Genome‐Wide Association Study of Dermatomyositis Reveals Genetic Overlap With Other Autoimmune Disorders

Abstract

Objective To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1178) and controls (n = 4724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Results Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5x10−8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that three SNPs linked with three genes were associated with DM, with a false discovery rate (FDR) < 0.05. These genes were phospholipase C like 1 (PLCL1, rs6738825, FDR=0.00089), B lymphoid tyrosine kinase (BLK, rs2736340, FDR=0.00031), and chemokine (C-C motif) ligand 21 (CCL21, rs951005, FDR=0.0076). None of these genes was previously reported to be associated with DM. Conclusion Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.

Inflammatory myopathy: diagnosis and clinical course, specific clinical scenarios and new complementary tools

“…This is also true for genetic studies. In fact, the first genome-wide association study in patients with inflammatory myopathy [78] was completed thanks to a genetic biorepository shared by different centers and countries. This project will certainly enhance our understanding of the pathogenesis of myositis and will probably help to define new diagnostic and therapeutic approaches for these patients.…”

Emerging Vitamin D Receptor-Centered Patterns of Genetic Overlap across Some Autoimmune Diseases and Associated Cancers

“…They are among human homologue candidates of DAF-12/vitamin D receptor (VDR) target genes [2,7,8,12]. However, Miller et al reporting on GWAS of Dermatomyositis (DM), found a genetic overlap with other ADs, as the first genetic predispositions towards ADs shared with DM [13]. The latest case is rpc-1 responsible for both the scleroderma and cancer [14].…”

“…The latest case is rpc-1 responsible for both the scleroderma and cancer [14]. Moreover, other patterns of genetic overlap across ADs have emerged [13,15]. Likely, a malfunction of VDR could affect the pathogenesis of RA and associated cancers expanding to many other ADs, Paraneoplastic Neurological Diseases(PND) and DM (Table 1) [1,13,14,16,[17][18][19][20][21][22][23][24].…”

Genotyping of immune-related genetic variants identifiesTYK2as a novel associated locus for idiopathic inflammatory myopathies

“…A Myositis Genetics Consortium dermatomyositis (DM) GWAS also suggests genetic overlap with other autoimmune disorders. 1 We sought to extend these findings to identify novel genetic risk factors in a large cohort of adult/juvenile patients with DM and polymyositis (PM), by genotyping immune-related single nucleotide polymorphisms (SNPs) not captured through the DM GWAS. 1 …”

“…2 Unique SNPs were identified (n=233), of which 99 had not been directly genotyped or captured (r 2 ≥0.8 with genotyped SNPs) through our DM GWAS. 1 These 99 SNPs were genotyped using Sequenom in 1001 European Caucasian individuals with definite/probable adult or juvenile DM or PM. 34 Eighty-three SNPs passed quality control.…”