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HLA 等位基因推算程序的比较。

Comparison of HLA allelic imputation programs.

作者信息

Karnes Jason H, Shaffer Christian M, Bastarache Lisa, Gaudieri Silvana, Glazer Andrew M, Steiner Heidi E, Mosley Jonathan D, Mallal Simon, Denny Joshua C, Phillips Elizabeth J, Roden Dan M

机构信息

Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, Arizona, United States of America.

Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

出版信息

PLoS One. 2017 Feb 16;12(2):e0172444. doi: 10.1371/journal.pone.0172444. eCollection 2017.

Abstract

Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLAIMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLAIMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations.

摘要

由于人类白细胞抗原(HLA)等位基因在人类疾病中的重要性、全基因组关联研究(GWAS)数据的广泛可得性以及HLA测序所需的专业知识,从单核苷酸多态性(SNP)水平数据推断HLA等位基因很有吸引力。然而,对HLA推断程序的全面评估有限。我们将HIBAG、SNP2HLA和HLAIMP:02的HLA推断结果与来自BioVU的3265个样本中测序的HLA等位基因进行了比较,BioVU是一个与DNA生物样本库相关联的去识别化电子健康记录数据库。我们使用长读长454 FLX测序对HLA-A、-B、-C、-DRB1、-DPB1和-DQB1进行了四位数字的HLA测序。所有样本均使用Illumina HumanExome BeadChip平台和一个GWAS平台进行基因分型。通过平台、等位基因频率和种族/民族比较了检出率和一致性率。在欧洲裔美国人(EA)中,各程序的总体一致性率相似(0.975 [SNP2HLA];0.939 [HLAIMP:02];0.976 [HIBAG])。SNP2HLA在检出率和推断的等位基因数量方面具有显著优势。非裔美国人(AA)的总体一致性率较低。当比较HLA基因座的准确性时,这些观察结果是一致的。对于低频HLA等位基因,所有推断程序的表现相似。从GWAS平台推断HLA等位基因时观察到的一致性率高于从HumanExome BeadChip推断时,这表明高基因组覆盖率作为HLA等位基因推断的输入更受青睐。这些发现为HLA推断方法提供了最佳使用指南,并阐明了它们的局限性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c05/5312875/52ff6b854f69/pone.0172444.g001.jpg

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