Medical genetics
Association between IL16 gene polymorphisms and susceptibility to alopecia areata in the Korean population Bark-Lynn Lew1, MD, Joo-Ho Chung2, MD, and Woo-Young Sim1, MD
1 Department of Dermatology, College of Medicine, Kyunghee University, and 2 Department of Pharmacology, College of Medicine, Kyunghee University, Seoul, South Korea
Abstract Background Alopecia areata (AA) is a chronic disease that presents as non-scarring hair loss. It is thought to be an organ-specific autoimmune disease characterized by T cell infiltrates and cytokine production around anagen-stage hair follicles. Interleukin-16 (IL-16) is a T cell-specific chemoattractant known to be associated with autoimmune disease.
Correspondence Woo-Young Sim, MD Department of Dermatology Kyunghee University Hospital at Gang-Dong 1 Sang-Il Dong Gang-Dong Gu Seoul 134-727 South Korea E-mail: [email protected] Funding: Kyung Hee University Research Fund in 2008 (KHU-20081563). Conflicts of interest: None.
Objectives This study was conducted to determine whether variation in the IL16 gene contributes to risk for AA in the Korean population. Methods A total of 270 control subjects and 229 AA patients were enrolled. Genomic DNA was prepared from peripheral blood. Four single nucleotide polymorphisms (SNPs) (rs17875486 [promoter], rs17875491 [promoter], rs11073001 [exon], rs1803275 [exon]) of the IL16 gene were selected. Genotypes were determined by direct sequencing. Sequence data were analyzed. Multiple logistic regression models were calculated. Results A significant difference emerged between the AA group and the control group for one SNP (rs17875491) of IL16. A further significant difference was found between patients with and without a family history of AA for a second SNP (rs11073001). Conclusions The present study found significant differences pertaining to two SNPs of the IL16 gene between, respectively, AA patients and controls (rs17875491) and AA patients with and without a family history of AA (rs11073001). Thus, IL16 polymorphisms may play a role in the pathophysiology of AA or in the expression of AA phenotypes. Further studies are required to elucidate the role of IL-16 in the pathogenesis and clinical manifestation of AA.
Introduction Alopecia areata (AA) is a common, chronic disease that presents as non-scarring hair loss. The pathogenesis of AA is not completely understood. However, AA is thought to be an organ-specific autoimmune disease characterized by T cell infiltrates and cytokine production around anagen-stage hair follicles. Interleukin-16 (IL-16) is a homotetramer discovered in 1982 as a T cell-specific chemoattractant factor. IL-16 plays a role in trafficking of several immune cells and may be a major chemotactic signal for CD4+ cells. IL-16 is also a potent chemoattractant for all peripheral immune cells expressing CD4, including CD4+ monocytes, eosinophils, and dendritic cells.1 Several reports have confirmed the association between IL-16 and autoimmune disease. Lee et al.2 established the first link between IL-16 and systemic lupus erythematosus (SLE), validating not only a significant increase in IL-16 protein levels in SLE patients but also a correlation of the IL-16 ª 2013 The International Society of Dermatology
protein level with disease severity. Tanyasiri et al.3 recently found IL-16 levels in AA patients to be significantly higher than those in normal individuals. The role of IL-16 in the pathogenesis of AA has not yet been studied; however, we suggest that IL-16 may be associated with AA as it is with other autoimmune diseases. The purpose of this study was to determine whether variation in the IL16 gene contributes to risk for AA in the Korean population. Materials and methods Study subjects Alopecia areata patients and control subjects were enrolled in this study. A total of 229 AA patients were enrolled. Patients were classified into two groups, according to the method described by a previous study.4 The early-onset group included patients who were aged 0.05). Genotypes were determined by direct sequencing. Genomic DNA was amplified using the following primers: rs17875486; rs17875491; rs11073001; and rs1803275. Samples were sequenced using an ABI Prism 3730XL Analyzer (Applied Biosystems, Inc., Foster City, CA, USA). Sequence data were analyzed using SeqManII software (DNASTAR, Inc., Madison, WI, USA). Statistical analysis Hardy–Weinberg equilibrium for two SNPs was assessed using SNPStats (http://bioinfo.iconcologia.net/index.php).5 A linkage disequilibrium (LD) block of polymorphisms was tested using Haploview Version 3.32.6 Multiple logistic regression models were calculated for odds ratios, 95% confidence intervals, and corresponding P-values, controlling for gender as a covariable. Calculations were made using SNPStats Helixtree software (Golden Helix, Inc., Bozeman, MT, USA) and SNPAnalyzer (ISTECH, Inc., Goyang, South Korea). International Journal of Dermatology 2014, 53, 319–322
Expression of IL16 polymorphisms according to clinical severity
There were no significant differences in expression of any SNPs of IL16 between patients with patch-type AA and those with alopecia universalis (AU) or alopecia totalis (AT). Further, there were no significant differences in the expression of any SNPs of IL16 according to body hair or nail involvement (data not shown).
Discussion Several studies of SNPs in AA have been reported. TaziAhnini et al.7 found a significant association between the rare allele (C961) of the AIRE polymorphism at position 961 and AA. This association is stronger and more significant in severe forms of the condition, such as AU. TaziAhnini et al.7 also examined two polymorphisms in the coding sequence of the Notch4 gene at positions +1297 and +3063 in a case–control study of 116 AA patients and 142 healthy control subjects. Polymorphisms within the MIF-173*C allele confer an increased risk for susceptibility to the extensive forms of AA, especially in patients with an early onset of disease. Therefore, macrophage migration inhibitory factor (MIF) is suggested to be closely implicated in the pathogenesis of the more extensive forms of AA.8 Polymorphisms of the IL17A gene and IL17RA gene were identified in our previous study.9 A significant difference between the AA patient group and the control group ª 2013 The International Society of Dermatology
ª 2013 The International Society of Dermatology
Promoter
Exon
Promoter
rs17875486
rs1803275
rs17875491
AA AG GG CC TC TT AA GA GG CC GC GG
Genotype 130 80 18 116 86 26 143 75 19 136 80 12
Cases, n 57.0 35.1 7.9 50.9 33.7 11.4 62.7 32.9 4.4 59.6 35.1 5.3
% 161 105 19 134 117 34 174 97 14 191 82 12
Controls, n 56.5 36.8 6.7 47.0 41.0 11.9 61.0 34.0 4.9 67.0 28.8 4.2
%
1.50 (1.08–2.07)
0.89 (0.68–1.17)
0.89 (0.68–1.17)
1.00 (0.75–1.34)
OR (95% CI)
Codominant
0.014
0.63
0.40
1.00
P-value
1.53 (1.04–2.25)
0.95 (0.65–1.39)
0.82 (0.56–1.18)
0.98 (0.68–1.42)
OR (95% CI)
Dominant
0.031
0.79
0.28
0.92
P-value
2.26 (0.93–5.50)
0.73 (0.31–1.73)
0.97 (0.54–1.73)
1.06 (0.53–2.13)
OR (95% CI)
Recessive
0.074
0.47
0.91
0.87
P-value
Promoter
Exon
Promoter
rs17875486
rs1803275
rs17875491
AA AG GG CC TC TT AA GA GG CC GC GG
Genotype 6 13 0 12 5 2 9 10 0 13 4 2
FHx+, n 31.6 68.4 0 63.2 26.3 10.5 47.4 52.6 0 68.4 21.1 10.5
% 124 67 18 104 81 24 134 65 10 123 76 10
FHx , n 59.3 32.1 8.6 49.8 38.8 11.5 64.1 31.1 4.8 58.9 36.4 4.8
%
0.91 (0.40–2.08)
1.38 (0.58–2.95)
0.71 (0.34–1.50)
1.52 (0.77–3.00)
OR (95% CI)
Codominant
0.83
0.41
0.36
0.24
P-value
0.67 (0.24–1.86)
2.41 (0.78–5.25)
0.57 (0.21–1.51)
3.17 (1.15–8.75)
OR (95% CI)
Dominant
0.43
0.15
0.25
0.02
P-value
2.55 (0.48–13.43)
2.02 (0.78–5.25)
0.89 (0.19–4.11)
0.00 (0.00–NA)
OR (95% CI)
Recessive
0.31
0.16
0.88
0.065
P-value
IL16 gene polymorphisms and alopecia areata
FHx, family history; OR, odds ratio; 95% CI, 95% confidence interval; SNP, single nucleotide polymorphism. P-values for logistic regression analyses of three models (codominant, dominant and recessive) for regression analyses are shown in four SNPs (rs17875486, rs17875491, rs11073001 and rs1803275).
Exon
rs11073001
Region
IL16
Table 3 Logistic regression analyses of IL16 polymorphisms in alopecia areata (AA) patients with and without a family history of AA
OR, odds ratio; 95% CI, 95% confidence interval; SNP, single nucleotide polymorphism. P-values for logistic regression analyses of three alternative models (codominant, dominant and recessive) for regression analyses are shown in four SNPs (rs17875486, rs17875491, rs11073001, and rs1803275).
Exon
rs11073001
Region
IL16
Table 2 Logistic regression analyses of IL16 polymorphisms in alopecia areata patients and normal control subjects
Lew et al. Medical genetics
International Journal of Dermatology 2014, 53, 319–322
321
322
Medical genetics
IL16 gene polymorphisms and alopecia areata
emerged for one SNP (rs879577) of IL17RA. Patients with early- and late-onset AA differed significantly for one SNP (rs4819554) of IL17RA. A single study has reported on the association between IL-16 and AA.3 Its authors classified AA into active AA and inactive AA.3 Active AA indicates the condition of active hair shedding as reflected in a positive hair pull test. Inactive AA indicates a condition without active hair shedding, in which the hair pull test is negative and exclamation point hair is absent. The IL-16 level of active AA patients was significantly higher than that in normal individuals or inactive AA patients, whereas no significant difference in IL-16 was observed between normal controls and inactive AA patients. In addition, a significant correlation was observed between HLA-DR expression by CD8+ T cells and IL-16 level in active AA patients. These results suggest that IL-16 may be a useful indicator of the activity of AA and that it may play an important role in the development of AA. Polymorphisms of the IL16 gene have been identified in a small number of epidemiologic studies. Among them, the IL16-295 SNP genotype may be a risk factor for several inflammatory disorders. In 2003, Glas et al.10 reported an association between the IL16-295 SNP and Crohn’s disease (CD). Subjects with CD had significantly higher T-allele and TT-genotype frequencies compared with control subjects. Reich et al.11 reported that the IL16-295 CC genotype was more common in subjects with polysensitized allergic contact dermatitis (ACD) than in healthy control subjects without ACD. In patients with SLE, individuals carrying the G allele of rs11556218, the C allele of rs4778889, and the T allele of rs4072111 are at a significantly higher risk for SLE compared with those carrying the T allele of rs11556218, the T allele of rs4778889, and the C allele of rs4072111, respectively.12 To the best of our knowledge, the present study represents the first investigation into the potential influence of IL16 gene polymorphisms in AA patients. This study found that expression of one SNP (rs17875491) of the IL16 gene located in the promoter region of chromosome 15q26.3 differed significantly between AA patients and healthy controls. In addition, a second SNP (rs11073001) of IL16 showed a significant difference in expression between patients with and without a family history of AA. We have demonstrated that IL16 polymorphisms may play a role in the pathophysiology of AA or in the
International Journal of Dermatology 2014, 53, 319–322
Lew et al.
expression of AA phenotypes. Further, expression of an rs11073001 polymorphism of IL16 may contribute to a familial tendency toward AA. Further studies are required to elucidate the role of IL-16 in the pathogenesis and clinical manifestation of AA. References 1 Kaser A, Dunzendorfer S, Offner FA, et al. A role for IL-16 in the cross-talk between dendritic cells and T cells. J Immunol 1999; 163: 3232–3238. 2 Lee S, Kaneko H, Sekigawa I, et al. Circulating interleukin-16 in systemic lupus erythematosus. Br J Rheumatol 1998; 37: 1334–1337. 3 Tanyasiri K, Hira K, Mitsuishi K, et al. Interleukin-16 in patients with alopecia areata. J Dermatol Sci 2005; 37: 55–57. 4 Colombe BW, Price VH, Khoury EL, et al. HLA class II antigen associations help to define two types of alopecia areata. J Am Acad Dermatol 1995; 33: 757–764. 5 Sole X, Guino E, Valls J, et al. SNPStats: a Web tool for the analysis of association studies. Bioinformatics 2006; 22: 1928–1929. 6 Barrett JC, Fry B, Maller J, et al. Haploview: analysis and visualization of linkage disequilibrium and haplotype maps. Bioinformatics 2005; 21: 263–265. 7 Tazi-Ahnini R, Cork MJ, Gawkrodger DJ, et al. Role of the autoimmune regulator (AIRE) gene in alopecia areata: strong association of a potentially functional AIRE polymorphism with alopecia universalis. Tissue Antigens 2002; 60: 489–495. 8 Shimizu T, Hizawa N, Honda A, et al. Promoter region polymorphism of macrophage migration inhibitory factor is strong risk factor for young onset of extensive alopecia areata. Genes Immun 2005; 6: 285–289. 9 Lew BL, Cho HR, Haw S, et al. Association between IL17A/IL17RA gene polymorphisms and susceptibility to alopecia areata in the Korean population. Ann Dermatol 2012; 24: 61–65. 10 Glas J, Torok HP, Unterhuber H, et al. The 295 T to C promoter polymorphism of the IL-16 gene is associated with Crohn’s disease. Clin Immunol 2003; 106: 197–200. 11 Reich K, Westphal G, Konig IR, et al. Association of allergic contact dermatitis with a promoter polymorphism in the IL16 gene. J Allergy Clin Immunol 2003; 112: 1191–1194. 12 Xue H, Gao L, Wu Y, et al. The IL-16 gene polymorphisms and the risk of the systemic lupus erythematosus. Clin Chim Acta 2009; 403: 223–225.
ª 2013 The International Society of Dermatology
Association between IL16 gene polymorphisms and susceptibility to alopecia areata in the Korean population Bark-Lynn Lew1, MD, Joo-Ho Chung2, MD, and Woo-Young Sim1, MD
1 Department of Dermatology, College of Medicine, Kyunghee University, and 2 Department of Pharmacology, College of Medicine, Kyunghee University, Seoul, South Korea
Abstract Background Alopecia areata (AA) is a chronic disease that presents as non-scarring hair loss. It is thought to be an organ-specific autoimmune disease characterized by T cell infiltrates and cytokine production around anagen-stage hair follicles. Interleukin-16 (IL-16) is a T cell-specific chemoattractant known to be associated with autoimmune disease.
Correspondence Woo-Young Sim, MD Department of Dermatology Kyunghee University Hospital at Gang-Dong 1 Sang-Il Dong Gang-Dong Gu Seoul 134-727 South Korea E-mail: [email protected] Funding: Kyung Hee University Research Fund in 2008 (KHU-20081563). Conflicts of interest: None.
Objectives This study was conducted to determine whether variation in the IL16 gene contributes to risk for AA in the Korean population. Methods A total of 270 control subjects and 229 AA patients were enrolled. Genomic DNA was prepared from peripheral blood. Four single nucleotide polymorphisms (SNPs) (rs17875486 [promoter], rs17875491 [promoter], rs11073001 [exon], rs1803275 [exon]) of the IL16 gene were selected. Genotypes were determined by direct sequencing. Sequence data were analyzed. Multiple logistic regression models were calculated. Results A significant difference emerged between the AA group and the control group for one SNP (rs17875491) of IL16. A further significant difference was found between patients with and without a family history of AA for a second SNP (rs11073001). Conclusions The present study found significant differences pertaining to two SNPs of the IL16 gene between, respectively, AA patients and controls (rs17875491) and AA patients with and without a family history of AA (rs11073001). Thus, IL16 polymorphisms may play a role in the pathophysiology of AA or in the expression of AA phenotypes. Further studies are required to elucidate the role of IL-16 in the pathogenesis and clinical manifestation of AA.
Introduction Alopecia areata (AA) is a common, chronic disease that presents as non-scarring hair loss. The pathogenesis of AA is not completely understood. However, AA is thought to be an organ-specific autoimmune disease characterized by T cell infiltrates and cytokine production around anagen-stage hair follicles. Interleukin-16 (IL-16) is a homotetramer discovered in 1982 as a T cell-specific chemoattractant factor. IL-16 plays a role in trafficking of several immune cells and may be a major chemotactic signal for CD4+ cells. IL-16 is also a potent chemoattractant for all peripheral immune cells expressing CD4, including CD4+ monocytes, eosinophils, and dendritic cells.1 Several reports have confirmed the association between IL-16 and autoimmune disease. Lee et al.2 established the first link between IL-16 and systemic lupus erythematosus (SLE), validating not only a significant increase in IL-16 protein levels in SLE patients but also a correlation of the IL-16 ª 2013 The International Society of Dermatology
protein level with disease severity. Tanyasiri et al.3 recently found IL-16 levels in AA patients to be significantly higher than those in normal individuals. The role of IL-16 in the pathogenesis of AA has not yet been studied; however, we suggest that IL-16 may be associated with AA as it is with other autoimmune diseases. The purpose of this study was to determine whether variation in the IL16 gene contributes to risk for AA in the Korean population. Materials and methods Study subjects Alopecia areata patients and control subjects were enrolled in this study. A total of 229 AA patients were enrolled. Patients were classified into two groups, according to the method described by a previous study.4 The early-onset group included patients who were aged 0.05). Genotypes were determined by direct sequencing. Genomic DNA was amplified using the following primers: rs17875486; rs17875491; rs11073001; and rs1803275. Samples were sequenced using an ABI Prism 3730XL Analyzer (Applied Biosystems, Inc., Foster City, CA, USA). Sequence data were analyzed using SeqManII software (DNASTAR, Inc., Madison, WI, USA). Statistical analysis Hardy–Weinberg equilibrium for two SNPs was assessed using SNPStats (http://bioinfo.iconcologia.net/index.php).5 A linkage disequilibrium (LD) block of polymorphisms was tested using Haploview Version 3.32.6 Multiple logistic regression models were calculated for odds ratios, 95% confidence intervals, and corresponding P-values, controlling for gender as a covariable. Calculations were made using SNPStats Helixtree software (Golden Helix, Inc., Bozeman, MT, USA) and SNPAnalyzer (ISTECH, Inc., Goyang, South Korea). International Journal of Dermatology 2014, 53, 319–322
Expression of IL16 polymorphisms according to clinical severity
There were no significant differences in expression of any SNPs of IL16 between patients with patch-type AA and those with alopecia universalis (AU) or alopecia totalis (AT). Further, there were no significant differences in the expression of any SNPs of IL16 according to body hair or nail involvement (data not shown).
Discussion Several studies of SNPs in AA have been reported. TaziAhnini et al.7 found a significant association between the rare allele (C961) of the AIRE polymorphism at position 961 and AA. This association is stronger and more significant in severe forms of the condition, such as AU. TaziAhnini et al.7 also examined two polymorphisms in the coding sequence of the Notch4 gene at positions +1297 and +3063 in a case–control study of 116 AA patients and 142 healthy control subjects. Polymorphisms within the MIF-173*C allele confer an increased risk for susceptibility to the extensive forms of AA, especially in patients with an early onset of disease. Therefore, macrophage migration inhibitory factor (MIF) is suggested to be closely implicated in the pathogenesis of the more extensive forms of AA.8 Polymorphisms of the IL17A gene and IL17RA gene were identified in our previous study.9 A significant difference between the AA patient group and the control group ª 2013 The International Society of Dermatology
ª 2013 The International Society of Dermatology
Promoter
Exon
Promoter
rs17875486
rs1803275
rs17875491
AA AG GG CC TC TT AA GA GG CC GC GG
Genotype 130 80 18 116 86 26 143 75 19 136 80 12
Cases, n 57.0 35.1 7.9 50.9 33.7 11.4 62.7 32.9 4.4 59.6 35.1 5.3
% 161 105 19 134 117 34 174 97 14 191 82 12
Controls, n 56.5 36.8 6.7 47.0 41.0 11.9 61.0 34.0 4.9 67.0 28.8 4.2
%
1.50 (1.08–2.07)
0.89 (0.68–1.17)
0.89 (0.68–1.17)
1.00 (0.75–1.34)
OR (95% CI)
Codominant
0.014
0.63
0.40
1.00
P-value
1.53 (1.04–2.25)
0.95 (0.65–1.39)
0.82 (0.56–1.18)
0.98 (0.68–1.42)
OR (95% CI)
Dominant
0.031
0.79
0.28
0.92
P-value
2.26 (0.93–5.50)
0.73 (0.31–1.73)
0.97 (0.54–1.73)
1.06 (0.53–2.13)
OR (95% CI)
Recessive
0.074
0.47
0.91
0.87
P-value
Promoter
Exon
Promoter
rs17875486
rs1803275
rs17875491
AA AG GG CC TC TT AA GA GG CC GC GG
Genotype 6 13 0 12 5 2 9 10 0 13 4 2
FHx+, n 31.6 68.4 0 63.2 26.3 10.5 47.4 52.6 0 68.4 21.1 10.5
% 124 67 18 104 81 24 134 65 10 123 76 10
FHx , n 59.3 32.1 8.6 49.8 38.8 11.5 64.1 31.1 4.8 58.9 36.4 4.8
%
0.91 (0.40–2.08)
1.38 (0.58–2.95)
0.71 (0.34–1.50)
1.52 (0.77–3.00)
OR (95% CI)
Codominant
0.83
0.41
0.36
0.24
P-value
0.67 (0.24–1.86)
2.41 (0.78–5.25)
0.57 (0.21–1.51)
3.17 (1.15–8.75)
OR (95% CI)
Dominant
0.43
0.15
0.25
0.02
P-value
2.55 (0.48–13.43)
2.02 (0.78–5.25)
0.89 (0.19–4.11)
0.00 (0.00–NA)
OR (95% CI)
Recessive
0.31
0.16
0.88
0.065
P-value
IL16 gene polymorphisms and alopecia areata
FHx, family history; OR, odds ratio; 95% CI, 95% confidence interval; SNP, single nucleotide polymorphism. P-values for logistic regression analyses of three models (codominant, dominant and recessive) for regression analyses are shown in four SNPs (rs17875486, rs17875491, rs11073001 and rs1803275).
Exon
rs11073001
Region
IL16
Table 3 Logistic regression analyses of IL16 polymorphisms in alopecia areata (AA) patients with and without a family history of AA
OR, odds ratio; 95% CI, 95% confidence interval; SNP, single nucleotide polymorphism. P-values for logistic regression analyses of three alternative models (codominant, dominant and recessive) for regression analyses are shown in four SNPs (rs17875486, rs17875491, rs11073001, and rs1803275).
Exon
rs11073001
Region
IL16
Table 2 Logistic regression analyses of IL16 polymorphisms in alopecia areata patients and normal control subjects
Lew et al. Medical genetics
International Journal of Dermatology 2014, 53, 319–322
321
322
Medical genetics
IL16 gene polymorphisms and alopecia areata
emerged for one SNP (rs879577) of IL17RA. Patients with early- and late-onset AA differed significantly for one SNP (rs4819554) of IL17RA. A single study has reported on the association between IL-16 and AA.3 Its authors classified AA into active AA and inactive AA.3 Active AA indicates the condition of active hair shedding as reflected in a positive hair pull test. Inactive AA indicates a condition without active hair shedding, in which the hair pull test is negative and exclamation point hair is absent. The IL-16 level of active AA patients was significantly higher than that in normal individuals or inactive AA patients, whereas no significant difference in IL-16 was observed between normal controls and inactive AA patients. In addition, a significant correlation was observed between HLA-DR expression by CD8+ T cells and IL-16 level in active AA patients. These results suggest that IL-16 may be a useful indicator of the activity of AA and that it may play an important role in the development of AA. Polymorphisms of the IL16 gene have been identified in a small number of epidemiologic studies. Among them, the IL16-295 SNP genotype may be a risk factor for several inflammatory disorders. In 2003, Glas et al.10 reported an association between the IL16-295 SNP and Crohn’s disease (CD). Subjects with CD had significantly higher T-allele and TT-genotype frequencies compared with control subjects. Reich et al.11 reported that the IL16-295 CC genotype was more common in subjects with polysensitized allergic contact dermatitis (ACD) than in healthy control subjects without ACD. In patients with SLE, individuals carrying the G allele of rs11556218, the C allele of rs4778889, and the T allele of rs4072111 are at a significantly higher risk for SLE compared with those carrying the T allele of rs11556218, the T allele of rs4778889, and the C allele of rs4072111, respectively.12 To the best of our knowledge, the present study represents the first investigation into the potential influence of IL16 gene polymorphisms in AA patients. This study found that expression of one SNP (rs17875491) of the IL16 gene located in the promoter region of chromosome 15q26.3 differed significantly between AA patients and healthy controls. In addition, a second SNP (rs11073001) of IL16 showed a significant difference in expression between patients with and without a family history of AA. We have demonstrated that IL16 polymorphisms may play a role in the pathophysiology of AA or in the
International Journal of Dermatology 2014, 53, 319–322
Lew et al.
expression of AA phenotypes. Further, expression of an rs11073001 polymorphism of IL16 may contribute to a familial tendency toward AA. Further studies are required to elucidate the role of IL-16 in the pathogenesis and clinical manifestation of AA. References 1 Kaser A, Dunzendorfer S, Offner FA, et al. A role for IL-16 in the cross-talk between dendritic cells and T cells. J Immunol 1999; 163: 3232–3238. 2 Lee S, Kaneko H, Sekigawa I, et al. Circulating interleukin-16 in systemic lupus erythematosus. Br J Rheumatol 1998; 37: 1334–1337. 3 Tanyasiri K, Hira K, Mitsuishi K, et al. Interleukin-16 in patients with alopecia areata. J Dermatol Sci 2005; 37: 55–57. 4 Colombe BW, Price VH, Khoury EL, et al. HLA class II antigen associations help to define two types of alopecia areata. J Am Acad Dermatol 1995; 33: 757–764. 5 Sole X, Guino E, Valls J, et al. SNPStats: a Web tool for the analysis of association studies. Bioinformatics 2006; 22: 1928–1929. 6 Barrett JC, Fry B, Maller J, et al. Haploview: analysis and visualization of linkage disequilibrium and haplotype maps. Bioinformatics 2005; 21: 263–265. 7 Tazi-Ahnini R, Cork MJ, Gawkrodger DJ, et al. Role of the autoimmune regulator (AIRE) gene in alopecia areata: strong association of a potentially functional AIRE polymorphism with alopecia universalis. Tissue Antigens 2002; 60: 489–495. 8 Shimizu T, Hizawa N, Honda A, et al. Promoter region polymorphism of macrophage migration inhibitory factor is strong risk factor for young onset of extensive alopecia areata. Genes Immun 2005; 6: 285–289. 9 Lew BL, Cho HR, Haw S, et al. Association between IL17A/IL17RA gene polymorphisms and susceptibility to alopecia areata in the Korean population. Ann Dermatol 2012; 24: 61–65. 10 Glas J, Torok HP, Unterhuber H, et al. The 295 T to C promoter polymorphism of the IL-16 gene is associated with Crohn’s disease. Clin Immunol 2003; 106: 197–200. 11 Reich K, Westphal G, Konig IR, et al. Association of allergic contact dermatitis with a promoter polymorphism in the IL16 gene. J Allergy Clin Immunol 2003; 112: 1191–1194. 12 Xue H, Gao L, Wu Y, et al. The IL-16 gene polymorphisms and the risk of the systemic lupus erythematosus. Clin Chim Acta 2009; 403: 223–225.
ª 2013 The International Society of Dermatology
