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Research ArticleAccepted Article

Prediction of ankylosing spondylitis in the population-based HUNT study by a genetic risk score combining 110 SNPs of genome-wide significance

Sina Rostami, Mari Hoff, Matthew A. Brown, Kristian Hveem, Oddgeir L. Holmen, Lars G. Fritsche and Vibeke Videm
The Journal of Rheumatology April 2019, jrheum.181209; DOI: https://doi.org/10.3899/jrheum.181209
Sina Rostami
From the Department of Clinical and Molecular Medicine, Department of Neuromedicine and Movement Science, and Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway; and Department of Rheumatology and Department of Immunology and Transfusion Medicine, St. Olavs University Hospital, Trondheim, Norway; and Institute of Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Queensland University of Technology, Brisbane, Australia; and Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, USA. The study was supported by the Liaison Committee between the Central Norway Regional Health Authority and NTNU (grant 5056/46051000 to VV), and the Research Council of Norway (project 249944 to SR and VV). MAB is supported by a National Health and Medical Research Council Senior Principal Research Fellowship (APP1024879). Address correspondence to Vibeke Videm, MD, PhD, Department Clinical and Molecular Medicine, Lab Center 3 East, St. Olavs Hospital, NO-7006 Trondheim, Norway. E-mail: vibeke.videm@ntnu.no
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Mari Hoff
From the Department of Clinical and Molecular Medicine, Department of Neuromedicine and Movement Science, and Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway; and Department of Rheumatology and Department of Immunology and Transfusion Medicine, St. Olavs University Hospital, Trondheim, Norway; and Institute of Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Queensland University of Technology, Brisbane, Australia; and Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, USA. The study was supported by the Liaison Committee between the Central Norway Regional Health Authority and NTNU (grant 5056/46051000 to VV), and the Research Council of Norway (project 249944 to SR and VV). MAB is supported by a National Health and Medical Research Council Senior Principal Research Fellowship (APP1024879). Address correspondence to Vibeke Videm, MD, PhD, Department Clinical and Molecular Medicine, Lab Center 3 East, St. Olavs Hospital, NO-7006 Trondheim, Norway. E-mail: vibeke.videm@ntnu.no
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Matthew A. Brown
From the Department of Clinical and Molecular Medicine, Department of Neuromedicine and Movement Science, and Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway; and Department of Rheumatology and Department of Immunology and Transfusion Medicine, St. Olavs University Hospital, Trondheim, Norway; and Institute of Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Queensland University of Technology, Brisbane, Australia; and Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, USA. The study was supported by the Liaison Committee between the Central Norway Regional Health Authority and NTNU (grant 5056/46051000 to VV), and the Research Council of Norway (project 249944 to SR and VV). MAB is supported by a National Health and Medical Research Council Senior Principal Research Fellowship (APP1024879). Address correspondence to Vibeke Videm, MD, PhD, Department Clinical and Molecular Medicine, Lab Center 3 East, St. Olavs Hospital, NO-7006 Trondheim, Norway. E-mail: vibeke.videm@ntnu.no
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Kristian Hveem
From the Department of Clinical and Molecular Medicine, Department of Neuromedicine and Movement Science, and Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway; and Department of Rheumatology and Department of Immunology and Transfusion Medicine, St. Olavs University Hospital, Trondheim, Norway; and Institute of Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Queensland University of Technology, Brisbane, Australia; and Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, USA. The study was supported by the Liaison Committee between the Central Norway Regional Health Authority and NTNU (grant 5056/46051000 to VV), and the Research Council of Norway (project 249944 to SR and VV). MAB is supported by a National Health and Medical Research Council Senior Principal Research Fellowship (APP1024879). Address correspondence to Vibeke Videm, MD, PhD, Department Clinical and Molecular Medicine, Lab Center 3 East, St. Olavs Hospital, NO-7006 Trondheim, Norway. E-mail: vibeke.videm@ntnu.no
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Oddgeir L. Holmen
From the Department of Clinical and Molecular Medicine, Department of Neuromedicine and Movement Science, and Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway; and Department of Rheumatology and Department of Immunology and Transfusion Medicine, St. Olavs University Hospital, Trondheim, Norway; and Institute of Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Queensland University of Technology, Brisbane, Australia; and Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, USA. The study was supported by the Liaison Committee between the Central Norway Regional Health Authority and NTNU (grant 5056/46051000 to VV), and the Research Council of Norway (project 249944 to SR and VV). MAB is supported by a National Health and Medical Research Council Senior Principal Research Fellowship (APP1024879). Address correspondence to Vibeke Videm, MD, PhD, Department Clinical and Molecular Medicine, Lab Center 3 East, St. Olavs Hospital, NO-7006 Trondheim, Norway. E-mail: vibeke.videm@ntnu.no
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Lars G. Fritsche
From the Department of Clinical and Molecular Medicine, Department of Neuromedicine and Movement Science, and Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway; and Department of Rheumatology and Department of Immunology and Transfusion Medicine, St. Olavs University Hospital, Trondheim, Norway; and Institute of Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Queensland University of Technology, Brisbane, Australia; and Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, USA. The study was supported by the Liaison Committee between the Central Norway Regional Health Authority and NTNU (grant 5056/46051000 to VV), and the Research Council of Norway (project 249944 to SR and VV). MAB is supported by a National Health and Medical Research Council Senior Principal Research Fellowship (APP1024879). Address correspondence to Vibeke Videm, MD, PhD, Department Clinical and Molecular Medicine, Lab Center 3 East, St. Olavs Hospital, NO-7006 Trondheim, Norway. E-mail: vibeke.videm@ntnu.no
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Vibeke Videm
From the Department of Clinical and Molecular Medicine, Department of Neuromedicine and Movement Science, and Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway; and Department of Rheumatology and Department of Immunology and Transfusion Medicine, St. Olavs University Hospital, Trondheim, Norway; and Institute of Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Queensland University of Technology, Brisbane, Australia; and Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, USA. The study was supported by the Liaison Committee between the Central Norway Regional Health Authority and NTNU (grant 5056/46051000 to VV), and the Research Council of Norway (project 249944 to SR and VV). MAB is supported by a National Health and Medical Research Council Senior Principal Research Fellowship (APP1024879). Address correspondence to Vibeke Videm, MD, PhD, Department Clinical and Molecular Medicine, Lab Center 3 East, St. Olavs Hospital, NO-7006 Trondheim, Norway. E-mail: vibeke.videm@ntnu.no
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Abstract

Objective The genetic component of ankylosing spondylitis (AS) development is ~90%. Of the known heritability, ~20% is explained by HLA-B27, and 113 identified AS-associated SNPs account for ~7.4%. The objectives were to construct a weighted genetic risk score (wGRS) using currently known genome-wide susceptibility SNPs, and evaluate its predictive ability for AS in the Norwegian population-based Nord- Trøndelag Health Study (HUNT).

Methods AS cases (n=164) and controls (n=49,032) were from the second (1995- 1997) and third (2006-2008) waves of the HUNT study, to which the entire adult population of the northern region of Trøndelag was invited. A wGRS based on 110 SNPs weighted by published odds ratios for AS was constructed, representing each person’s carriage of all risk variants. Logistic regression models including the wGRS alone or in combination with HLA-B27 carrier state and other adjustment variables (gender, age, smoking, body mass index, and hypertension) were developed. Discrimination among models was compared using area-under-the-curve (AUC).

Results The wGRS was associated with AS (OR: 1.7; 95% CI: 1.4-2.1), but showed low discrimination (AUC: 0.62 (0.58-0.67)). HLA-B27 was significantly associated with AS (OR: 50(32-81), showing high discrimination (AUC: 0.88 (0.85-0.90)). Combining the wGRS and HLA-B27 improved prediction (AUC: 0.90 (0.87-0.92)), p<0.001 vs. wGRS alone, p<0.01 vs. HLA-B27 alone). Further inclusion of adjustment variables gave a small improvement (AUC: 0.91 (0.89-0.94), P=0.03).

Conclusion Prediction in a population-based setting based on all currently known AS susceptibility SNPs was better than HLA-B27 carrier state alone, although the improvement was small and of uncertain clinical value.

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The Journal of Rheumatology
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1 Feb 2023
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Accepted manuscript
Prediction of ankylosing spondylitis in the population-based HUNT study by a genetic risk score combining 110 SNPs of genome-wide significance
Sina Rostami, Mari Hoff, Matthew A. Brown, Kristian Hveem, Oddgeir L. Holmen, Lars G. Fritsche, Vibeke Videm
The Journal of Rheumatology Apr 2019, jrheum.181209; DOI: 10.3899/jrheum.181209

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Accepted manuscript
Prediction of ankylosing spondylitis in the population-based HUNT study by a genetic risk score combining 110 SNPs of genome-wide significance
Sina Rostami, Mari Hoff, Matthew A. Brown, Kristian Hveem, Oddgeir L. Holmen, Lars G. Fritsche, Vibeke Videm
The Journal of Rheumatology Apr 2019, jrheum.181209; DOI: 10.3899/jrheum.181209
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