Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing Spondylitis
ObjectivesTo further elucidate the role of the MHC in ankylosing spondylitis by typing 17 genes, searching for HLA-B∗27 independent associations and assessing the impact of sex on this male biased disease.MethodsHigh-confidence two-field resolution genotyping was performed on 310 cases and 2196 cont...
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Frontiers Media S.A.
2021-07-01
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Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2021.659042/full |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jessika Nordin Jessika Nordin Mats Pettersson Lina Hultin Rosenberg Argyri Mathioudaki Åsa Karlsson Eva Murén Karolina Tandre Lars Rönnblom Alf Kastbom Alf Kastbom Jan Cedergren Jan Cedergren Per Eriksson Per Eriksson Peter Söderkvist Kerstin Lindblad-Toh Kerstin Lindblad-Toh Jennifer R. S. Meadows |
spellingShingle |
Jessika Nordin Jessika Nordin Mats Pettersson Lina Hultin Rosenberg Argyri Mathioudaki Åsa Karlsson Eva Murén Karolina Tandre Lars Rönnblom Alf Kastbom Alf Kastbom Jan Cedergren Jan Cedergren Per Eriksson Per Eriksson Peter Söderkvist Kerstin Lindblad-Toh Kerstin Lindblad-Toh Jennifer R. S. Meadows Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing Spondylitis Frontiers in Genetics ankylosing spondylitis HLA-B∗27 positive HLA-A∗24:02 sex biased major histocompatibility complex HLA allele typing |
author_facet |
Jessika Nordin Jessika Nordin Mats Pettersson Lina Hultin Rosenberg Argyri Mathioudaki Åsa Karlsson Eva Murén Karolina Tandre Lars Rönnblom Alf Kastbom Alf Kastbom Jan Cedergren Jan Cedergren Per Eriksson Per Eriksson Peter Söderkvist Kerstin Lindblad-Toh Kerstin Lindblad-Toh Jennifer R. S. Meadows |
author_sort |
Jessika Nordin |
title |
Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing Spondylitis |
title_short |
Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing Spondylitis |
title_full |
Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing Spondylitis |
title_fullStr |
Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing Spondylitis |
title_full_unstemmed |
Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing Spondylitis |
title_sort |
association of protective hla-a with hla-b∗27 positive ankylosing spondylitis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Genetics |
issn |
1664-8021 |
publishDate |
2021-07-01 |
description |
ObjectivesTo further elucidate the role of the MHC in ankylosing spondylitis by typing 17 genes, searching for HLA-B∗27 independent associations and assessing the impact of sex on this male biased disease.MethodsHigh-confidence two-field resolution genotyping was performed on 310 cases and 2196 controls using an n-1 concordance method. Protein-coding variants were called from next-generation sequencing reads using up to four software programs and the consensus result recorded. Logistic regression tests were applied to the dataset as a whole, and also in stratified sets based on sex or HLA-B∗27 status. The amino acids driving association were also examined.ResultsTwenty-five HLA protein-coding variants were significantly associated to disease in the population. Three novel protective associations were found in a HLA-B∗27 positive population, HLA-A∗24:02 (OR = 0.4, CI = 0.2–0.7), and HLA-A amino acids Leu95 and Gln156. We identified a key set of seven loci that were common to both sexes, and robust to change in sample size. Stratifying by sex uncovered three novel risk variants restricted to the female population (HLA-DQA1∗04.01, -DQB1∗04:02, -DRB1∗08:01; OR = 2.4–3.1). We also uncovered a set of neutral variants in the female population, which in turn conferred strong effects in the male set, highlighting how population composition can lead to the masking of true associations.ConclusionPopulation stratification allowed for a nuanced investigation into the tightly linked MHC region, revealing novel HLA-B∗27 signals as well as replicating previous HLA-B∗27 dependent results. This dissection of signals may help to elucidate sex biased disease predisposition and clinical progression. |
topic |
ankylosing spondylitis HLA-B∗27 positive HLA-A∗24:02 sex biased major histocompatibility complex HLA allele typing |
url |
https://www.frontiersin.org/articles/10.3389/fgene.2021.659042/full |
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doaj-fb5667a8b5954d309890b049f71970322021-07-15T15:47:58ZengFrontiers Media S.A.Frontiers in Genetics1664-80212021-07-011210.3389/fgene.2021.659042659042Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing SpondylitisJessika Nordin0Jessika Nordin1Mats Pettersson2Lina Hultin Rosenberg3Argyri Mathioudaki4Åsa Karlsson5Eva Murén6Karolina Tandre7Lars Rönnblom8Alf Kastbom9Alf Kastbom10Jan Cedergren11Jan Cedergren12Per Eriksson13Per Eriksson14Peter Söderkvist15Kerstin Lindblad-Toh16Kerstin Lindblad-Toh17Jennifer R. S. Meadows18Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, SwedenDepartment of Rheumatology, University Hospital Linköping, Linköping, SwedenDepartment of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Rheumatology, University Hospital Linköping, Linköping, SwedenDepartment of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Rheumatology, University Hospital Linköping, Linköping, SwedenDepartment of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenScience for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, SwedenBroad Institute of MIT and Harvard, Cambridge, MA, United StatesScience for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, SwedenObjectivesTo further elucidate the role of the MHC in ankylosing spondylitis by typing 17 genes, searching for HLA-B∗27 independent associations and assessing the impact of sex on this male biased disease.MethodsHigh-confidence two-field resolution genotyping was performed on 310 cases and 2196 controls using an n-1 concordance method. Protein-coding variants were called from next-generation sequencing reads using up to four software programs and the consensus result recorded. Logistic regression tests were applied to the dataset as a whole, and also in stratified sets based on sex or HLA-B∗27 status. The amino acids driving association were also examined.ResultsTwenty-five HLA protein-coding variants were significantly associated to disease in the population. Three novel protective associations were found in a HLA-B∗27 positive population, HLA-A∗24:02 (OR = 0.4, CI = 0.2–0.7), and HLA-A amino acids Leu95 and Gln156. We identified a key set of seven loci that were common to both sexes, and robust to change in sample size. Stratifying by sex uncovered three novel risk variants restricted to the female population (HLA-DQA1∗04.01, -DQB1∗04:02, -DRB1∗08:01; OR = 2.4–3.1). We also uncovered a set of neutral variants in the female population, which in turn conferred strong effects in the male set, highlighting how population composition can lead to the masking of true associations.ConclusionPopulation stratification allowed for a nuanced investigation into the tightly linked MHC region, revealing novel HLA-B∗27 signals as well as replicating previous HLA-B∗27 dependent results. This dissection of signals may help to elucidate sex biased disease predisposition and clinical progression.https://www.frontiersin.org/articles/10.3389/fgene.2021.659042/fullankylosing spondylitisHLA-B∗27 positiveHLA-A∗24:02sex biasedmajor histocompatibility complexHLA allele typing |