HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

2021 | journal article. A publication with affiliation to the University of Göttingen.

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​HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders​
Le Clerc, S.; Lombardi, L.; Baune, B. T.; Amare, A. T.; Schubert, K. O.; Hou, L. & Clark, S. R. et al.​ (2021) 
Scientific Reports11(1) art. 17823​.​ DOI: https://doi.org/10.1038/s41598-021-97140-7 

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Authors
Le Clerc, Sigrid; Lombardi, Laura; Baune, Bernhard T.; Amare, Azmeraw T.; Schubert, Klaus Oliver; Hou, Liping; Clark, Scott R.; Papiol, Sergi ; Cearns, Micah; Heilbronner, Urs ; Tamouza, Ryad
Abstract
Abstract Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1 11:01 classical allele, associated with a better response to Li ( p  < 1 × 10 −3 ; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Abstract Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1 11:01 classical allele, associated with a better response to Li ( p  < 1 × 10 −3 ; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Issue Date
2021
Journal
Scientific Reports 
eISSN
2045-2322
Language
English

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