A Genetic Association Test Accounting for Skewed X-Inactivation With Application to Biotherapy Immunogenicity in Patients With Autoimmune Diseases

Frontiers in Medicine

article

Signe Hässler¹  Sophie Camilleri-Broët³  Matthieu Allez⁴  Florian Deisenhammer⁵  Anna Fogdell-Hahn⁶  Xavier Mariette⁷  Marc Pallardy⁸  Philippe Broët⁹ 

[1] INSERM UMR 959, Immunology-Immunopathology-Immunotherapy ,(i3), Sorbonne Université;Assistance Publique Hôpitaux de Paris, Hôpital Pitié Salpêtrière;OPTILAB-MUHC, Division of Pathology, Department of Laboratory Medicine, McGill University Health Center;Department of Gastroenterology, Hôpital Saint-Louis, AP-HP, Université Paris-Diderot;Department of Neurology, Medical University of Innsbruck;Department of Clinical Neuroscience, Karolinska Institutet;Université Paris-Saclay, INSERM UMR1184, Center for Immunology of Viral Infections and Autoimmune Diseases;Université Paris-Saclay, INSERM, Inflammation, Microbiome, Immunosurveillance, Châtenay-Malabry;University Paris-Saclay, CESP, INSERM, AP-HP, Université Paris-Sud, Hôpitaux Universitaires Paris-Sud

关键词: immunogenicity;    anti-drug antibodies;    biotherapy;    autoimmune disease;    X-chromosome;    skewed X-Chromosome inactivation;    additive hazard model;   

DOI  :  10.3389/fmed.2022.856917

学科分类：社会科学、人文和艺术（综合）

来源: Frontiers

【 摘 要 】

Despite being assayed on commercialized DNA chips, the X chromosome is commonly excluded from genome-wide association studies (GWAS). One of the reasons is the complexity to analyze the data taking into account the X-chromosome inactivation (XCI) process in women and in particular the XCI process with a potentially skewed pattern. This is the case when investigating the role of X-linked genetic variants in the occurrence of anti-drug antibodies (ADAs) in patients with autoimmune diseases treated by biotherapies. In this context, we propose a novel test statistic for selecting loci of interest harbored by the X chromosome that are associated with time-to-event data taking into account skewed X-inactivation (XCI-S). The proposed statistic relies on a semi-parametric additive hazard model and is straightforward to implement. Results from the simulation study show that the test provides higher power gains than the score tests from the Cox model (under XCI process or its escape) and the Xu et al.'s XCI-S likelihood ratio test. We applied the test to the data from the real-world observational multicohort study set-up by the IMI-funded ABIRISK consortium for identifying X chromosome susceptibility loci for drug immunogenicity in patients with autoimmune diseases treated by biotherapies. The test allowed us to select two single nucleotide polymorphisms (SNPs) with high linkage disequilibrium (rs5991366 and rs5991394) located in the cytoband Xp22.2 that would have been overlooked by the Cox score tests and the Xu et al.'s XCI-S likelihood ratio test. Both SNPs showed a similar protective effect for drug immunogenicity without any occurrence of ADA positivity for the homozygous females and hemizygous males for the alternative allele. To our knowledge, this is the first study to investigate the association between X chromosome loci and the occurrence of anti-drug antibodies. We think that more X-Chromosome GWAS should be performed and that the test is well-suited for identifying X-Chromosome SNPs, while taking into account all patterns of the skewed X-Chromosome inactivation process.

【 授权许可】

CC BY