GLIS3 and TYK2 Single Nucleotide Polymorphisms Are Not Associated with Dermatomyositis/Polymyositis in Chinese Han Population

Abstract

Aim:

Racial differences and genetic overlap have been shown to be responsible for the difference in susceptibility to dermatomyositis (DM)/polymyositis (PM) in a variety of populations. Single nucleotide polymorphisms (SNPs) in the GLI-similar 3 (GLIS3) and tyrosine kinase 2 (TYK2) genes have been associated with various autoimmune diseases. The aim of this study was to investigate whether SNPs in GLIS3 (rs7020673, rs10758593, and rs10814916) and TYK2 (rs280519, rs2304256, rs17000730, and rs280501) were associated with an increase in susceptibility to DM/PM in a Chinese Han population.

Materials and Methods:

SNPs in GLIS3 and TYK2 were analyzed in a cohort of 1017 patients with DM/PM and 1280 healthy controls using a Sequenom MassArray system. Association analyses were performed using the PLINK v1.07 software.

Results:

In our study, the GLIS3 polymorphisms rs7020673 and rs10758593 were initially found to be predisposing risk factors for PM and PM with interstitial lung disease (p < 0.05). Both rs7020673 and rs10758593 were associated with PM in both additive and dominant models (p < 0.05); however, these observed associations were not apparent after Bonferroni correction. Other SNPs examined in our study were not associated with susceptibility to DM/PM.

Conclusion:

GLIS3 and TYK2 polymorphisms are not associated with DM/PM in the Chinese Han population. As associations of SNPs in these genes in patients with DM/PM have been previously reported in other populations, we may conclude that the lack of association in our study may be the result of differences in genetic background. Further studies in other populations are needed to confirm our findings.

Introduction

Dermatomyositis (DM) and polymyositis (PM) are two main subgroups of idiopathic inflammatory myopathies, characterized by skeletal involvement, and inflammatory cell infiltrates in muscle biopsies (Bohan and Peter, 1975a, 1975b; Callen, 2000). DM/PM primarily affects striated muscle, leading to proximal muscle weakness. Other organs, in particular the lungs, may also be affected (Marie et al., 2001, 2002, 2011; Fathi et al., 2004; Chen et al., 2009). Interstitial lung disease (ILD) is a common pulmonary complication in DM/PM, which results in increased morbidity and mortality (Marie et al., 2002, 2011). Although environmental factors such as injectable cosmetic collagen (Cukier et al., 1993), ultraviolet radiation (Okada et al., 2003), and genetic risk factors, such as the human leukocyte antigen (HLA) 8.1 ancestral haplotype (Miller et al., 2015), phospholipase C-like 1 (PLCL1), B lymphoid tyrosine kinase (BLK), chemokine (C-C motif) ligand 21 (CCL21) (Miller et al., 2013), human leukocyte antigen-DP beta 1 (HLA-DPB1), prolactin induced protein (PIP), and carboxypeptidase N subunit 1 (CPN1) (Zhang et al., 2016), have been shown to augment susceptibility to DM/PM, the pathogenesis of DM/PM remains elusive. A genome-wide association study (GWAS) performed by Miller et al. (2013) has indicated that DM has a genetic overlap in nonmajor histocompatibility complex single nucleotide polymorphisms (SNPs), which are also associated with type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and other autoimmune diseases (Miller et al., 2013). Collectively these findings suggest that SNPs that are associated with other autoimmune diseases may also be related to DM/PM.

The influence of genetic background on DM/PM in the Chinese Han population is poorly understood. Considering the influence of genetic overlap, we hypothesized that SNPs in GLI-similar 3 (GLIS3) and tyrosine kinase 2 (TYK2) genes may be associated with an increased susceptibility to DM/PM. Indeed, previous studies have shown that GLIS3 rs7020673 was associated with an increased susceptibility to T1D (Barrett et al., 2009) and RA (Kiani et al., 2015a). In addition, an association of this SNP with DM has been reported in European populations (Miller et al., 2013; Jani et al., 2014). Nevertheless, association with DM/PM in Chinese Han population has not been previously examined. Furthermore, GLIS3 rs10758593 has been associated with T1D (Bradfield et al., 2011) and type 2 diabetes (T2D) (Morris et al., 2012), while GLIS3 rs10814916 has been associated with T2D (Li et al., 2013). TYK2 rs280519 and rs2304256 have been associated with Crohn's disease (Sato et al., 2009), and rs2304256 has also been reported as a predisposing risk factor for SLE (Sigurdsson et al., 2005; Tang et al., 2015), RA (Kiani et al., 2015a), and T1D (Wallace et al., 2010), as well as DM in a European population (Jani et al., 2014). However, its possible association with DM/PM has not been previously examined in the Chinese Han population. TYK2 rs280501 has not been reported to be associated with SLE (Sigurdsson et al., 2005) or any other condition. To our knowledge, the association of TYK2 rs17000730 with any autoimmune diseases has not been studied to date. A detailed association between these six SNPs and disease susceptibility is presented in Supplementary Table S1 (Supplementary Data are available online at www.liebertpub.com/gtmb).

Based on these previous findings, we performed the first case-control study examining the association between GLIS3 (rs7020673, rs10758593, and rs10814916) and TYK2 (rs280519, rs2304256, rs17000730, and rs280501) polymorphisms with susceptibility to DM/PM in the Chinese Han population.

Materials and Methods

Study populations

Peripheral blood samples from 569 patients with DM/PM and 1280 healthy controls were collected by the Rheumatology Department of Peking Union Medical College Hospital, and 448 DM/PM patients were recruited from multiple medical centers in China (Table 1). Exclusion criteria for healthy controls included a significant history of disease or abnormal biochemical and immunological profiles. ILD in patients was identified with high-resolution chest computed tomography. All participants were unrelated individuals of Han Chinese ethnicity and signed informed consent. The recruited DM/PM patients were diagnosed according to the Bohan and Peter criteria (Bohan and Peter, 1975a). This study was approved by the ethics committee of Peking Union Medical College Hospital.

Table 1.

Demographics and Clinical Features of Samples

	Cases	Controls
	Total (N = 1017)	Total (N = 1280)
Mean age ± SD	46.1 ± 15.2	41.8 ± 12.7
Gender, male/female	261/756	165/1115
DM, n (%)	654 (64.3)
PM, n (%)	363 (35.7)
ILD, n (%)	585 (57.5)
DM with ILD, n (%)	390 (38.3)
PM with ILD, n (%)	195 (19.2)

DM, dermatomyositis; ILD, interstitial lung disease; PM, polymyositis; SD, standard deviation.

DNA extraction and genotyping

Genomic DNA from each participant was extracted using genomic DNA kits (Tiangen, Beijing, China). SNP genotyping was conducted using Sequenom MassArray system (San Diego, CA) according to the manufacturer's instructions. Primers for multiplex polymerase chain reaction (PCR) and locus-specific extension were designed by MassArray Assay Design 4.0 software (Sequenom). Briefly, 10-20 ng of genomic DNA was amplified by multiplex PCR and the products were subjected to locus-specific single-base extension reaction. The final products were desalted and dispensed onto a 384-element Spectro CHIP array. Allele detection was performed using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Finally, the mass spectrograms and genotypes were analyzed by the MassArray Typer v4.0 (Sequenom).

Statistical analysis for association

The χ² test was applied to analyze the Hardy-Weinberg equilibrium (HWE) of each SNP in healthy controls. SNPs that deviated from HWE (pc < 0.05) were excluded from subsequent analysis. PLINK v1.07 (Shaun Purcell, Boston, MA) was used to compare allele and genotype frequencies between patients and controls (Skol et al., 2006). Three logistic regression models (additive, dominant, and recessive) were used to analyze genotype frequencies. The odds ratio (OR) and confidence interval (95% CI) were calculated. pc < 0.05 (a p value after Bonferroni correction) was regarded to be statistically significant.

Results

Patients' characteristics

Our study included 1017 DM/PM patients (DM: n = 654; PM: n = 363; mean age ± standard deviation [SD]: 46.1 ± 15.2; 261 males and 756 females) as well as 1280 normal controls (mean age ± SD: 41.8 ± 12.7; 165 males and 1115 females) (Table 1). Of the 1017 patients included in the study, 585 subjects had ILD (DM-ILD: n = 390; PM-ILD: n = 195).

SNP allele and genotype analysis in DM/PM cases and controls

DNA of all subjects included in the study was genotyped for seven selected SNPs and the results are presented in Table 2. Among the seven SNPs genotyped, TYK2 rs2304256 deviated from the HWE in the healthy controls (pc < 0.001) and was therefore excluded from further analysis. Six SNPs, including GLIS3 rs7020673, rs10758593, and rs10814916 as well as TYK2 rs280519, rs17000730, and rs280501, did not deviate from the HWE in the controls (pc > 0.05). The genotype call rate of each selected SNP was >96%.

Table 2.

The Information of Seven Single Nucleotide Polymorphisms

Gene	SNP	Chromosome	Position	Function class	Allele	MAF in CHB (dbSNP)	MAF	p	pc for HWE	Call rate (%)
GLIS3	rs7020673	9	4291747	Intron	G > C	0.415	0.452	0.2582	NS	99.80
GLIS3	rs10758593	9	4292083	Intron	A > G	0.463	0.392	0.9529	NS	99.80
GLIS3	rs10814916	9	4293150	Intron	C > A	0.415	0.432	0.4588	NS	100.00
TYK2	rs280519	19	10362257	Intron	G > A	0.427	0.474	0.4322	NS	99.41
TYK2	rs2304256	19	10364976	NA	C > A	0.427	0.413	5.27 × 10⁻⁶	3.69 × 10⁻⁵	92.63
TYK2	rs17000730	19	10380572	NA	A > G	NA	0.037	0.456	NS	96.46
TYK2	rs280501	19	10380646	NA	C > T	0.088	0.033	1	NS	99.71

Bold values indicate statistical significance (pc <0.05), the information was gathered from dbSNP database in NCBI.

CHB, Han Chinese in Beijing, China; HWE, Hardy-Weinberg equilibrium; MAF, minor allele frequency; NA, not available; NS, not significant, pc, p value corrected by Bonferroni method; SNPs, single nucleotide polymorphisms.

Three GLIS3 SNPs (rs7020673, rs10758593, and rs10814916) and three TYK2 SNPs (rs280519, rs17000730, and rs280501) were genotyped in 1017 DM/PM patients and 1280 healthy controls. Allele and genotype frequencies are presented in Table 3. In the GLIS3 region, allele frequencies of rs7020673 and rs10758593 showed associations with PM (p = 0.031, OR = 1.20, 95% CI: 1.02-1.42; p = 0.033, OR = 1.20, 95% CI: 1.02-1.42; respectively), while rs7020673 and rs10758593 genotype frequencies showed a trend for association with PM (p = 0.053; p = 0.075, respectively). Both the rs7020673 minor allele (G) and rs10758593 minor allele (A) were more frequent in PM patients than in controls (rs7020673-G: 49.31% in PM vs. 44.77% in controls; rs10758593-A: 42.94% in PM vs. 38.54% in controls). However, the observed associations of rs7020673 and rs10758593 with PM were not apparent following Bonferroni correction. In addition, the remaining GLIS3 SNP (rs10814916) and three TYK2 SNPs (rs280519, rs17000730, and rs280501) showed no significant association with DM/PM (p > 0.05).

Table 3.

Allele and Genotype Frequencies of the Six Single Nucleotide Polymorphisms in Dermatomyositis/Polymyositis Patients and Healthy Controls

Gene	SNP	Groups	Allele (%)		OR (95% CI)	p	pc	Genotype (%)			χ2	p	pc
GLIS3	rs7020673		G	C				GG	GC	CC
		DM	573	735	0.96 (0.84-1.10)	0.57	NS	131	311	212	2.29	0.319	NS
		PM	356	366	1.20 (1.02-1.42)	0.031	0.186	79	198	84	5.88	0.053	0.318
		DM/PM	929	1101	1.04 (0.93-1.17)	0.5	NS	210	509	296	0.77	0.681	NS
		Controls	1146	1414				246	654	380
GLIS3	rs10758593		A	G				AA	AG	GG
		DM	503	805	1.00 (0.87-1.14)	0.961	NS	104	295	255	1.07	0.587	NS
		PM	310	412	1.20 (1.02-1.42)	0.033	0.198	62	186	113	5.18	0.075	0.45
		DM/PM	813	1217	1.07 (0.95-1.20)	0.297	NS	166	481	368	1.22	0.543	NS
		Controls	985	1571				189	607	482
GLIS3	rs10814916		C	A				CC	CA	AA
		DM	552	756	0.97 (0.85-1.11)	0.668	NS	117	318	219	0.45	0.8	NS
		PM	335	391	1.14 (0.97-1.34)	0.123	0.738	71	193	99	3.06	0.217	NS
		DM/PM	1098	1406	1.03 (0.91-1.16)	0.642	NS	188	511	318	0.22	0.895	NS
		Controls	1098	1460				229	640	410
TYK2	rs280519		A	G				AA	AG	GG
		DM	630	670	1.06 (0.93-1.21)	0.374	NS	149	332	169	1.63	0.442	NS
		PM	341	381	1.01 (0.86-1.19)	0.894	NS	86	169	106	0.44	0.803	NS
		DM/PM	971	1051	1.04 (0.93-1.17)	0.471	NS	235	501	275	0.64	0.728	NS
		Controls	1201	1357				289	623	367
TYK2	rs17000730		C	T				CC	CT	TT
		DM	40	1214	0.79 (0.54-1.14)	0.201	NS	0	40	587	NA	NA	NA
		PM	23	685	0.80 (0.51-1.27)	0.342	NS	0	23	331	NA	NA	NA
		DM/PM	63	1899	0.79 (0.57-1.09)	0.149	0.894	0	63	918	NA	NA	NA
		Controls	103	2455				3	97	1179
TYK2	rs280501		T	C				TT	TC	CC
		DM	48	1258	1.25 (0.86-1.80)	0.24	NS	0	48	605	NA	NA	NA
		PM	27	695	1.27 (0.81-1.98)	0.296	NS	0	27	334	NA	NA	NA
		DM/PM	75	1953	1.25 (0.91-1.74)	0.171	NS	0	75	939	NA	NA	NA
		Controls	76	2482				1	1278

Bold values indicate statistical significance (p < 0.05).

CI, confidence interval; OR, odds ratio; χ², chi-square test.

Logistic regression analysis

Three genetic models (additive, dominant, and recessive) were used to analyze six SNPs in DM/PM patients, and the results are summarized in Table 4. In brief, GLIS3 rs7020673 was associated with PM in additive and dominant models (p = 0.027, OR = 1.21, 95% CI: 1.02-1.44; p = 0.017, OR = 1.39, 95% CI: 1.06-1.83; respectively). Similarly, GLIS3 rs10758593 was significantly associated with PM in additive and dominant models (p = 0.032, OR = 1.20, 95% CI: 1.02-1.43; p = 0.026, OR = 1.33, 95% CI: 1.04-1.71; respectively). However, there was no statistically significant difference after Bonferroni corrections of data were performed. The remaining GLIS3 SNP (rs10814916) and three TYK2 SNPs (rs280519, rs17000730, and rs280501) did not show association with DM/PM in these three logistic regression models (p > 0.05).

Table 4.

Analysis of the Six Single Nucleotide Polymorphisms Based on Additive, Dominant, and Recessive Model

				Additive model			Dominant model			Recessive model
Gene	SNP	Allele	Group	p	pc	OR (95% CI)	p	pc	OR (95% CI)	p	pc	OR (95% CI)
GLIS3	rs7020673	G	DM	0.568	NS	0.96 (0.84-1.10)	0.218	NS	0.88 (0.72-1.08)	0.67	NS	1.05 (0.83-1.33)
			PM	0.027	0.162	1.21 (1.02-1.44)	0.017	0.102	1.39 (1.06-1.83)	0.262	NS	1.05 (0.83-1.33)
			DM/PM	0.495	NS	1.04 (0.93-1.17)	0.784	NS	1.03 (0.86-1.23)	0.381	NS	1.10 (0.89-1.35)
GLIS3	rs10758593	A	DM	0.961	NS	1.00 (0.87-1.14)	0.585	NS	0.95 (0.78-1.15)	0.519	NS	1.09 (0.84-1.41)
			PM	0.032	0.192	1.20 (1.02-1.43)	0.026	0.156	1.33 (1.04-1.71)	0.267	NS	1.09 (0.84-1.41)
			DM/PM	0.299	NS	1.07 (0.95-1.20)	0.473	NS	1.07 (0.90-1.26)	0.303	NS	1.13 (0.90-1.41)
GLIS3	rs10814916	C	DM	0.665	NS	0.97 (0.85-1.11)	0.526	NS	0.94 (0.77-1.15)	0.994	NS	1.00 (0.78-1.28)
			PM	0.117	0.702	1.14 (0.97-1.35)	0.082	0.492	1.26 (0.97-1.63)	0.472	NS	1.00 (0.78-1.28)
			DM/PM	0.638	NS	1.03 (0.91-1.16)	0.687	NS	1.04 (0.87-1.24)	0.72	NS	1.04 (0.84-1.29)
TYK2	rs280519	A	DM	0.376	NS	1.06 (0.93-1.21)	0.212	NS	1.15 (0.93-1.42)	0.871	NS	1.02 (0.81-1.28)
			PM	0.896	NS	1.01 (0.86-1.19)	0.804	NS	0.97 (0.75-1.25)	0.624	NS	1.02 (0.81-1.28)
			DM/PM	0.475	NS	1.04 (0.93-1.17)	0.43	NS	1.08 (0.90-1.30)	0.714	NS	1.04 (0.85-1.26)
TYK2	rs17000730	C	DM	0.204	NS	0.79 (0.54-1.14)	0.259	NS	0.80 (0.55-1.18)	NA	NA	NA
			PM	0.345	NS	0.80 (0.51-1.27)	0.405	NS	0.82 (0.51-1.31)	NA	NA	NA
			DM/PM	0.149	0.894	0.79 (0.57-1.09)	0.204	NS	0.81 (0.58-1.12)	NA	NA	NA
TYK2	rs280501	T	DM	0.237	NS	1.25 (0.86-1.81)	0.206	NS	1.27 (0.88-1.85)	NA	NA	NA
			PM	0.294	NS	1.27 (0.81-2.00)	0.263	NS	1.30 (0.82-2.05)	NA	NA	NA
			DM/PM	0.167	NS	1.26 (0.91-1.75)	0.141	0.846	1.28 (0.92-1.79)	NA	NA	NA

Bold values indicate statistical significance (p < 0.05)

Associations between SNPs and patients with ILD and without ILD

Six GLIS3 and TYK2 SNPs were genotyped in 390 DM-ILD, 195 PM-ILD, and 1280 healthy controls. In our study, we compared the frequencies of analyzed SNPs in patients with ILD with those in patients without ILD, as well as in patients with ILD compared with healthy controls. In addition, we examined the frequencies of analyzed SNPs in patients without ILD with healthy controls in DM, PM, and DM/PM groups, respectively. According to our results, PM-ILD was associated with GLIS3 rs7020673 (p = 0.027, OR = 1.27, 95% CI: 1.03-1.58) as well as GLIS3 rs10758593 (p = 0.024, OR = 1.28, 95% CI: 1.03-1.59), as shown in Table 5. However, none of the observed associations retained statistical significance after Bonferroni correction of analyzed data. No statistically significant association was found between the remaining GLIS3 SNP (rs10814916) and three TYK2 SNPs (rs280519, rs17000730, and rs280501) and patient groups (p > 0.05).

Table 5.

Association of the Six Single Nucleotide Polymorphisms and Dermatomyositis/Polymyositis Patients with Interstitial Lung Disease

		rs7020673 (GLIS3)			rs10758593 (GLIS3)			rs10814916 (GLIS3)			rs280519 (TYK2)			rs17000730 (TYK2)			rs280501 (TYK2)
Disease	Group	p	pc	OR (95% CI)	p	pc	OR (95% CI)	p	pc	OR (95% CI)	p	pc	OR (95% CI)	p	pc	OR (95% CI)	p	pc	OR (95% CI)
DM	P versus N	0.518	NS	0.93 (0.74-1.16)	0.912	NS	0.99 (0.79-1.24)	0.984	NS	1.00 (0.80-1.25)	0.563	NS	0.94 (0.75-1.17)	0.248	NS	0.69 (0.37-1.30)	0.674	NS	1.14 (0.63-2.06)
	P versus C	0.406	NS	0.93 (0.79-1.10)	0.919	NS	0.99 (0.84-1.17)	0.713	NS	0.97 (0.82-1.14)	0.679	NS	1.04 (0.88-1.22)	0.096	0.576	0.66 (0.41-1.08)	0.218	NS	1.31 (0.85-2.01)
	N versus C	0.96	NS	1.01 (0.83-1.21)	0.966	NS	1.00 (0.83-1.22)	0.771	NS	0.97 (0.80-1.18)	0.299	NS	1.11 (0.92-1.33)	0.874	NS	0.96 (0.59-1.57)	0.594	NS	1.15 (0.68-1.94)
PM	P versus N	0.397	NS	1.14 (0.85-1.52)	0.345	NS	1.15 (0.86-1.55)	0.761	NS	1.05 (0.78-1.40)	0.963	NS	0.99 (0.74-1.33)	0.259	NS	1.64 (0.69-3.93)	0.864	NS	0.94 (0.43-2.02)
	P versus C	0.027	0.162	1.27 (1.03-1.58)	0.024	0.144	1.28 (1.03-1.59)	0.165	0.99	1.16 (0.94-1.44)	0.942	NS	1.01 (0.81-1.25)	0.942	NS	0.98 (0.56-1.70)	0.485	NS	1.23 (0.69-2.20)
	N versus C	0.323	NS	1.12 (0.89-1.41)	0.37	NS	1.11 (0.88-1.40)	0.364	NS	1.11 (0.88-1.40)	0.898	NS	1.02 (0.81-1.28)	0.159	0.954	0.60 (0.29-1.24)	0.37	NS	1.31 (0.72-2.39)
DM/PM	P versus N	0.885	NS	0.99 (0.83-1.18)	0.712	NS	1.03 (0.86-1.24)	0.944	NS	1.01 (0.84-1.20)	0.647	NS	0.96 (0.80-1.15)	0.816	NS	0.94 (0.57-1.56)	0.821	NS	1.06 (0.66-1.69)
	P versus C	0.625	NS	1.04 (0.90-1.19)	0.281	NS	1.08 (0.94-1.25)	0.668	NS	1.03 (0.90-1.19)	0.721	NS	1.03 (0.89-1.18)	0.189	NS	0.77 (0.52-1.14)	0.195	NS	1.28 (0.88-1.87)
	N versus C	0.546	NS	1.05 (0.90-1.23)	0.585	NS	1.05 (0.89-1.22)	0.76	NS	1.03 (0.88-1.20)	0.398	NS	1.07 (0.92-1.25)	0.353	NS	0.82 (0.53-1.25)	0.368	NS	1.22 (0.79-1.86)

Bold values indicate statistical significance (p < 0.05).

Group P, patients with ILD; Group N, patients without ILD; Group C, healthy controls, Group P (DM: n = 390, PM: n = 195, DM/PM: n = 585), Group N (DM: n = 264, PM: n = 168, DM/PM: n = 432), Group C (n = 1280).

Discussion

DM and PM are rare autoimmune diseases with unclear etiopathogenesis. Previous studies have indicated that autoimmune diseases share common genetic susceptibility factors (Miceli-Richard et al., 2007; Lill et al., 2013; Miller et al., 2013; Terao et al., 2013). GLIS3 is a member of the GLI-similar zinc finger protein family and encodes for a nuclear protein containing five C2H2-type zinc finger domains (Kim et al., 2003). The protein is expressed early during embryogenesis and functions as a repressor and activator of transcription (Kim et al., 2003; Beak et al., 2008). GLIS3 is a susceptibility locus relating to an increased risk of autoimmune diseases, such as T1D (Barrett et al., 2009; Bradfield et al., 2011; Kiani et al., 2015b) and RA (Kiani et al., 2015a). TYK2 belongs to the Janus kinase family and plays an important role in innate and adaptive immune mechanisms (Karaghiosoff et al., 2000; Liang et al., 2014). The protein functions as a critical mediator in signal transduction, in response to immunomodulatory cytokines, including type I interferons (IFNs), interleukin (IL)-6, IL-10, IL-12, and IL-23 (O'Shea and Plenge 2012; Sohn et al., 2013). In addition, it has also been shown in previous studies that TYK2 is a shared genetic risk factor among Crohn's disease (Sato et al., 2009), SLE (Sigurdsson et al., 2005; Tang et al., 2015), RA (Kiani et al., 2015a), and T1D (Wallace et al., 2010).

To explore the relationship between GLIS3 and TYK2 polymorphisms and genetic susceptibility to DM/PM, we examined the association of six GLIS3 and TYK2 polymorphisms with DM/PM in 1017 Chinese Han patients and 1280 healthy controls. GLIS3 SNPs (rs7020673 and rs10758593) as well as TYK2 rs280519 have been previously associated with a variety of autoimmune disorders (Supplementary Table S1), while GLIS3 rs10814916 and TYK2 rs17000730 and rs280501 have not been previously associated with autoimmune conditions. In this study, among the three GLIS3 SNPs (rs7020673, rs10758593, and rs10814916), no association with DM/PM risk was found after Bonferroni correction. A genotyping study of immune-related SNPs performed in 1149 European Caucasian DM/PM patients and 3572 healthy controls (Jani et al., 2014), as well as a study using GWAS performed in 1178 European DM patients and 4724 healthy controls (Miller et al., 2013), reached the same conclusion that rs7020673 was associated with susceptibility to DM (p = 0.002, p = 0.042, respectively). However, in our study, we were unable to demonstrate any association of this SNP with DM. The lack of association in our study may be due to different ethnic populations examined. Further studies in other Asian populations, such as Japanese or Korean patients, are needed to confirm our observation. In addition, TYK2 rs280519, rs17000730, and rs280501 were not associated with DM/PM in the Chinese Han population, which indicated there is most likely a degree of genetic heterogeneity between DM/PM and other autoimmune diseases. However, other TYK2 SNPs, which remain unidentified, may be involved in the development of DM/PM. Further studies should be performed to investigate the prevalence of other SNPs in TYK2, and their role in DM/PM.

Studies examining SNP associations in DM/PM patients in different populations may increase heterogeneity of outcomes due to differences in genetic background, while small sample sizes result in lower statistical power. To avoid this limitation, we performed a large-scale study in DM/PM patients from the Chinese Han population. To the best of our knowledge, this is the first study to investigate the association of GLIS3 (rs7020673, rs10758593, and rs10814916) and TYK2 (rs280519, rs17000730, and rs280501) polymorphisms with an increase in susceptibility to DM/PM. The limitation of our study is that it included the analysis of six selected GLIS3 and TYK2 SNPs, while the possible influence of other SNPs in these genes cannot be excluded. In addition, GLIS3 rs7020673 has previously been reported to be associated with DM in a European population; however, in our study, we were unable to demonstrate an association of this SNP with an increased susceptibility to DM in a Chinese Han population. Therefore, further studies are needed to examine the possible association of this SNP with DM in other Asian populations.

In conclusion, no association between GLIS3 (rs7020673, rs10758593, and rs10814916) and TYK2 (rs280519, rs17000730, and rs280501) polymorphisms and susceptibility to DM/PM was found. Further studies examining the possible association of rs7020673 with DM in other Asian ethnic groups are needed.

Footnotes

Acknowledgments

The authors thank all the participants for their cooperation. We also thank the other hospital staff who have helped us collect the blood samples and clinical data. This study is supported by funding from the Research Special Fund for Public Welfare Industry of Health (201202004), the National Natural Science Foundation of China Grants (81172857, 81373188), the Chinese National High Technology Research and Development Program, Ministry of Science and Technology Grants (2011AA02A113), the National Science Technology Pillar Program in the 12nd Five-year Plan (2014BAI07B00), and the Capital Health Research and Development of Special (2014-1-4011).

Author Disclosure Statement

No competing financial interests exist.

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