Meta-analysis of Immunochip data of four autoimmune diseases reveals novel single-disease and cross-phenotype associations

Genome Medicine

Coeliac Disease Immunochip Consortium¹  Type 1 Diabetes Genetics Consortium¹  International Scleroderma Group¹  Rheumatoid Arthritis Consortium International for Immunochip (RACI)¹  Wei-Min Chen²  Stephen S. Rich²  Suna Onengut-Gumuscu²  Cisca Wijmenga³  Alexandra Zhernakova³  Maureen D. Mayes⁴  Soumya Raychaudhuri⁵  Miguel A. González-Gay⁶  Javier Martín⁷  Ana Márquez⁷  Martin Kerick⁷  Luis Rodriguez-Rodriguez⁸  Isidoro González-Álvaro⁹  Raquel Rios-Fernández^1,10  Javier Gutierrez-Achury^1,11 

[1]

[2]Center for Public Health Genomics, University of Virginia

[3]Department of Genetics, University of Groningen, University Medical Centre Groningen

[4]Division of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center-Houston

[5]Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School

[6]Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, IDIVAL

[7]Instituto de Parasitología y Biomedicina “López-Neyra”, CSIC, PTS Granada

[8]Rheumatology Service, Hospital Clinico San Carlos, IdiSSC

[9]Rheumatology Service, Hospital Universitario La Princesa, IIS-IP

[10]Systemic Autoimmune Diseases Unit, Complejo Hospitalario de Granada, Hospital Campus de la Salud

[11]Wellcome Trust Sanger Institute

关键词: Celiac disease;    Rheumatoid arthritis;    Systemic sclerosis;    Type 1 diabetes;    Cross-disease meta-analysis, Immunochip;    Autoimmune disease, functional enrichment analysis;   

DOI  :  10.1186/s13073-018-0604-8

来源: DOAJ

【 摘 要 】

Abstract Background In recent years, research has consistently proven the occurrence of genetic overlap across autoimmune diseases, which supports the existence of common pathogenic mechanisms in autoimmunity. The objective of this study was to further investigate this shared genetic component. Methods For this purpose, we performed a cross-disease meta-analysis of Immunochip data from 37,159 patients diagnosed with a seropositive autoimmune disease (11,489 celiac disease (CeD), 15,523 rheumatoid arthritis (RA), 3477 systemic sclerosis (SSc), and 6670 type 1 diabetes (T1D)) and 22,308 healthy controls of European origin using the R package ASSET. Results We identified 38 risk variants shared by at least two of the conditions analyzed, five of which represent new pleiotropic loci in autoimmunity. We also identified six novel genome-wide associations for the diseases studied. Cell-specific functional annotations and biological pathway enrichment analyses suggested that pleiotropic variants may act by deregulating gene expression in different subsets of T cells, especially Th17 and regulatory T cells. Finally, drug repositioning analysis evidenced several drugs that could represent promising candidates for CeD, RA, SSc, and T1D treatment. Conclusions In this study, we have been able to advance in the knowledge of the genetic overlap existing in autoimmunity, thus shedding light on common molecular mechanisms of disease and suggesting novel drug targets that could be explored for the treatment of the autoimmune diseases studied.

【 授权许可】

Unknown