期刊
GENOME MEDICINE
卷 14, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13073-022-01058-2
关键词
Asthma; HLA; Fine-mapping
资金
- [U19 AI62310]
- [R01 HL085197]
- [R01 HD21244]
- [UG3 OD023282]
- [UM1 AI114271]
- [T32 GM007197]
- [K08 HL153955]
- [TL1 TR002388]
- [T32 HL007605]
This study investigates the association between asthma and variation in the human leukocyte antigen (HLA) complex. The results show shared and distinct causal variation in the HLA class I and class II regions for childhood-onset and adult-onset asthma. Gene expression levels and amino acid variation contribute to asthma risk. The study identifies potential causal variation and genes in the HLA region, with a focus on HLA-DQA2, HLA-DQB2, and HLA-DQA1*03:01 allele in adult-onset asthma.
Background Genome-wide association studies of asthma have revealed robust associations with variation across the human leukocyte antigen (HLA) complex with independent associations in the HLA class I and class II regions for both childhood-onset asthma (COA) and adult-onset asthma (AOA). However, the specific variants and genes contributing to risk are unknown. Methods We used Bayesian approaches to perform genetic fine-mapping for COA and AOA (n=9432 and 21,556, respectively; n=318,167 shared controls) in White British individuals from the UK Biobank and to perform expression quantitative trait locus (eQTL) fine-mapping in immune (lymphoblastoid cell lines, n=398; peripheral blood mononuclear cells, n=132) and airway (nasal epithelial cells, n=188) cells from ethnically diverse individuals. We also examined putatively causal protein coding variation from protein crystal structures and conducted replication studies in independent multi-ethnic cohorts from the UK Biobank (COA n=1686; AOA n=3666; controls n=56,063). Results Genetic fine-mapping revealed both shared and distinct causal variation between COA and AOA in the class I region but only distinct causal variation in the class II region. Both gene expression levels and amino acid variation contributed to risk. Our results from eQTL fine-mapping and amino acid visualization suggested that the HLA-DQA1*03:01 allele and variation associated with expression of the nonclassical HLA-DQA2 and HLA-DQB2 genes accounted entirely for the most significant association with AOA in GWAS. Our studies also suggested a potentially prominent role for HLA-C protein coding variation in the class I region in COA. We replicated putatively causal variant associations in a multi-ethnic cohort. Conclusions We highlight roles for both gene expression and protein coding variation in asthma risk and identified putatively causal variation and genes in the HLA region. A convergence of genomic, transcriptional, and protein coding evidence implicates the HLA-DQA2 and HLA-DQB2 genes and HLA-DQA1*03:01 allele in AOA.
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