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Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Abstract: Objective: Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies. Methods: We meta-analysed ~6.5?million single nucleotide polymorphisms in 11?678 cases and 19?704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases. Results: Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study. Conclusions: We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.

 Fuente: Annals of the Rheumatic Diseases, 2019, 78, 311-319

 Editorial: BMJ Publishing Group

 Año de publicación: 2019

 Nº de páginas: 9

 Tipo de publicación: Artículo de Revista

 DOI: 10.1136/annrheumdis-2018-214127

 ISSN: 0003-4967,1468-2060

 Proyecto español: SAF2015-66761-P

 Url de la publicación: http://dx.doi.org/10.1136/annrheumdis-2018-214127

Autoría

ACOSTA HERRERA, MARIALBERT

KERICK, MARTIN

GONZÁLEZ SERNA, DAVID

MYOSITIS GENETICS CONSORTIUM

SCLERODERMA GENETICS CONSORTIUM

WIJMENGA, CISCA

FRANKE, ANDRE

GREGERSEN, PETER K.

PADYUKOV, LEONID

WORTHINGTON, JANE

VYSE, TIMOTHY JAMES

ALARCÓN-RIQUELME, MARTA EUGENIA

MAYES, MAUREEN D.

MARTÍN IBAÑEZ, JAVIER