http://informahealthcare.com/aut ISSN: 0891-6934 (print), 1607-842X (electronic) Autoimmunity, 2014; 47(6): 372–377 ! 2014 Informa UK Ltd. DOI: 10.3109/08916934.2014.910769

ORIGINAL ARTICLE

Association between TLR1 polymorphisms and alopecia areata Hosik Seok1, Dong Woo Suh2, Byungchul Jo1, Hwang-Bin Lee1, Hyang Mi Jang3, Hun Kuk Park3, Bark-Lynn Lew2, Joo-Ho Chung1, and Woo-Young Sim2 1

Department of Pharmacology and Kohwang Medical Research Institute, College of Medicine, Kyung Hee University, Seoul, Republic of Korea, Department of Dermatology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea, and 3Department of Biomedical Engineering, College of Medicine, Kyung Hee University, Seoul, Republic of Korea

Autoimmunity Downloaded from informahealthcare.com by University of Bristol on 02/25/15 For personal use only.

2

Abstract

Keywords

Toll-like receptors (TLRs) may contribute to the process of autoimmune attacks on hair follicles. To investigate whether the TLR1 gene polymorphisms are associated with the development and clinical features of alopecia areata (AA), a case-control comparison of two single nucleotide polymorphisms (SNPs) (rs4833095, Asn248Ser and rs5743557, 414C4T) of TLR1 were studied in 239 AA patients and 248 controls. Using multiple logistic regression model, odds ratios, 95% confidence intervals and corresponding p values were estimated. Clinical features were analyzed based on the age of onset, family history, type of AA, nail involvement and body hair involvement. The missense SNP rs4833095 was significantly associated with the development of AA (codominant2, p ¼ 0.002; recessive, p ¼ 0.001; log-additive, p ¼ 0.0071; and allele frequency, p ¼ 0.0066). The promoter SNP rs5743557 was weakly associated with the development of AA (codominant2, p ¼ 0.019; recessive, p ¼ 0.032; log-additive, p ¼ 0.020; and allele frequency, p ¼ 0.03). In the clinical features, rs4833095 was only weakly associated with age of onset between 15 and 50 years (codominant2, p ¼ 0.043 and recessive, p ¼ 0.022). The results suggest that rs4833095 of TLR1 may be associated with the susceptibility for AA in the Korean population.

Alopecia areata, single nucleotide polymorphisms, TLR1

Introduction Alopecia areata (AA) shows interesting features of autoimmune disease, characterized by various size and shapes of nonscarring and inflammatory hair loss lesions on the scalp and body [1]. AA lesions typically involve the presence of inflammatory infiltrates, such as CD4 + and CD8 + T lymphocytes, macrophages and Langerhans cells, and the infiltrates around hair follicles are suggested to be participating autoimmune attacks [2]. Hair follicles are normally protected from immunologic attacks because expression of human leukocyte antigen (HLA) class I, II and ICAM-1 molecules are absent in them; however, their expression is increased in AA [3,4]. In studies of AA etiology, genetic factors for AA have been considered important [5]. Genome-wide association studies (GWAS) suspected many genes of HLA-region; however, genes outside the HLA-region, including SPATA5, interleukin (IL)_2 and IL-21 were associated with AA [6,7]. Furthermore, IL17A and IL17RA polymorphisms are associated with the

Correspondence: Joo-Ho Chung, Department of Pharmacology and Kohwang Medical Research Institute, College of Medicine, Kyung Hee University, 26 Kyung hee-daero, Dongdaemun-gu, Seoul 130-701, Republic of Korea. E-mail: [email protected] Woo-Young Sim, Department of Dermatology, College of Medicine, Kyung Hee University, 26 Kyung hee-daero, Dongdaemun-gu, Seoul 130-701, Republic of Korea. E-mail: [email protected]

History Received 16 December 2013 Revised 2 February 2014 Accepted 30 March 2014 Published online 29 April 2014

development of AA [8]. Such genes may modulate the activities of NK cells in AA [9]. In addition, other genes outside HLA region were associated with other dermatologic manifestations of autoimmune diseases. The autoimmune regulator gene polymorphism may confer susceptibility to vitiligo [10], PTPN22, NCF2, STAT4, SLC15A4, NLRP1, and many other genes were associated with systemic lupus erythematosus (SLE) [11–13], and single nucleotide polymorphisms (SNPs) of IL12B and IL23R were associated with psoriasis [14]. Including such diseases, dermatologic manifestations of autoimmune reactions may be triggered by the functions of the Toll-like receptor genes (TLRs) [15]. TLRs are expressed by epithelial cells, endothelial cells and leukocytes, and they play a role in the binding of pathogens and endogenous molecules produced in inflammations [16]. Each of TLRs are associated with different molecules; however, TLR1 is the most expressed molecule among TLRs, which functions in the heterodimerized forms with other TLRs [15,17,18]. Action of TLR2 requires TLR1 [19], and TLR2 may play a role in the maturation of dendritic cells with TLR7 [20]. TLR7 also triggers IL10 productions in B cells [21], which is associated with susceptibility to AA [22]. Polymorphisms in TLR1 may affect the development of autoimmune skin inflammations including CD4 + and CD8 + T cell pathophysiology in leprosy [23–25], and cutaneous lichen planus [26]. Such features are the major disease features of AA [2]; however, there has been

TLR1 SNPs and alopecia areata

DOI: 10.3109/08916934.2014.910769

few studies reported whether the association between TLR1 and AA. Therefore, we investigated whether TLR1 SNPs were associated with AA cases and controls in a Korean population.

Materials and methods

Autoimmunity Downloaded from informahealthcare.com by University of Bristol on 02/25/15 For personal use only.

Patients and controls Two-hundred thirty-nine AA patients (109 men and 129 women, 28.5 ± 13.4 years, mean ± SD) (Table 1) were enrolled in this study. Two-hundred forty-eight controls (105 men and 143 women, 32.9 ± 9.2 years) (Table 1) were recruited from healthy participants in the general health checkup program. Informed consent was obtained from all individuals. This study was conducted according to the guidelines of the Helsinki Declaration and was approved by the Institutional Review Board of Kyung Hee University Hospital at Gangdong. Clinical subtypes of AA patients For the clinical phenotypes, age of onset, family history of AA, type of AA, nail involvement and body hair involvement were analyzed in the AA case group (Table 1). The age of onset was divided into a group of patients with onset age between 15 and 50 years and other group of else. Type of AA was divided into a group was patchy type AA patients, and other group of alopecia totalis (AT) and alopecia universalis (AU). Nail involvement and body hair involvement were divided each into negative finding group and positive finding group (Table 1). SNP selection and genotyping SNPs in the coding region or 50 near gene region (promoter) of TLR1 with a minor allele frequency40.05, and with allele frequency data of Asian populations were searched in dbSNP Table 1. The demographic and clinical characteristics of controls and alopecia areata (AA) patients. Controls Percentage Number of subjects 248 Age (mean ± SD) 32.9 ± 9.2 Sex Male 105 Female 143 Age of onset 530 years 30 years 15 years and 50 years 515 years or 450 years Family history (+) () Type Patch Totalis or universalis Nail involvement (+) () Body hair involvement (+) () SD: standard deviations.

AA

Percentage

373

137 of the NCBI database (http://www.ncbi.nlm.nih.gov/ SNP). There was only one missense SNP rs4833095 (Asn248Ser) found under these conditions. In the promoter region, rs56357984 and rs5743557, rs5743556, rs5743553 and rs45588337 were near promoter SNPs; however, rs5743557 was selected for use in this study because rs5743557 was used in a previous TLR1 polymorphism study in the Korean population with IgA nephropathy (IgAN) [27], which is also an autoimmune disease, and rs5743557 has the most detailed Asian frequency data (http://www. ncbi.nlm.nih.gov/SNP). Genomic DNA was extracted from peripheral blood with a genomic DNA Isolation Kit (Roche, Indianapolis, IN) and amplified by PCR using the following primers (rs4833095: sense 50 -CACTGAGAGTCTGCACATTGTG-30 , antisense 50 TAGACAAGGCCTTCAAGGAAGT-30 , 347 bp; rs2275913: sense 50 -CAGTGGAAAAAAATTCAGCACC-30 , antisense 50 -CTGTGGGTTACCTGATAGGCCT-30 , 401 bp). The PCR products were genotyped by direct sequencing. Statistical analysis SNPStats (http://bioinfo.iconcologia.net/index.php) [28] and SPSS 20.0 software (SPSS Inc., Chicago, IL) were used in the statistical analysis. A linkage disequilibrium (LD) block of polymorphisms was tested using Haploview 4.2 (http://www.broadinstitute.org/scientific-community/science/ programs/medical-and-population-genetics/haploview/haplo view) [29]. Multiple logistic regression models [Codominant1 (major allele homozygotes vs. heterozygotes), codominant2 (major allele homozygotes vs. minor allele homozygotes), dominant (major allele homozygotes vs. heterozygotes + minor allele homozygotes), recessive (major allele homozygotes + heterozygotes vs. minor allele homozygotes) and log-additive (major allele homozygotes vs. heterozygotes vs. minor allele homozygotes, with r-fold risk for subjects with heterozygotes and 2r-fold for subjects with minor allele homozygotes) [30,31] were calculated for the odds ratios (ORs), 95% confidence intervals (CIs) and corresponding p values, using age and sex as covariables. Sample power for each SNPs was estimated with the Genetic Power Calculator

238 28.5 ± 13.4 42.3 57.7

109 129

45.8 54.2

162 77 158 80

67.8 32.2 66.4 33.6

19 219

8.0 92.0

166 73

69.5 30.5

35 203

14.7 85.3

37 201

15.5 84.5 Figure 1. The linkage disequilibrium block consisted of rs4833095 and rs5743557.

374

H. Seok et al.

Autoimmunity, 2014; 47(6): 372–377

(http://pngu.mgh.harvard.edu/~purcell/gpc/cc2.html) to assess the required sample size.

Results

Autoimmunity Downloaded from informahealthcare.com by University of Bristol on 02/25/15 For personal use only.

Assessment of TLR1 SNPs rs4833095 and rs2275913 with the development of AA The genotype frequencies of the two tested SNPs (rs4833095 and rs5743557) from the study populations were within the range of the Hardy–Weinberg equilibrium test (p40.05, data not shown). Table 2 presents the genotype and allele frequency for the control group and AA group. For rs4833095, the frequency of CC, CT and TT genotypes were 34.7%, 45.2% and 20.2% in the control group and 40.5%, 50.2% and 9.3% in the AA group. For rs5743557, the frequency of CC, CT and TT genotypes were 30.2%, 50.4% and 19.4% in the control group and 23.2%, 50.2% and 26.6% in the AA group. In the genotype analyses of the missense SNP rs4833095 (Table 2), the TT genotype was associated with a decreased risk for AA, compared to the CC genotype (codominant2, p ¼ 0.002, OR ¼ 0.39, 95% CI ¼ 0.22–0.71). The TT genotype was associated more strongly with a decreased risk for AA, compared to the CC and CT genotype (recessive, p ¼ 0.001, OR ¼ 0.41, 95% CI ¼ 0.24–0.71). In the log-additive model comparing the CC, CT and TT genotypes, the number of T alleles correlated with a decrease in AA risk (log-additive, p ¼ 0.0071, OR ¼ 0.69, 95% CI ¼ 0.53–0.91). The differences in allelic frequencies were significant, and the C allele showed increased risk for the development of AA, compared to the T allele (p ¼ 0.0066, OR ¼ 1.43, 95% CI ¼ 1.10–1.86). The promoter SNP rs5743557 showed that the TT genotype was weakly associated with an increased risk for AA, compared to the CC genotype (codominant2, p ¼ 0.019, OR ¼ 1.87, 95% CI ¼ 1.11–3.17). The TT genotype was also slightly associated with an increased risk for AA, compared to the CC and the CT genotype (recessive, p ¼ 0.032, OR ¼ 1.61, 95% CI ¼ 1.04–2.50). In the log-additive model, the number of T alleles was weakly correlated with an increase in AA risk (log-additive, p ¼ 0.020, OR ¼ 1.36, 95% CI ¼ 1.05–1.77).

The differences in allelic frequencies were weak; however, the T allele was associated with an increased risk for the development of AA, compared to the C allele (p ¼ 0.03, OR ¼ 1.32, 95% CI ¼ 1.03–1.70) (Table 2). The LD was calculated between rs4833095 and rs5743557; however, LD block was not strongly formed in the result (D0 ¼ 0.876 by the CIs, 0.881 by the solid spine of LD, Figure 1). Haplotype frequencies are listed in Table 3. The frequencies of CT, TC, CC and TT haplotypes were 0.457, 0.364, 0.157 and 0.022, respectively. The TC haplotype differed between the control and AA groups (p ¼ 0.0081). These results suggest that the haplotype that consisted of rs4833095 and rs5743557 may be associated with the development of AA. The sample power for each SNP (a ¼ 0.05, genotype relative risk ¼ two-fold, N of case for 80% power) was 0.881 for rs4833095 (N ¼ 188) and 0.742 for rs5743557 (N ¼ 272). These values indicate that the number of cases used in this study was sufficient to assess the effect of the missense SNP rs4833095 on AA. Assessment of TLR1 SNPs rs4833095 and rs2275913 with the onset age of AA Table 4 shows the result of analysis for the two groups divided based on the age of onset. One group represents an age of onset between 15 and 50 years, and other group represents the age of onset as age younger than 15 years or older than 50 years. For rs4833095, the frequencies of CC, CT and TT genotypes were 46.5%, 50.7% and 2.8% in the control group and 38.1%, 49.4% and 12.5% in the AA group. For rs5743557, the frequencies of TT, CT and CC genotypes were 32.4%, 49.3% and 18.3%, respectively, in the control group and 24.4%, 50.0% and 25.6%, respectively, in the AA group. In the genotype analyses of the missense SNP rs4833095 (Table 4), the TT genotype was marginally associated with an age of onset between 15 and 50 years compared to the CC genotype (codominant2, OR ¼ 4.93, 95% CI ¼ 1.05–23.04, p ¼ 0.043). Analyses based on the other clinical features of the patient group, such as family history, type of AA (AA, AU or AT),

Table 2. The genotypes and allele frequencies of TLR1 polymorphisms in controls and alopecia areata (AA) patients. Controls

AA

n (%)

n (%)

Model

ORa

95% CIa

pb

C/C C/T T/T

86 (34.7%) 112 (45.2%) 50 (20.2%)

96 (40.5%) 119 (50.2%) 22 (9.3%)

Codominant1 Codominant2 Dominant Recessive Log-additive

0.93 0.39 0.76 0.41 0.69

0.62–1.38 0.22–0.71 0.52–1.11 0.24–0.71 0.53–0.91

0.71 0.0020 0.16 0.0010 0.0071

T C C/C C/T T/T

212 284 75 125 48

163 313 55 119 63

Allele Codominant1 Codominant2 Dominant Recessive Log-additive

1.43 1.26 1.87 1.42 1.61 1.36

1.10–1.86 0.81–1.95 1.11–3.17 0.94–2.15 1.04–2.50 1.05–1.77

0.0066 0.30 0.019 0.09 0.032 0.020

C T

275 (55.4%) 221 (44.6%)

Allele

1.32

1.03–1.70

0.030

SNP rs4833095 Asn248Ser

rs5743557 414C4T

(42.7%) (57.3%) (30.2%) (50.4%) (19.4%)

(34.2%) (65.8%) (23.2%) (50.2%) (26.6%)

231 (48.5%) 245 (51.5%)

TLR1: toll-like receptor 1; OR: odds ratio; and CI: confidence interval. a The ORs, 95% CIs and p values were calculated from logistic regression analyses after adjusting for sex and age. b Bold numbers indicate statistically significant associations.

TLR1 SNPs and alopecia areata

DOI: 10.3109/08916934.2014.910769

375

Table 3. Haplotype analysis of TLR1 SNPs in controls and alopecia areata (AA) patients. Control Haplotype CT TC CC TT

AA

Frequency

+



+



Chi Square

pa

0.457 0.364 0.157 0.022

209.3 200.3 74.7 11.7

286.7 295.7 421.3 484.3

235.3 153.3 77.7 9.7

240.7 322.7 398.3 466.3

5.124 7.016 0.293 0.117

0.024 0.0081 0.59 0.73

TLR1: toll-like receptor 1. a Bold numbers indicate statistically significant associations. Table 4. The genotypes and allele frequencies of TLR1 polymorphisms in the groups based on age of onset of alopecia areata (AA).

Autoimmunity Downloaded from informahealthcare.com by University of Bristol on 02/25/15 For personal use only.

SNP rs4833095 Asn248Ser

rs5743557 414C4T

C/C C/T T/T C T T/T C/T C/C T C

Age of onset 515 or 450 years

Age of onset 15 and 50 years

n (%)

n (%)

Model

ORa

95% CIa

pb

pFc

33 (46.5%) 36 (50.7%) 2 (2.8%)

61 (38.1%) 79 (49.4%) 20 (12.5%)

Codominant1 Codominant2 Dominant Recessive Log-additive

1.19 4.93 1.41 4.47 1.58

0.64–2.23 1.05–23.04 0.77–2.60 0.99–20.16 0.96–2.59

0.58 0.043 0.27 0.022 0.07

0.50

Allele Codominant1 Codominant2 Dominant Recessive Log-additive

1.49 1.52 1.82 1.61 1.40 1.36

0.97–2.30 0.75–3.09 0.77–4.33 0.83–3.13 0.67–2.93 0.88–2.10

0.07 0.65 0.17 0.16 0.37 0.16

Allele

1.38

0.93–2.05

0.11

102 40 23 35 13

(71.8%) (28.2%) (32.4%) (49.3%) (18.3%)

81 (57.0%) 61 (43.0%)

203 119 39 80 41

(63.0%) (37.0%) (24.4%) (50.0%) (25.6%)

158 (49.1%) 164 (50.9%)

TLR1: toll-like receptor 1; OR: odds ratio; CI: confidence interval; pF: Fisher’s exact p value. The ORs, 95% CIs and p values were calculated from logistic regression analyses after adjusting for sex and age. b Bold numbers indicate statistically significant associations. c Fisher’s exact p value was calculated for the model contains any cell with n  5. a

nail involvement and body hair involvement were done; however, genotype and allele frequency of tested two SNPs of TLR1 were not associated with these clinical features (data not shown).

Discussion TLR polymorphisms are related to the function of APCs such as Langerhans cell and HLA-II recognition by CD4 + T cells [32,33], and may contribute to the development of autoimmune diseases via functional on/off of molecular binding or excessive signaling [32]. TLRs have endogeneous molecule-recognizing properties, including heat shock proteins, hyaluronan, HMGB1 and other inflammatory pathway products [32,34]. Such endogeneous inflammatory pathway products are part of damage-associated molecular patterns [34], therefore, TLR pathways may be activated by the products of systemic autoimmune reactions, such as dermatologic manifestations in SLE [12,35], scleroderma [36], malignant melanoma [37], vitiligo [38] and cutaneous lichen planus [39]. Heterogeneous recognizing functions of each TLRs other than TLR1 may be affected by TLR1 [34]. TLR1 is the most expressed type of TLRs, which may form heterodimers with other TLRs [32]. TLR2 forms heterodimer with TLR1 or TLR6 to activate T cell signals, and the signal is an important factor for sterile inflammation [19]. It was also shown that

TLR1 and TLR2 expression may together have role in cutaneous lichen planus [26], which shows chronic T cellmediated autoimmune skin pathology. Besides, TLR1 and TLR2 are suggested to regulate pro-inflammatory cytokine production and autoinflammatory tissue reactions in cartilage degradation [40]. TLR2 SNP Arg753Gln is associated with vitiligo [38]. Autoantigenic target of AA and vitiligo includes melanocyte [41]. Immune cells and cytokines affecting each disease are similar, and they were reported to share common genetic backgrounds [42], although association between TLR1 and vitiligo is still obscure. Furthermore, a recent GWAS indicated that an exonic SNP rs117033348 of TLR1 is associated with AU in Korean alopecia patients [43]; however, they did not indicate the SNPs in our study, and there was no other previous study reported association between TLR1 or TLR2 and AA. Focusing on the tested SNPs of this study, rs4833095 and rs5743557 were significantly associated with the onset of AA (p  0.0071 and p  0.032, respectively; Table 2), and the TC haplotype was significantly associated with the development of AA (p ¼ 0.081; Table 4). rs4833095 was further associated with onset age of AA (p ¼ 0.043 in codominant2; Table 4). There have been previous studies reported that missense SNP rs4833095 is related to autoimmunity, such as leprosy [23–25], atopic features [44], sepsis [45] and IgAN [27]. The genotype of rs4833095 (Asn248Ser, N248S) was previously reported to be associated with responses to leprosy [23] and

Autoimmunity Downloaded from informahealthcare.com by University of Bristol on 02/25/15 For personal use only.

376

H. Seok et al.

immune regulatory function in peripheral blood mononuclear cells in bacterial infection, and they suggested that 248S shows different molecular dynamic structure from 248N [24]. Interestingly, rs4833095was associated with serologic antiHelicobacter pylori IgG positivity in GWAS meta-analysis [46]; however, they did not indicate rs4833095 as their main result, because rs4833095 was also associated with significant changes of TLR1 mRNA expression, which may cause therapeutic failures [46]. Another GWAS has indicated rs4833095, which among the SNPs in a closely related complex of TLR10/TLR1/TLR6 on chromosome 4, may strongly affect TLR1- and TLR2-mediated responses [47]. In the study of atopic features in neonates [44], the authors found that regulatory T cell markers may be modified by TLR1 SNP rs4833095. Moreover, the two SNPs (rs4833095 and rs5743557) in our study were also significantly associated with mortality in patients with severe sepsis [45]. In addition, IgAN may be contributed from rs4833095genotype, as shown in Korean children [27]; however, rs5743557was previously shown weak association with IgAN in Korean children; however, the association was not significant after Bonferroni’s correction [27]. The above-mentioned studies, with our study, suggest that the C allele of rs4833095 may confer increased risks for immunologic responses in AA when compared to the T allele of rs4833095. In Table 4, an onset age group between 15 and 50 years is for the common type and onset age of AA [48], and another group of the others is for pediatric [49] and late onset AA [50]. It was shown in previous study that AA patient group with onset age between 15 and 50 may manifest similar disease courses, such as disease duration, recurs and location and types of AA lesions [48], while pediatric or late-onset AA may differ in the course of disease [49,50]. Association between rs4833095 and these groups suggest that TLR1 genotypes of AA patients may be related to different disease courses; however, the associations were weak in this study (p ¼ 0.032 in codominant2 and p ¼ 0.022 in recessive; Table 4). In conclusion, these results suggest that the missense SNP rs4833095 of TLR1 may be associated with susceptibility for AA in the Korean population. This study has limitation that only common SNPs in Korean population were tested. Therefore, future studies in larger samples or other populations will be needed to confirm our results.

Declaration of interest There was no conflict of interest declared by any author. This work was supported by a grant of KyungHee University (KHU-20121738).

References 1. Alexis, A. F., R. Dudda-Subramanya, and A. A. Sinha. 2004. Alopecia areata: autoimmune basis of hair loss. Eur. J. Dermatol. 14: 364–370. 2. Perret, C., L. Wiesner-Menzel, and R. Happle. 1984. Immunohistochemical analysis of T-cell subsets in the peribulbar and intrabulbar infiltrates of alopecia areata. Acta Derm. Venereol. 64: 26–30. 3. Bystryn, J. C., and J. Tamesis. 1991. Immunologic aspects of hair loss. J. Invest. Dermatol. 96: 88S–89S.

Autoimmunity, 2014; 47(6): 372–377

4. Messenger, A. G., and S. S. Bleehen. 1985. Expression of HLA-DR by anagen hair follicles in alopecia areata. J. Invest. Dermatol. 85: 569–572. 5. Green, J., and R. D. Sinclair. 2000. Genetics of alopecia areata. Australas J. Dermatol. 41: 213–218. 6. Forstbauer, L. M., F. F. Brockschmidt, V. Moskvina, et al. 2012. Genome-wide pooling approach identifies SPATA5 as a new susceptibility locus for alopecia areata. Eur. J. Hum. Genet. 20: 326–332. 7. Petukhova, L., M. Duvic, M. Hordinsky, et al. 2010. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature. 466: 113–117. 8. Lew, B. L., H. R. Cho, S. Haw, et al. 2012. Association between IL17A/IL17RA gene polymorphisms and susceptibility to alopecia areata in the Korean population. Ann. Dermatol. 24: 61–65. 9. Zakka, L. R., E. Fradkov, D. B. Keskin, et al. 2012. The role of natural killer cells in autoimmune blistering diseases. Autoimmunity. 45: 44–54. 10. Tazi-Ahnini, R., A. J. McDonagh, D. A. Wengraf, et al. 2008. The autoimmune regulator gene (AIRE) is strongly associated with vitiligo. Br. J. Dermatol. 159: 591–596. 11. Bucala, R. 2013. MIF, MIF alleles, and prospects for therapeutic intervention in autoimmunity. J. Clin. Immunol. 33(Suppl 1): S72–S78. 12. Cui, Y., Y. Sheng, and X. Zhang. 2013. Genetic susceptibility to SLE: recent progress from GWAS. J. Autoimmun. 41: 25–33. 13. Pontillo, A., M. Girardelli, A. J. Kamada, et al. 2012. Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus. Autoimmunity. 45: 271–278. 14. Oka, A., T. Mabuchi, S. Ikeda, et al. 2013. IL12B and IL23R gene SNPs in Japanese psoriasis. Immunogenetics. 65: 823–828. 15. Li, J., X. Wang, F. Zhang, and H. Yin. 2013. Toll-like receptors as therapeutic targets for autoimmune connective tissue diseases. Pharmacol Ther. 138: 441–451. 16. Huebener, P., and R. F. Schwabe. 2013. Regulation of wound healing and organ fibrosis by toll-like receptors. Biochim. Biophys. Acta. 1832: 1005–1017. 17. Fekonja, O., M. Avbelj, and R. Jerala. 2012. Suppression of TLR signaling by targeting TIR domain-containing proteins. Curr. Protein Pept. Sci. 13: 776–788. 18. Santegoets, K. C., L. van Bon, W. B. van den Berg, et al. 2011. Toll-like receptors in rheumatic diseases: are we paying a high price for our defense against bugs? FEBS Lett. 585: 3660–3666. 19. van Bergenhenegouwen, J., T. S. Plantinga, L. A. Joosten, et al. 2013. TLR2 & Co: a critical analysis of the complex interactions between TLR2 and coreceptors. J. Leukoc. Biol. 94: 885–902. 20. Sanchez-Quintero, M. J., M. J. Torres, A. B. Blazquez, et al. 2013. Synergistic effect between amoxicillin and TLR ligands on dendritic cells from amoxicillin-delayed allergic patients. PLoS One. 8: e74198. 21. Georg, P., and I. Bekeredjian-Ding. 2012. Plasmacytoid dendritic cells control B cell-derived IL-10 production. Autoimmunity. 45: 579–583. 22. Freyschmidt-Paul, P., K. J. McElwee, R. Happle, et al. 2002. Interleukin-10-deficient mice are less susceptible to the induction of alopecia areata. J. Invest. Dermatol. 119: 980–982. 23. Schuring, R. P., L. Hamann, W. R. Faber, et al. 2009. Polymorphism N248S in the human Toll-like receptor 1 gene is related to leprosy and leprosy reactions. J. Infect. Dis. 199: 1816–1819. 24. Marques Cde, S., V. N. Brito-de-Souza, L. T. Guerreiro, et al. 2013. Toll-like receptor 1 N248S single-nucleotide polymorphism is associated with leprosy risk and regulates immune activation during mycobacterial infection. J. Infect. Dis. 208: 120–129. 25. Boisseau-Garsaud, A. M., G. Vezon, R. Helenon, et al. 2000. High prevalence of vitiligo in lepromatous leprosy. Int. J. Dermatol. 39: 837–839. 26. Rashtak, S., and M. R. Pittelkow. 2008. Skin involvement in systemic autoimmune diseases. Curr. Dir. Autoimmun. 10: 344–358. 27. Lee, J. S., H. K. Park, J. S. Suh, et al. 2011. Toll-like receptor 1 gene polymorphisms in childhood IgA nephropathy: a case-control study in the Korean population. Int. J. Immunogenet. 38: 133–138.

TLR1 SNPs and alopecia areata

Autoimmunity Downloaded from informahealthcare.com by University of Bristol on 02/25/15 For personal use only.

DOI: 10.3109/08916934.2014.910769

28. Sole, X., E. Guino, J. Valls, et al. 2006. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 22: 1928–1929. 29. Barrett, J. C., B. Fry, J. Maller, and M. J. Daly. 2005. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 21: 263–265. 30. Kim, S. K., H. J. Park, H. Seok, et al. 2013. Missense polymorphisms in XIAP-associated factor-1 (XAF1) and risk of papillary thyroid cancer: correlation with clinicopathological features. Anticancer Res. 33: 2205–2210. 31. Park, H. J., S. K. Kim, J. W. Kim, et al. 2013. Involvement of fibroblast growth factor receptor genes in benign prostate hyperplasia in a Korean population. Dis. Markers. 35: 869–875. 32. Brown, J., H. Wang, G. N. Hajishengallis, and M. Martin. 2011. TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. J. Dent. Res. 90: 417–427. 33. Omueti, K. O., D. J. Mazur, K. S. Thompson, et al. 2007. The polymorphism P315L of human toll-like receptor 1 impairs innate immune sensing of microbial cell wall components. J. Immunol. 178: 6387–6394. 34. Piccinini, A. M., and K. S. Midwood. 2010. DAMPening inflammation by modulating TLR signalling. Mediators Inflamm. 2010: 672395 (1–21). 35. Perl, A. 2010. Pathogenic mechanisms in systemic lupus erythematosus. Autoimmunity. 43: 1–6. 36. Farina, A., M. Cirone, M. York, et al. 2014. Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblastmyofibroblast conversion in scleroderma. J. Invest. Dermatol. 134: 954–964. 37. Gast, A., J. L. Bermejo, R. Claus, et al. 2011. Association of inherited variation in Toll-like receptor genes with malignant melanoma susceptibility and survival. PLoS One. 6: e24370. 38. Karaca, N., G. Ozturk, B. T. Gerceker, et al. 2013. TLR2 and TLR4 gene polymorphisms in Turkish vitiligo patients. J. Eur. Acad. Dermatol. Venereol. 27: e85–e90. 39. Salem, S. A., R. M. Abu-Zeid, and O. H. Nada. 2013. Immunohistochemical study of Toll-like receptors 1 and 2

40.

41. 42. 43.

44.

45.

46.

47.

48. 49.

50.

377

expression in cutaneous lichen planus lesions. Arch. Dermatol. Res. 305: 125–131. Sillat, T., G. Barreto, P. Clarijs, et al. 2013. Toll-like receptors in human chondrocytes and osteoarthritic cartilage. Acta Orthop. 84: 585–592. Randall, V. A. 2001. Is alopecia areata an autoimmune disease? Lancet. 358: 1922–1924. Harris, J. E. 2013. Vitiligo and alopecia areata: apples and oranges? Exp. Dermatol. 22: 785–789. Lee, S., S. H. Paik, H. J. Kim, et al. 2013. Exomic sequencing of immune-related genes reveals novel candidate variants associated with alopecia universalis. PLoS One. 8: e53613. Liu, J., D. Radler, S. Illi, et al. 2011. TLR2 polymorphisms influence neonatal regulatory T cells depending on maternal atopy. Allergy. 66: 1020–1029. Thompson, C. M., T. D. Holden, G. Rona, et al. 2014. Toll-like receptor 1 polymorphisms and associated outcomes in sepsis after traumatic injury: a candidate gene association study. Ann. Surg. 259: 179–185. Mayerle, J., C. M. den Hoed, C. Schurmann, et al. 2013. Identification of genetic loci associated with Helicobacter pylori serologic status. JAMA. 309: 1912–1920. Mikacenic, C., A. P. Reiner, T. D. Holden, et al. 2013. Variation in the TLR10/TLR1/TLR6 locus is the major genetic determinant of interindividual difference in TLR1/2-mediated responses. Genes. Immun. 14: 52–57. Ikeda, T. 1965. A new classification of alopecia areata. Dermatologica. 131: 421–445. Sarifakioglu, E., A. E. Yilmaz, C. Gorpelioglu, and E. Orun. 2012. Prevalence of scalp disorders and hair loss in children. Cutis. 90: 225–229. Wu, M. C., C. C. Yang, R. Y. Tsai, and W. C. Chen. 2013. Late-onset alopecia areata: a retrospective study of 73 patients from Taiwan. J. Eur. Acad. Dermatol. Venereol. 27: 468–472.

Association between TLR1 polymorphisms and alopecia areata.

Toll-like receptors (TLRs) may contribute to the process of autoimmune attacks on hair follicles. To investigate whether the TLR1 gene polymorphisms a...
208KB Sizes 0 Downloads 3 Views