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. Author manuscript; available in PMC: 2015 Jun 18.
Published in final edited form as: Ann Rheum Dis. 2014 May 7;73(9):1750–1752. doi: 10.1136/annrheumdis-2014-205440

Genotyping of immune-related genetic variants identifies TYK2 as a novel associated locus for idiopathic inflammatory myopathies

M Jani 1, J Massey 1,2, L R Wedderburn 3, J Vencovský 4, K Danko 5, I E Lundberg 6, L Padyukov 6, A Selva-O’Callaghan 7, T Radstake 8, H Platt 9, R B Warren 2, C E Griffiths 2, A Lee 10, P K Gregersen 10, F W Miller 11, W E Ollier 9, R G Cooper 12, H Chinoy 1,9, J A Lamb 9; EUMYONET
PMCID: PMC4471138  EMSID: EMS63703  PMID: 24812289

Idiopathic inflammatory myopathies (IIMs) may present as a primary autoimmune disorder, or overlap with other autoimmune/connective tissue diseases. The aetiology of IIM likely includes interactions between genetic and environmental factors. Several genetic variants common to multiple autoimmune disorders have been identified in recent genome-wide association studies (GWAS). 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

SNPs significantly associated (p<5×10−8) with 10 autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, coeliac disease, Crohn’s disease, ulcerative colitis, psoriasis, type 1 diabetes, multiple sclerosis and systemic sclerosis) were identified from published GWAS or the National Human Genome Research Institute GWAS catalogue.2 Unique SNPs were identified (n=233), of which 99 had not been directly genotyped or captured (r2≥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.3,4 Eighty-three SNPs passed quality control. GWAS data2 were imputed to the 1000G_phase 1 integrated_v3 reference panel using IMPUTE2.5 Concordance rates were >98% for 444/1001 cases overlapping the GWAS data set. INFO scores for the 83 SNPs were >0.6. The 1001 Sequenom cases were merged with 168 unique cases from the GWAS. Samples with >5% missing data were excluded, resulting in 1149 cases and 3572 controls (table 1). Association tests were performed for the 83 SNPs in DM and PM subgroups including juvenile cases, and the overall IIM group (SNPTEST V.2.4.1). Imputed genotype uncertainty was accounted for using the ‘score’ method. A random-effects meta-analysis of the individual country data sets was performed (META V.1.5). Local research ethics committee approval and informed consent were obtained.

Table 1.

Polymyositis, dermatomyositis and matched control sample numbers included in the final analysis

Country DM cases
 PM cases
 Cases total Controls total
JDM DM DM total JPM PM PM total
1. Czech Republic 11 134 145 – 61 61 206 166
2. Hungary 14 71 85 2 79 81 166 90
3. Netherlands/Sweden 4 54 58 – 67 67 125 642
4. Spain 4 61 65 – – – 65 259
5. UK 183 203 386 6 195 201 587 2415
TOTAL 216 523 739 8 402 410 1149 3572
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DM, dermatomyositis; JDM, juvenile dermatomyositis; JPM, juvenile polymyositis; PM, polymyositis.

Outside the major histocompatibility complex (MHC), a non-synonymous SNP rs2304256 in TYK2 was identified reaching Bonferroni corrected significance in DM and the overall IIM group, but not in the PM subgroup (p=0.17) (table 2). TYK2 encodes a member of the Janus tyrosine kinase protein family, contributing to cytokine receptor signaling via its catalytic activity or kinase-independent scaffolding function, and may play a role in antiviral immunity. The associated SNP is predicted to be damaging to protein function using SIFT (Sorting Intolerant From Tolerant, a program that predicts whether an amino acid substitution affects protein function), but benign by Polyphen. rs2304256 is in the protein FERM (4.1 protein, ezrin, radixin, moesin) domain, which mediates interaction with Janus kinase and microtubule interacting protein 1, suggesting a possible increased interaction in DM cases. TYK2 has been associated with rheumatoid arthritis,6 juvenile idiopathic arthritis,7 systemic lupus erythematosus,8 type 1 diabetes9 and multiple sclerosis.10 Two SNPs 2335 bp 5′ of BLK (rs13277113) and within BLK (rs2618476) were associated with DM but not PM (table 2). These SNPs are highly correlated (r2>0.95, HapMap CEU) with rs2736340, 7.5 kb 5′ of BLK, supporting the previous DM GWAS results,1 and suggesting a role of B cells in development of DM. No non-MHC SNPs were associated with PM at a Bonferroni corrected significance level.

Table 2.

SNPs associated with dermatomyositis, polymyositis or IIM

Phenotype Chr SNP Position (hg19) Locus* p Value Risk/non-risk
allele		 RAF cases RAF controls β p Heterogeneity Disease association
for non-HLA SNPs3
DM 6 rs116152465 32603007 5′ HLA-DQA1 1.48542E-05 G/A 0.25667 0.20135 0.40 0.31
DM 19 rs2304256 10475652 TYK2 0.00020 C/A 0.75478 0.7067 −0.25 0.59 T1DM
DM 6 rs114424451 32413051 3′ HLA-DRA1 0.00021 G/A 0.91272 0.86887 0.34 0.99
DM 8 rs13277113 11349186 5′ BLK 0.00045 A/G 0.28098 0.24403 0.25 0.54 SLE
DM 8 rs2618476 11352541 BLK 0.00062 C/T 0.28903 0.25312 0.24 0.56 SLE
DM 9 rs7020673 4291747 GLIS3 0.0023 C/G 0.53583 0.49292 −0.18 0.64 T1DM
DM 5 rs6859219 55438580 ANKRD55 0.0023 C/A 0.82304 0.79178 −0.24 0.80 RA
DM 2 rs13385731 33701890 RASGRP3 0.0049 T/C 0.947972 0.928019 −0.38 0.67 SLE
DM 12 rs11171739 56470625 5′ ERBB3 0.0069 T/C 0.62421 0.57102 0.28 0.09 T1DM
DM 3 rs11712165 119118796 ARHGAP31 0.0071 G/T 0.40245 0.38066 0.16 0.85 Celiac
DM 2 rs10210302 234158839 5′ ATG16L1 0.0094 C/T 0.51259 0.46989 −0.17 0.36 Crohn’s
PM 6 rs116152465 32603007 5′ HLA-DQA1 0.00044 G/A 0.33252 0.20135 0.76 0.01
PM 6 rs114424451 32413051 3′ HLA-DRA1 0.0033 G/A 0.910976 0.86887 0.35 0.53
PM 6 rs615672 32574171 Intergenic (HLA-DRB1) 0.0035 C/G 0.51585 0.35732 0.52 0.01
PM 14 rs4900384 98498951 Intergenic (c14orf64) 0.0072 A/G 0.67073 0.71415 0.23 0.74 T1DM
IIM 6 rs114424451 32413051 3′ HLA-DRA1 9.09513E-06 G/A 0.912097 0.86887 0.35 0.88
IIM 6 rs116152465 32603007 5′ HLA-DQA1 1.04525E-05 G/A 0.28442 0.20135 0.51 0.06
IIM 19 rs2304256 10475652 TYK2 0.00027 C/A 0.74672 0.7067 −0.21 0.51 T1DM
IIM 12 rs11171739 56470625 5′ ERBB3 0.0054 T/C 0.62753 0.57102 0.30 0.02 T1DM
IIM 11 rs6590330 128311059 Intergenic (ETS1) 0.0064 A/G 0.12931 0.10279 0.22 0.65 SLE
IIM 17 rs7221109 38770286 Intergenic (SMARCE1) 0.0071 T/C 0.37882 0.34209 −0.15 0.44 T1DM
IIM 2 rs10210302 234158839 5′ ATG16L1 0.0071 C/T 0.50503 0.46989 −0.14 0.45 Crohn’s
IIM 8 rs13277113 11349186 5′ BLK 0.0077 A/G 0.27101 0.24403 0.21 0.24 SLE
IIM 3 rs11712165 119118796 ARHGAP31 0.0080 G/T 0.39723 0.38066 0.14 0.80 Celiac
IIM 8 rs2618476 11352541 BLK 0.0082 C/T 0.279 0.25312 0.20 0.27 SLE
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SNPs in bold reached Bonferroni significance.

*

Gene is annotated where closest gene is <10 kb, otherwise annotated as intergenic with closest gene in parentheses. Chr, chromosome; DM, dermatomyositis; HLA, human leukocyte antigen; IIM, idiopathic inflammatory myopathy; PM, polymyositis; p value, p value from random-effects meta-analysis; p heterogeneity, p value of test for heterogeneity; β, effect size (META V.1.5); RA, rheumatoid arthritis; RAF, risk allele frequency; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; T1DM, type 1 diabetes mellitus.

We have identified TYK2 as a novel associated locus for DM. This study confirms TYK2 as an autoimmune gene and suggests a genetic overlap of DM with other autoimmune disorders, indicating genetic heterogeneity between PM and DM, although the difference may be due to the smaller PM sample size. These results require replication in an independent cohort and functional studies of the pathogenic role of TYK2 in myositis. Our analysis supports the study of additional immune-related loci in larger cohorts, using SNP arrays such as the Immunochip.

Acknowledgements

The authors thank the other members of the EUMYONET and Myositis Genetics Consortium (MYOGEN) for their scientific and logistic support. A full list of investigators who contributed to the UK MYONET (Adult Onset Myositis Immunogenetic Collaboration) and JDM study can be found in Miller FW et al.1 This study also makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113.

Funding This work was funded by Arthritis Research UK grant 18474, in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, the European Science Foundation for EuMyoNet support and Association Francaise Contre Les Myopathies (AFM). The UK JDM Cohort and Biomarker study was supported by grants from the Wellcome Trust UK (085860), Action Medical Research UK, (SP4252), The Myositis Support Group UK, Arthritis Research UK (14518) and The Henry Smith Charity. The JDM Cohort study is adopted onto the Comprehensive Research Network through the Medicines for Children Research Network (http://www.mcrn.org.uk). The Czech cohort was supported by MH CZ-DRO Institute of Rheumatology 00023728.

Footnotes

Competing interests None.

Ethics approval Local ethics committees for each city.

Provenance and peer review Not commissioned; externally peer reviewed.

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