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

Sigrid Le Clerc 1 Laura Lombardi 2, 3, 4 Bernhard T Baune 5, 6, 7 Azmeraw T Amare 8 Klaus Oliver Schubert 8 Liping Hou 9 Scott R Clark 8 Sergi Papiol 10 Micah Cearns 8 Urs Heilbronner 10 Franziska Degenhardt 11 Fasil Tekola-Ayele Yi-Hsiang Hsu Tatyana Shekhtman Mazda Adli Nirmala Akula Kazufumi Akiyama Raffaella Ardau Bárbara Arias Jean-Michel Aubry Lena Backlund Abesh Kumar Bhattacharjee Frank Bellivier Antonio Benabarre Susanne Bengesser Joanna M Biernacka Armin Birner Clara Brichant-Petitjean Pablo Cervantes Hsi-Chung Chen Caterina Chillotti Sven Cichon Cristiana Cruceanu Piotr M Czerski Nina Dalkner Alexandre Dayer Maria del Zompo J. Raymond Raymond Depaulo Bruno Étain Stephane Jamain Peter Falkai Andreas J Forstner Louise Frisen Mark A Frye Janice M Fullerton Sébastien Gard Julie S Garnham Fernando S Goes Maria Grigoroiu-Serbanescu Paul Grof Ryota Hashimoto Joanna Hauser Stefan Herms Per Hoffmann Esther Jiménez Jean-Pierre Kahn Layla Kassem Po-Hsiu Kuo Tadafumi Kato John R Kelsoe Sarah Kittel-Schneider Ewa Ferensztajn-Rochowiak Barbara König Ichiro Kusumi Gonzalo Laje Mikael Landén Catharina Lavebratt Susan G Leckband Alfonso Tortorella Mirko Manchia Lina Martinsson Michael J Mccarthy Susan L Mcelroy Francesc Colom Vincent Millischer Marina Mitjans Francis M Mondimore Palmiero Monteleone Caroline M Nievergelt Markus M Nöthen Tomas Novák Claire O’donovan Norio Ozaki Urban Ösby Andrea Pfennig James B Potash Andreas Reif Eva Reininghaus Guy A Rouleau Janusz K Rybakowski Martin Schalling Peter R Schofield Barbara W Schweizer Giovanni Severino Paul D Shilling Katzutaka Shimoda Christian Simhandl Claire M Slaney Claudia Pisanu Alessio Squassina Thomas Stamm Pavla Stopkova Mario Maj Gustavo Turecki Eduard Vieta Julia Veeh Stephanie H Witt Adam Wright Peter P Zandi Philip B Mitchell Michael Bauer Martin Alda Marcella Rietschel Francis J Mcmahon Thomas G Schulze Jean-Louis Spadoni 1 Wahid Boukouaci Jean-Romain Richard Philippe Le Corvoisier Caroline Barrau Jean-François Zagury 1 Marion Leboyer Ryad Tamouza 3, 2, 4, * 
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.
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https://hal-cnam.archives-ouvertes.fr/hal-03500675
Contributor : Marie-Liesse Bertram Connect in order to contact the contributor
Submitted on : Wednesday, December 22, 2021 - 2:39:31 PM
Last modification on : Wednesday, September 28, 2022 - 5:57:57 AM
Long-term archiving on: : Wednesday, March 23, 2022 - 6:30:35 PM

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Sigrid Le Clerc, Laura Lombardi, Bernhard T Baune, Azmeraw T Amare, Klaus Oliver Schubert, et al.. HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders. Scientific Reports, 2021, 11 (1), ⟨10.1038/s41598-021-97140-7⟩. ⟨hal-03500675⟩

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