Publications Repository - Gdańsk University of Technology

The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10-8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.

Authors

• Lara Kular,
• Yun Liu,
• Sabrina Ruhrmann,
• Galina Zheleznyakova,
• Francesco Marabita,
• David Gomez-Cabrero,
• Tojo James,
• Ewoud Ewing,
• Magdalena Lindén,
• dr inż. Bartosz Górnikiewicz link open in new tab ,
• Shahin Aeinehband,
• Pernilla Stridh,
• Jenny Link,
• Till Andlauer,
• Christiane Gasperi,
• Heinz Wiendl,
• Frauke Zipp,
• Ralf Gold,
• Björn Tackenberg,
• Frank Weber,
• Bernhard Hemmer,
• Konstantin Strauch,
• Stefanie Heilmann-Heimbach,
• Rajesh Rawal,
• Ulf Schminke,
• Carsten Schmidt,
• Tim Kacprowski,
• Andre Franke,
• Matthias Laudes,
• Alexander Dilthey,
• Elisabeth Celius,
• Helle Søndergaard,
• Jesper Tegnér,
• Hanne Harbo,
• Annette Oturai,
• Sigurgeir Olafsson,
• Hannes Eggertsson,
• Bjarni Halldorsson,
• Haukur Hjaltason,
• Elias Olafsson,
• Ingileif Jonsdottir,
• Kari Stefansson,
• Tomas Olsson,
• Fredrik Piehl,
• Tomas Ekström,
• Ingrid Kockum,
• Andrew Feinberg,
• Maja Jagodic