Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes

Miller, Frederick W.; Chen, W; O’Hanlon, Terrance P.; Cooper, Robert G.; Vencovský, Jiří; Rider, Lisa G.; Dankó, Katalin; Wedderburn, Lucy R.; Lundberg, Ingrid E.; Pachman, Lauren M.; Reed, Ann M.; Ytterberg, Steven R.; Padyukov, Leonid; Selva-O’Callaghan, Albert; Radstake, Timothy R. D. J.; Isenberg, David; Chinoy, Hector; Ollier, William; Scheet, Paul; Peng, Bo; Lee, A; Byun, Jinyoung; Lamb, Janine A.; Gregersen, Peter K.; Amos, Christopher I.

doi:10.1038/gene.2015.28

Cited by 112 publications

(93 citation statements)

References 46 publications

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“…Recently, two large HLA imputation studies confirmed that HLA‐DRB1*03:01 and HLA‐B*08:01 , two alleles inherited together on the 8.1 AH, are strongly associated with MSs . Nevertheless, authors reported contrasting results when analyzed HLA alleles according to specific autoimmune phenotype.…”

Section: The 81 Ah and Aidsmentioning

confidence: 99%

Autoimmune diseases and 8.1 ancestral haplotype: An update

Gambino

Aiello

Accardi

et al. 2018

HLA

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The aim of the present review is to provide an update of the current research into the pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype. This is a common Caucasoid haplotype carried by most people who type for HLA-B8, DR3. Numerous genetic studies reported that individuals with certain HLA alleles have a higher risk of specific autoimmune disorders than those without these alleles. However, much remains to be learned about the heritability of autoimmune conditions. Recently, progress and advances in the field of genome-wide-association studies have revolutionized the capacity to perform large, economically feasible, and statistically robust analyses of HLA within 8.1 ancestral haplotype, and understand its contribute to autoimmune events. In this paper, the characteristic features of this haplotype that might give rise to diverse autoimmune phenotypes are reviewed, focusing on the contribution of the HLA-DRB1 gene, the most polymorphic sequence within the HLA II region.

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Section: The 81 Ah and Aidsmentioning

confidence: 99%

Autoimmune diseases and 8.1 ancestral haplotype: An update

Gambino

Aiello

Accardi

et al. 2018

HLA

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“…We enrolled 6270 control subjects without history of autoimmune diseases (mean age, 57.0±13.8 years; female, 48.2%) through the Biobank project 20. The European subjects (21 CADM cases) were recruited as part of an international myositis genetics consortium (MYOGEN),17 and four controls for each case (84 controls) were matched for ethnicity using principal components analysis (PCA) coordinates 21…”

Section: Methodsmentioning

confidence: 99%

Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis

et al. 2018

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Objectives Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis (PM), dermatomyositis (DM), and clinically amyopathic DM (CADM), we performed the first genome-wide association study (GWAS) for IIM in an Asian population.Methods We genotyped and tested 496,819 SNPs for association using 576 IIM patients and 6,270 control subjects. We also examined the causal mechanism of disease associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. ResultsWe identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; odds ratio (OR)=3.87; P=1.5×10 Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9, and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis, to a greater extent in the tr-WDFY4-transfected cells.Conclusions As CADM is characterized by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.

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“…98 MHC SNPs have also been strongly associated with disease susceptibility in patients with poly- and dermatomyositis, as have risk loci at PLCL1, BLK and CCL21 . 99,100 Substantial overlap in risk loci exists between the aforementioned CTDs and patients with Sjogren's syndrome (SS), which can result in several types of lung pathology, including ILD. In a GWAS of patients with SS, risk loci were again identified within MHC genes, along with IRF5, BLK and STAT5 .…”

Section: Disease-specific Pharmacogenetic Biomarkersmentioning

confidence: 99%

Pharmacogenetics and interstitial lung disease

Oldham

Noth

Martínez

2016

Current Opinion in Pulmonary Medicine

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Purpose of review Interstitial lung disease (ILD) is comprised of a heterogeneous group of disorders with highly variable natural histories and response to therapies. Pharmacogenetics focuses on the variability in drug response due to the presence of genetic factors that influence drug metabolism or disease activity. In this article, we review relevant drug-specific and disease-specific polymorphisms that may influence therapeutic response, and then highlight a recently identified drug-gene interaction in patients with idiopathic pulmonary fibrosis (IPF). Recent findings The emergence of high-throughput genomic technology has allowed for identification of gene polymorphisms associated with susceptibility to specific disease states, including IPF and several connective tissue diseases known to cause ILD. IPF risk loci span a diverse group of genes, while most associated with CTD are critical to immune signaling. A recent pharmacogenetic analysis of patients enrolled in an IPF clinical trial identified a variant within TOLLIP to be associated with differential response to N-acetylcysteine therapy. Summary Though few pharmacogenetic investigations have been conducted in patients with ILD to date, ample opportunities for pharmacogenetic exploration exist in this patient population. Such exploration will advance our understanding of specific ILDs and help usher in an era of personalized medicine.

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Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes

Cited by 112 publications

References 46 publications

Autoimmune diseases and 8.1 ancestral haplotype: An update

Autoimmune diseases and 8.1 ancestral haplotype: An update

Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis

Pharmacogenetics and interstitial lung disease

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