儿童期和成人期哮喘的遗传结构区别
2019/08/27
摘要
儿童期发病（COA）和成人发病（AOA）哮喘之间共享遗传风险因素的程度目前尚未得到评估。根据英国生物库研究的数据（n = 447,628），我们发现疾病倾向差异COA（发病年龄在0到19岁之间; h2g=25.6％）高于AOA （发病年龄在20至60岁之间; h2g=10.6％）。COA和AOA之间的遗传相关性（rg）为0.67。COA个体的发病年龄变化遗传倾向低（h2g= 5％），我们在独立研究以及在AOA个体中证实了这一点。为了确定亚型特异性遗传关联，我们在英国生物库的COA（3,962人）和AOA（26,582人）中分别进行了全基因组关联研究（GWAS），两项研究使用了共同的对照组（300,671人）。我们确定了123个独立的COA关联和56个AOA关联（37个重叠）；其中，分别有98个和34个在独立研究（n = 262,767）中得到验证。有28个关联之前并没有报告过。对于96个COA相关变异型（包括代表COA特异性风险因子的5个变体），风险等位基因在COA中比在AOA个体中更为常见。相反地，我们确定了三种变异型，这些变异是AOA更强的风险因素。肥胖和吸烟相关的变异型对AOA的风险要强于COA。最后，我们鉴定了109个可能的相关变异靶基因，主要基于特征基因座相关表达数量（n = 31,684）。根据发病年龄得出的GWAS可以识别亚型特异性风险变异，这可以帮助我们理解COA和AOA之间病理生理学的差异，因此可以为药物开发提供信息。
Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.
Ferreira MAR, Mathur R, Vonk JM, Szwajda A, Brumpton B, Granell R, Brew BK, Ullemar V, Lu Y,Jiang Y; 23andMe Research Team; eQTLGen Consortium; BIOS Consortium, Magnusson PKE, Karlsson R,Hinds DA, Paternoster L, Koppelman GH, Almqvist C.
Abstract
The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h2g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h2g = 10.6%). The genetic correlation (rg) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h2g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.
儿童期发病（COA）和成人发病（AOA）哮喘之间共享遗传风险因素的程度目前尚未得到评估。根据英国生物库研究的数据（n = 447,628），我们发现疾病倾向差异COA（发病年龄在0到19岁之间; h2g=25.6％）高于AOA （发病年龄在20至60岁之间; h2g=10.6％）。COA和AOA之间的遗传相关性（rg）为0.67。COA个体的发病年龄变化遗传倾向低（h2g= 5％），我们在独立研究以及在AOA个体中证实了这一点。为了确定亚型特异性遗传关联，我们在英国生物库的COA（3,962人）和AOA（26,582人）中分别进行了全基因组关联研究（GWAS），两项研究使用了共同的对照组（300,671人）。我们确定了123个独立的COA关联和56个AOA关联（37个重叠）；其中，分别有98个和34个在独立研究（n = 262,767）中得到验证。有28个关联之前并没有报告过。对于96个COA相关变异型（包括代表COA特异性风险因子的5个变体），风险等位基因在COA中比在AOA个体中更为常见。相反地，我们确定了三种变异型，这些变异是AOA更强的风险因素。肥胖和吸烟相关的变异型对AOA的风险要强于COA。最后，我们鉴定了109个可能的相关变异靶基因，主要基于特征基因座相关表达数量（n = 31,684）。根据发病年龄得出的GWAS可以识别亚型特异性风险变异，这可以帮助我们理解COA和AOA之间病理生理学的差异，因此可以为药物开发提供信息。
(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)
(Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022.)
(Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022.)
Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.
Ferreira MAR, Mathur R, Vonk JM, Szwajda A, Brumpton B, Granell R, Brew BK, Ullemar V, Lu Y,Jiang Y; 23andMe Research Team; eQTLGen Consortium; BIOS Consortium, Magnusson PKE, Karlsson R,Hinds DA, Paternoster L, Koppelman GH, Almqvist C.
Abstract
The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h2g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h2g = 10.6%). The genetic correlation (rg) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h2g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.
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哮喘患者IgE结合后嗜碱性粒细胞脱颗粒反应由独特的昼夜节律钟所控制
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确诊为中度及重度哮喘前血清中IL-5，IL-6，IL-8，IL-13和IL-17A水平的变化
