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

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

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.659042

DOI=10.3389/fgene.2021.659042

ISSN=1664-8021

ABSTRACT=<sec><title>Objectives</title><p>To further elucidate the role of the MHC in ankylosing spondylitis by typing 17 genes, searching for <italic>HLA-B<sup>∗</sup>27</italic> independent associations and assessing the impact of sex on this male biased disease.</p></sec><sec><title>Methods</title><p>High-confidence two-field resolution genotyping was performed on 310 cases and 2196 controls using an <italic>n-1</italic> 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 <italic>HLA-B<sup>∗</sup>27</italic> status. The amino acids driving association were also examined.</p></sec><sec><title>Results</title><p>Twenty-five <italic>HLA</italic> protein-coding variants were significantly associated to disease in the population. Three novel protective associations were found in a <italic>HLA-B<sup>∗</sup>27</italic> positive population, <italic>HLA-A<sup>∗</sup>24:02</italic> (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 (<italic>HLA-DQA1<sup>∗</sup>04.01, -DQB1<sup>∗</sup>04:02, -DRB1<sup>∗</sup>08:01;</italic> 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.</p></sec><sec><title>Conclusion</title><p>Population stratification allowed for a nuanced investigation into the tightly linked MHC region, revealing novel <italic>HLA-B<sup>∗</sup>27</italic> signals as well as replicating previous <italic>HLA-B<sup>∗</sup>27</italic> dependent results. This dissection of signals may help to elucidate sex biased disease predisposition and clinical progression.</p></sec>