Genome-wide Study Identifies Association between HLA-B∗55:01 and Self-Reported Penicillin Allergy.,American Journal of Human Genetics

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Genome-wide Study Identifies Association between HLA-B∗55:01 and Self-Reported Penicillin Allergy.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2020-09-03 , DOI: 10.1016/j.ajhg.2020.08.008
Kristi Krebs ₁ , Jonas Bovijn ₂ , Neil Zheng ₃ , Maarja Lepamets ₁ , Jenny C Censin ₂ , Tuuli Jürgenson ₄ , Dage Särg ₅ , Erik Abner ₄ , Triin Laisk ₄ , Yang Luo ₆ , Line Skotte ₇ , Frank Geller ₇ , Bjarke Feenstra ₇ , Wei Wang ₈ , Adam Auton ₈ , ₈ , Soumya Raychaudhuri ₉ , Tõnu Esko ₄ , Andres Metspalu ₄ , Sven Laur ₁₀ , Dan M Roden ₁₁ , Wei-Qi Wei ₃ , Michael V Holmes ₁₂ , Cecilia M Lindgren ₁₃ , Elizabeth J Phillips ₁₄ , Reedik Mägi ₄ , Lili Milani ₄ , João Fadista ₁₅

Affiliation

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK.
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia.
Institute of Computer Science, University of Tartu, Tartu 51009, Estonia.
Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, Denmark.
23andMe, Inc., Sunnyvale, CA 94086, USA.
Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Centre for Genetics and Genomics Versus Arthritis, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK.
Institute of Computer Science, University of Tartu, Tartu 51009, Estonia; STACC, Tartu 51009, Estonia.
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, TN 37232, USA.
Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 7LE, UK; Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK; Medical Research Council Population Health Research Unit (MRC PHRU), Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 7LE, UK; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, TN 37232, USA; Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch, WA 6150, Australia.
Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, Denmark; Department of Clinical Sciences, Lund University Diabetes Centre, 214 28 Malmö, Sweden; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.

Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center’s BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe’s research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B^∗55:01 allele (OR 1.41 95% CI 1.33–1.49, p value 2.04 × 10⁻³¹) and confirmed by independent replication in 23andMe’s research cohort (OR 1.30 95% CI 1.25–1.34, p value 1.00 × 10⁻⁴⁷). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B^∗55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.

中文翻译：

全基因组研究确定了 HLA-B*55:01 与自我报告的青霉素过敏之间的关联。

对药物的过敏反应通常是不可预测的，并且可能危及生命，这凸显了了解其潜在机制和风险因素的必要性。种系遗传变异对常见药物过敏（例如青霉素过敏）风险的影响程度仍然很大程度上未知。我们从来自英国、爱沙尼亚和范德比尔特大学医学中心 BioVU 生物库的 600,000 多名参与者的电子健康记录中提取数据，以研究遗传变异在自我报告的青霉素过敏反应发生中的作用。我们使用来自这些队列的 HLA 分型数据的 SNP 估算值来进一步精细绘制人类白细胞抗原 (HLA) 关联图，并在 23andMe 涉及总共 112 万人的研究队列中复制我们的结果。青霉素过敏的全基因组荟萃分析揭示了两个基因座，其中一个位于 6 号染色体上的 HLA 区域。该信号进一步精细映射到 HLA-B ^* 55:01 等位基因（OR 1.41 95% CI 1.33–1.49），p 值 2.04 × 10 ^-31 ），并通过 23andMe 研究队列的独立复制得到证实（OR 1.30 95% CI 1.25–1.34，p 值 1.00 × 10 ^-47 ）。主要 SNP 还与较低的淋巴细胞计数相关，计算机随访表明对 HLA-B ^* 55:01 的 T 淋巴细胞有潜在影响。我们还观察到PTPN22显着下降，并且 GWAS 结果与类风湿性关节炎和牛皮癣的遗传学相关。我们提供了强有力的证据来证明主要组织相容性复合体 (MHC) I 基因HLA-B的等位基因在青霉素过敏发生中的作用。

更新日期：2020-10-02

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