observed with the same sex-specific effect directions for high eosinophil count (P interaction=0.0058). Gene expression of ZNF33B (zinc finger protein 33B), located at 10q11.21, was moderately associated with atopy in girls, but not in boys.
Conclusions: We report SNPs in/near a zinc finger gene as novel sex-differential loci for atopy-related markers with opposite effect directions in females and males. A potential role for ZNF33B should be studied further as an important driver of sex-divergent features of atopy in childhood asthma.
背景：与免疫反应相关的性别差异可影响儿童哮喘的特应性表现。虽然全基因组关联研究调查了免疫反应的性别特异性遗传结构，但儿童哮喘中性互作基因特应性相关标志物，包括过敏皮肤试验、免疫球蛋白E和嗜酸性粒细胞，尚未被广泛分析。
方法：本研究基于来自哥斯达黎加哮喘遗传流行病学研究（GACRS）的889个三组和来自儿童哮喘管理计划（CAMP）的284个三组的全基因组测序数据，对特应性相关标记物进行了全基因组的性互作基因分析。我们还对英国Biobank参与者进行了自我报告的儿童哮喘研究。此外，GACRS的下游分析整合了基因表达来解开观察到的关联。
结果：在10q11.21处的SNP rs1255383证明了特应性（阳性皮肤试验）的全基因组显著性基因间相互作用（P相互作用=9.08×10-10），女性和男性之间的作用方向相反。在有儿童哮喘病史的英国Biobank参与者中，高嗜酸性粒细胞计数的性别特异性效应方向一致（P相互作用=0.0058）。位于10q11.21的ZNF33B（锌指蛋白33B）基因表达与女孩的特应性中度相关，但与男孩无关。
结论：我们报告了锌指基因中/附近的SNP作为特应性相关标记的新的性别差异位点，在女性和男性中具有相反的作用方向。ZNF33B作为儿童哮喘特应性反应性别差异特征的重要驱动因素，其潜在作用有待进一步研究。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Eur Respir J. 2022 Aug 11;2200479. doi: 10.1183/13993003.00479-2022.)
(Eur Respir J. 2022 Aug 11;2200479. doi: 10.1183/13993003.00479-2022.)
Zinc finger protein 33B demonstrates sex-interaction with atopy-related markers in childhood asthma
Sanghun Lee, Dmitry Prokopenko, Rachel S Kelly, Sharon Lutz, Jessica Ann Lasky-Su, Michael H Cho, Cecelia Laurie, Juan C Celedón, Christoph Lange, Scott T Weiss, Julian Hecker, Dawn L DeMeo
Abstract
Background: Sex differences related to immune responses can influence atopic manifestations in childhood asthma. While genome-wide association studies have investigated a sex-specific genetic architecture of the immune response, gene-by-sex interactions have not extensively been analyzed for atopy-related markers including allergy skin tests, immunoglobulin E, and eosinophils in child asthmatics.
Methods: We performed a genome-wide gene-by-sex interaction analysis for atopy-related markers using whole genome sequencing data based on 889 trios from the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) and 284 trios from the Childhood Asthma Management Program (CAMP). We also tested the findings in UK Biobank participants with self-reported childhood asthma. Furthermore, downstream analyses in GACRS integrated gene expression to disentangle observed associations.
Results: SNP rs1255383 at 10q11.21 demonstrated a genome-wide significant gene-by-sex interaction (P interaction=9.08×10-10) for atopy (positive skin test) with opposite direction of effects between females and males. In the UK Biobank participants with a history of childhood asthma, the signal was consistently observed with the same sex-specific effect directions for high eosinophil count (P interaction=0.0058). Gene expression of ZNF33B (zinc finger protein 33B), located at 10q11.21, was moderately associated with atopy in girls, but not in boys.
Conclusions: We report SNPs in/near a zinc finger gene as novel sex-differential loci for atopy-related markers with opposite effect directions in females and males. A potential role for ZNF33B should be studied further as an important driver of sex-divergent features of atopy in childhood asthma.
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