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

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

doi:10.3389/fgene.2021.659042

Abstract

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.

Highlights

Ankylosing spondylitis (AS) is a chronic inflammatory disease defined by the inflammation of the spine and sacroiliac joints, which if left untreated, leads to vertebrae fusion (Cortes et al, 2013)
Together with HLA-B, more than 45 genes have been suggested to contribute to disease risk, e.g., ERAP1, IL23R, and RUNX3 (Burton et al, 2007; Evans et al, 2011; Cortes et al, 2013; Ranganathan et al, 2017), but combined, these explain less than 30% of the genetic heritability (Burton et al, 2007; Evans et al, 2011; Cortes et al, 2013) of this highly heritable disease (h2 > 90%, Cortes et al, 2013)
This rate was driven by a combination of data input and software biases, where some genes were genotyped at a higher rate with targeted data than WGS (e.g., TAP2) and some gene call rates were affected by variant availability and software choice (Supplementary Table 3 and Supplementary Figures 4–6)

Summary

Introduction

Ankylosing spondylitis (AS) is a chronic inflammatory disease defined by the inflammation of the spine and sacroiliac joints, which if left untreated, leads to vertebrae fusion (Cortes et al, 2013). The disease prevalence in Sweden is 0.18% (Exarchou et al, 2015) and Europe in 0.24% (Dean et al, 2014), and contrary to most immunological diseases, AS affects males more often than females [Sweden 1.6:1 (Exarchou et al, 2015), Europe 2–3:1 (Lee et al, 2008)]. 80% of AS cases are HLA-B∗27 positive, while only a small fraction ( 90%, Cortes et al, 2013)

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