Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing Spondylitis

Jessika Nordin; Mats Pettersson; Lina Hultin Rosenberg; Argyri Mathioudaki; Åsa Karlsson; Eva Murén; Karolina Tandre; Lars Rönnblom; Alf Kastbom; Jan Cedergren; Per Eriksson; Peter Söderkvist; Kerstin Lindblad-Toh; Jennifer R S Meadows

doi:10.3389/fgene.2021.659042

Association of Protective HLA-A With HLA-B^∗27 Positive Ankylosing Spondylitis

Front Genet. 2021 Jul 15:12:659042. doi: 10.3389/fgene.2021.659042. eCollection 2021.

Authors

Jessika Nordin^{1

2}, Mats Pettersson¹, Lina Hultin Rosenberg¹, Argyri Mathioudaki³, Åsa Karlsson¹, Eva Murén¹, Karolina Tandre³, Lars Rönnblom³, Alf Kastbom^{4

5}, Jan Cedergren^{4

5}, Per Eriksson^{4

5}, Peter Söderkvist⁵, Kerstin Lindblad-Toh^{1

6}, Jennifer R S Meadows¹

Affiliations

¹ Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
² Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
³ Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
⁴ Department of Rheumatology, University Hospital Linköping, Linköping, Sweden.
⁵ Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA, United States.

Abstract

Objectives: To 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.

Methods: High-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.

Results: Twenty-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.

Conclusion: Population 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.

Keywords: HLA allele typing; HLA-A∗24:02; HLA-B∗27 positive; ankylosing spondylitis; major histocompatibility complex; sex biased.