Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
J Allergy Clin Immunol. 2009 Dec;124(6):1204-9.e9. doi: 10.1016/j.jaci.2009.09.013.
Common genetic variations in the IL4 gene have been associated with asthma and atopy in European and Asian populations, but not in African Americans.
Because populations of African descent have increased levels of genetic variation compared with other populations, particularly with respect to low frequency or rare variants, we hypothesized that rare variants in the IL4 gene contribute to the development of asthma in African Americans.
To test this hypothesis, we sequenced the IL4 locus in 72 African Americans with asthma and 70 African American controls without asthma to identify novel and rare polymorphisms in the IL4 gene that may be contributing to asthma susceptibility.
We report an excess of private noncoding single nucleotide polymorphisms (SNPs) in the subjects with asthma compared with control subjects without asthma (P = .031). Tajima's D is significantly more negative in subjects with asthma (-0.375) than controls (-0.073; P = .04), reflecting an excess of rare variants in the subjects with asthma.
Our findings indicate that SNPs at the IL4 locus that are potentially exclusive to African Americans are associated with susceptibility to asthma. Only 3 of the 26 private SNPs (ie, SNPs present only in the subjects with asthma or only in the controls) are tagged by single SNPs on one of the common genotyping platforms used in genome-wide association studies. We also find that most of the private SNPs cannot be reliably imputed, highlighting the importance of sequencing to identify genetic variants contributing to common diseases in African Americans.
白细胞介素 4（IL4）基因中的常见遗传变异与欧洲和亚洲人群的哮喘和过敏有关，但与非裔美国人无关。
由于非洲裔人群的遗传变异水平高于其他人群，特别是低频或罕见变异，我们假设 IL4 基因中的罕见变异导致非裔美国人发生哮喘。
为了验证这一假设，我们对 72 名患有哮喘的非裔美国人和 70 名无哮喘的非裔美国对照进行了 IL4 基因座测序，以确定可能导致哮喘易感性的 IL4 基因中的新的罕见多态性。
与无哮喘的对照相比，哮喘患者的个体存在过多的非编码单核苷酸多态性（SNP）（P =.031）。哮喘患者的 Tajima's D 值明显低于对照组（-0.375 对-0.073；P =.04），表明哮喘患者中存在过多的罕见变异。
我们的研究结果表明，IL4 基因座的 SNP 可能仅存在于非裔美国人中，与哮喘易感性相关。在 26 个个体特异性 SNP 中，只有 3 个（即仅存在于哮喘患者或仅存在于对照中的 SNP）被其中一个常见的全基因组关联研究基因分型平台上的单个 SNP 标记。我们还发现，大多数个体特异性 SNP 无法可靠地推断，这突出了测序在鉴定导致非裔美国人常见疾病的遗传变异方面的重要性。
