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Polygenic Risk Scores have high diagnostic capacity in ankylosing spondylitis
  1. Zhixiu Li1,
  2. Xin Wu2,
  3. Paul J Leo1,
  4. Erika De Guzman3,
  5. Nurullah Akkoc4,
  6. Maxime Breban5,6,7,
  7. Gary J Macfarlane8,9,
  8. Mahdi Mahmoudi10,
  9. Helena Marzo-Ortega11,12,
  10. Lisa K Anderson3,
  11. Lawrie Wheeler3,
  12. Chung-Tei Chou13,14,
  13. Andrew A Harrison15,
  14. Simon Stebbings16,
  15. Gareth T Jones8,9,
  16. So-Young Bang17,
  17. Geng Wang18,
  18. Ahmadreza Jamshidi10,
  19. Elham Farhadi10,
  20. Jing Song2,
  21. Li Lin2,
  22. Mengmeng Li2,
  23. James Cheng-Chung Wei19,20,21,
  24. Nicholas G Martin22,
  25. Margaret J Wright23,
  26. MinJae Lee24,
  27. Yuqin Wang25,
  28. Jian Zhan26,
  29. Jin-San Zhang27,28,
  30. Xiaobing Wang29,
  31. Zi-Bing Jin30,
  32. Michael H Weisman31,
  33. Lianne S Gensler32,
  34. Michael M Ward33,
  35. Mohammad Hossein Rahbar34,
  36. Laura Diekman35,
  37. Tae-Hwan Kim17,
  38. John D Reveille35,
  39. Bryan Paul Wordsworth36,
  40. Huji Xu2,37,38,
  41. Matthew A Brown27,39
  42. TCRI AS Group
    1. 1 Queensland University of Technology, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Translational Research Institute, Woolloongabba, Queensland, Australia
    2. 2 Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, Shanghai, China
    3. 3 Australian Translational Genomics Centre, Queensland University of Technology (QUT), Translational Research Institute, Woolloongabba, Queensland, Australia
    4. 4 Department of Internal Medicine, Division of Rheumatology, School of Medicine, Manisa Celal Bayar University, Manisa, Turkey
    5. 5 UMR 1173, Inserm, University of Versailles Saint-Quentin, Montigny-le-Bretonneux, France
    6. 6 Service de Rhumatologie, Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France
    7. 7 Laboratoire d'Excellence Inflamex, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
    8. 8 Epidemiology Group, Institute of Applied Health Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, UK
    9. 9 Aberdeen Centre for Arthritis and Musculoskeletal Health, University of Aberdeen, Foresterhill, Aberdeen, UK
    10. 10 Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Tehran, Iran (the Islamic Republic of)
    11. 11 NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
    12. 12 Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
    13. 13 Division of Allergy, Immunology, Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
    14. 14 School of Medicine, National Yang-Ming University, Taipei, Taiwan
    15. 15 Department of Medicine, University of Otago Wellington, Wellington, New Zealand
    16. 16 Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
    17. 17 Hanyang University Hospital for Rheumatic Diseases, Hanyang University, Seoul, Korea (the Republic of)
    18. 18 University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia
    19. 19 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
    20. 20 Department of Medicine, Chung Shan Medical University, Taichung, Taiwan
    21. 21 Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
    22. 22 QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
    23. 23 Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
    24. 24 Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA
    25. 25 State Key Laboratory of Optometry, Ophthalmology, and Vision Science, Affiliated Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
    26. 26 Institute for Glycomics, Griffith University, Nathan, Queensland, Australia
    27. 27 Center for Precision Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
    28. 28 Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang, China
    29. 29 Rheumatology Department, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
    30. 30 Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing, Beijing, China
    31. 31 Department of Medicine/Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA
    32. 32 Division of Medicine/Rheumatology, University of California San Francisco, San Francisco, California, USA
    33. 33 Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
    34. 34 Internal Medicine, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, Texas, USA
    35. 35 Department of Internal Medicine, Division of Rheumatology, McGovern Medical School at The University of Texas Health Science Center, Houston, Texas, USA
    36. 36 NIHR Oxford Musculoskeletal Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford, Oxfordshire, UK
    37. 37 School of Clinical Medicine, Tsinghua University, Beijing, Beijing, China
    38. 38 Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing, China
    39. 39 NIHR Biomedical Research Centre at Guy's and Saint Thomas' NHS Foundation Trust and King's College London, London, UK
    1. Correspondence to Professor Matthew A Brown, NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London, London, SE1 9RT, United Kingdom; matt.brown{at}kcl.ac.uk; Professor Huji Xu, Department of Rheumatology and Immunology, Changzheng Hospital, The Second Military Medical University, Shanghai, China; xuhuji{at}smmu.edu.cn

    Abstract

    Objective We sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain.

    Methods PRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), HLA-B27 and sacroiliac MRI.

    Results In people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for HLA-B27 testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with HLA-B27 testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for HLA-B27, these values were 51.9% and 97.9%, respectively.

    Conclusions PRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or HLA-B27 status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied.

    • spondylitis
    • ankylosing
    • magnetic resonance imaging
    • polymorphism
    • genetic
    • low back pain

    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. Details of the polygenic risk scores will be made available depending on completion of data transfer agreements with King's College London.

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. Details of the polygenic risk scores will be made available depending on completion of data transfer agreements with King's College London.

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    Footnotes

    • Handling editor Josef S Smolen

    • Twitter @nurullahakkoc, @UAberdeenEpi, @hteraG_senoJ

    • ZL and XW contributed equally.

    • HX and MAB contributed equally.

    • Collaborators TCRI AS Group Jian Yin1, Lei Jiang1, Lin Zhou1, Ting Li1, Qingwen Wang2, Tianwang Li3, Guanmin Gao4, Shengqian Xu5, Weiguo Xiao6, Hui Shen6, Jingguo Zhou7, Yuquan You8, Dongbao Zhao9, Qing Cai9, Shengming Dai10, Lan He11, Ping Zhu12, Zhenyu Jiang13, Jian Xu14, Huaxiang Wu15, Lie Dai16, Yang Li17, Feng Ding18, Xiaochun Zhu19, Chongyang Liu20, Dongyi He21, Liyun Zhang22, Zhijun Li23, Futao Zhao24, Hanshi Xu25, Niansong Wang10, Youlian Wang26, Lindi Jiang27, Yu Zhang28, Jinwei Chen29, Fang Cheng24, Zhiyi Zhang30, Yifang Mei30,Liangjing Lv31, Lingli Dong32, Jing Yang33, Yinong Li34, Xiaodong Wang35, Xiaofeng Li36, Hongsheng Sun37, Xianming Long38, Xiao Zhang39, Qinghong Yu40, Xiaodan Kong41, Yi Zheng42, Miaojia Zhang43, Yi Tao44, Yisha Li45, Xinwang Duan46, Qianghua Wei47, Xiaofei Wang48, Jie Han49, Rong Mu50, Yiping Lin51, Jian Zhu52, Xiaoyuan Chen53. 1. Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University; 2. Peking University Shenzhen Hospital; 3. Guangdong Second Provincial General Hospital; 4. The First Affiliated Hospital of Zhengzhou University; 5. The First Affiliated Hospital of Anhui Medical University; 6. The First Affiliated Hospital of China Medical University; 7. The Affiliated Hospital of North Sichuan Medical College; 8. Quanzhou Orthopedic-Traumatological Hospital of Fujian Traditional Chinese Medical University; 9. Shanghai Changhai hospital; 10. Shanghai Sixth People's Hospital; 11. The First Affiliated Hospital of Xi'an Jiaotong University; 12. Xijing Hospital; 13. Bethune First Hospital of Jilin University; 14. The First Affiliated Hospital of Kunming Medical University; 15. The Second Affiliated Hospital of Zhejiang University School of Medicine; 16. The Second Affiliated Hospital of Sun Yat-sen University; 17. The Second Affiliated Hospital of Harbin Medical University; 18. Qilu Hospital of Shandong University; 19. The First Affiliated Hospital of Wenzhou Medical University; 20. The Third Affiliated Hospital of Chongqing Medical University; 21. Shanghai GuangHua Hospital of Integrated Traditiongnal Chinese and Western Medicine; 22. Shanxi Dayi Hospital; 23. The First Affiliated Hospital of Bengbu Medical College; 24. Shanghai Ninth People's Hospital; 25. The First Affiliated Hospital of Sun Yat-sen University; 26. Jiangxi Provincial People's Hospital; 27. Shanghai Zhongshan Hospital; 28. Northern Jiangsu People's Hospital; 29. The Second Xiangya Hospital of Central South University; 30. The First Affiliated Hospital of Harbin Medical University; 31. Shanghai Renji Hospital; 32. Tongji Hospital of Huazhong University of Science & Technology; 33. Mianyang Hospital of Traditional Chinese Medicine; 34. Fujian armed police hospital; 35. Affiliated Hopital of Weifang Medical University; 36. The Second Affiliated Hospital of Shanxi Medical University; 37. Shandong Provincial Hospital; 38. The First Affiliated Hospital to Soochow University; 39. Guangdong General Hospital; 40. Zhujiang Hospital of Southern Medical University; 41. The Second Affiliated Hospital of Dalian Medical University; 42. Beijing Chao-Yang Hospital; 43. Jiangsu Province Hospital; 44. The Second Affiliated Hospital of Guangzhou Medical University; 45. The First Xiangya Hospital of Central South University; 46. The Second Affiliated Hospital of Nanchang University; 47. Shanghai General Hospital; 48. Shengjing Hospital of China Medical University; 49. Shanghai Dongfang Hospital; 50. Peking University People's Hospital; 51. The People's Liberation Army's 202 Hospital; 52. Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University; 53. Tsinghua Clinical Research Center, School of Medicine, Tsinghua University. Ann Morgan, NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK, and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.

    • Contributors Study design was performed by ZL, XW, PL, MHW, LG, MMW, MHR, JDR, BPW, HX and MAB. Case recruitment was performed by XW, NA, MA, GM, MM, HMO, CTC, AAH, SS, GTJ, SYB, GW, AJ, EF, JS, LL, ML, JCCW, NM, MJW, MJL, YW, JZ, JSZ, XW, JZB, MHW, LG, MMW, MHR, LD, THK, JDR, BPW, HX and MAB. Genotyping and/or analysis were performed by ZL,XW, ML PL, GW, EDG, LA, LW, XH and MAB. The manuscript was prepared by ZL, JDR, BPW, XH and MAB. All authors were involved in completion of, and approved, the final manuscript.

    • Funding This study was funded, in part, by Arthritis Research UK (Grants 19536 and 18797), by the Wellcome Trust (grant number 076113) and by the Oxford Comprehensive Biomedical Research Centre ankylosing spondylitis chronic disease cohort (Theme Code: A91202). XH is supported by the National Natural Science Foundation of China (Grant No. 31821003), National Key Research and Development Project (Grant No. 2018AAA0100302), Shanghai Municipal Key Clinical Specialty (shslczdzk02602), and Shanghai Science and Technology Development Funds (2020-SH-XY-2). ZBJ was funded by a grant from the Zhejiang Provincial Natural Science Foundation of China (LD18H120001LD). The New Zealand data were derived from participants in the Spondyloarthritis Genetics and the Environment Study (SAGE) and was funded by The Health Research Council, New Zealand. We acknowledge the Understanding Society: The UK Household Longitudinal Study. This is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen and the genome-wide scan data were analysed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website https:www.understandingsociety.ac.uk/. HMO is supported by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. French sample collection was performed by the Groupe Française d’Etude Génétique des Spondylarthrites, coordinated by Professor Maxime Breban and funded by the Agence Nationale de Recherche GEMISA grant reference ANR-10-MIDI-0002. We acknowledge and thank the TCRI AS Group for their support in recruiting patients for the study (see below). The authors acknowledge the sharing of data and samples by the BSRBR-AS Register in Aberdeen. Chief Investigator, Professor Gary Macfarlane and Dr Gareth Jones, Deputy Chief Investigator created the BSRBR-AS study which was commissioned by the British Society for Rheumatology, funded in part by Abbvie, Pfizer and UCB. We are grateful to every patient, past and present staff of the BSRBR-AS register team and to all clinical staff who recruited patients, followed them up and entered data—details here: https://www.abdn.ac.uk/iahs/research/epidemiology/spondyloarthritis.php%23panel1011. The QIMR control samples were from parents of adolescent twins collected in the context of the Brisbane Longitudinal Twin Study 1992–2016, support by grants from NHMRC (NGM) and ARC (MJW). We thank Anjali Henders, Lisa Bowdler, Tabatha Goncales for biobank collection and Kerrie McAloney and Scott Gordon for curating samples for this study. MAB is funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship (1024879), and support for this study was received from a National Health and Medical Research Council (Australia) program grant (566938) and project grant (569829), and from the Australian Cancer Research Foundation and Rebecca Cooper Medical Research Foundation. We are also very grateful for the invaluable support received from the National Ankylosing Spondylitis Society (UK) and Spondyloarthritis Association of America in case recruitment. Additional financial and technical support for patient recruitment was provided by the National Institute for Health Research Oxford Musculoskeletal Biomedical Research Unit and NIHR Thames Valley Comprehensive Local Research and an unrestricted educational grant from Abbott Laboratories. This research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London and/or the NIHR Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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