ORIGINAL ARTICLE
Functional Polymorphisms of the FAS Gene Associated with Risk of Vitiligo in Chinese Populations: A Case–Control Analysis Miao Li1,3, Dongjie Sun1,3, Chunying Li1,3, Zhengdong Zhang2, Lin Gao1, Kai Li1, Hong Li1 and Tianwen Gao1 The FAS/FASLG system plays a key role in regulating apoptosis. Previous findings have shown that CD4dependent destruction of melanocytes is partially inhibited by blocking FAS–FASLG interactions in autoimmune vitiligo. Functional polymorphisms of the FAS and FASLG genes can alter their transcriptional activities. In a hospital-based case–control study of 750 vitiligo patients and 756 controls, we genotyped the FAS1377 G4A, FAS670 A4G, and FASLG844 T4C polymorphisms and assessed their association with the risk of vitiligo. We found that a significantly increased risk of vitiligo was associated with the FAS1377 AA genotype (adjusted odds ratio (OR), 1.49; 95% confidence interval (CI), 1.07–2.08) and the FAS1377 AG genotype (adjusted OR, 1.31; 95% CI, 1.05–1.63) when compared with the FAS1377 GG genotype. However, no evident risk was associated with FAS670 G4A genotypes. In the combined analysis of the two variant alleles of FAS, genotypes with 3 to 4 risk alleles were associated with an increased risk of vitiligo compared with those having 0–2 variants (adjusted OR, 2.87; 95% CI, 1.90–4.32). In conclusion, genetic variants in the FAS gene may affect the risk of vitiligo in Chinese populations. Journal of Investigative Dermatology (2008) 128, 2820–2824; doi:10.1038/jid.2008.161; published online 12 June 2008
INTRODUCTION Vitiligo is an acquired pigmentary disorder characterized by depigmentation of the skin and loss of epidermal melanocytes. Various etiologic hypotheses have been suggested; the most compelling evidence involves a combination of environmental, genetic, and immunologic factors whose interactions contribute to autoimmune melanocyte destruction (Spritz 2006; Gopal et al., 2007). FAS, also known as TNFRSF6/CD95/APO–1, is a cell surface factor, and FASLG, also known as TNFSF6/CD95L, is a member of the tumor necrosis factor superfamily. FAS participates in apoptotic signaling in many types of cells (Sharma et al., 2000), and FASLG can trigger a cell death signal cascade by crosslinking with FAS (Kavurma and Khachigian, 2003). Thus, the FAS/FASLG system plays a crucial role in modulating apoptosis. The human FAS gene, which is mapped to chromosome 10q24.1, consists of nine exons and eight introns. It has been
1
Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Shaanxi, China and 2Department of Molecular Genetic Toxicology, Nanjing Medical University, Jiangsu, China
3
These authors equally contributed to this paper.
Correspondence: Dr Tianwen Gao, Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Changlexi Road no. 15, Xi’an, Shaanxi 710032, China. E-mail:
[email protected] Abbreviations: CI, confidence interval; OR, odds ratio Received 7 November 2007; revised 26 April 2008; accepted 30 April 2008; published online 12 June 2008
2820 Journal of Investigative Dermatology (2008), Volume 128
reported that two polymorphisms in the promoter region, a G to A substitution at position 1377 (FAS1377 G4A, rs2234767) in the silencer region, and an A to G substitution at position 670 (FAS670 A4G, rs1800682) in the enhancer region, destroy the binding elements for stimulatory protein 1 and signal transducer and activator of transcription protein 1, respectively, thereby diminishing promoter activity and decreasing FAS expression (Kanemitsu et al., 2002; Sibley et al., 2003). The human FASLG gene is located on chromosome 1q23 and comprises four exons. A polymorphism in the promoter region, T to C substitution at position 844 (FASLG844 T4C, rs763110), which is located within a putative binding motif of CAAT/enhanced binding protein b transcription factor, may cause higher basal expression of FASLG (Wu et al., 2003). Therefore, these FAS/FASLG single-nucleotide polymorphisms appear to be functional and might be associated with diseases in which FAS/FASLG genes are involved. Several studies have demonstrated that the FAS and FASLG polymorphisms are associated with an increased risk of autoimmune diseases, including Sjo¨gren’s syndrome (Mullighan et al., 2004), systemic lupus erythematosus (Nolsøe et al., 2005), autoimmune hepatitis (Agarwal et al., 2007), and Guillain–Barre´ syndrome (Geleijns et al., 2005). However, to the best of our knowledge, there is no reported study on the associations between the FAS and FASLG polymorphisms and risk of vitiligo. Previous studies suggested the involvement of T-cell-mediated cytotoxicity and apoptosis in the development of vitiligo lesions (Steitz et al., 2004). Recent findings also showed that CD4-dependent destruction & 2008 The Society for Investigative Dermatology
M Li et al. Polymorphism of FAS Gene and Risk of Vitiligo
of melanocytes is partially inhibited by blocking FAS–FASLG interactions in an animal model of autoimmune vitiligo (Lambe et al., 2006). As the FAS/FASLG system plays an important role in regulating apoptosis in many cell types including T lymphocytes, and abnormal expression of FAS and FASLG has been observed in vitiligo (Kim et al., 2007), we hypothesized that the functional polymorphisms in the FAS and FASLG genes might be associated with risk of vitiligo. To test this hypothesis, we genotyped the FAS1377 G4A, FAS670 A4G, and FASLG844 T4C polymorphisms in our ongoing, hospital-based case–control study of vitiligo in Han Chinese populations. RESULTS Characteristics of the study population
The cases and controls appeared to be well matched regarding age and sex: the mean age was 24.32±13.28 years for cases and 26.59±13.33 years for controls (P ¼ 0.165), and they had the same sex ratios (P ¼ 0.988). Among the cases, 5.9% had segmental vitiligo and the rest had non-segmental vitiligo. There were 628 active (83.7%) and 122 stable (16.3%) vitiligo patients among the cases. Cases were considered to have a family history if they had one or more first- to third-degree relatives afflicted with the condition (n ¼ 130, 17.3%). Patients were considered as having early onset vitiligo (n ¼ 473, 63.1%) if the age of onset was less than 20 years (Prc´ic´ et al., 2002). Association between FAS genotypes and risk of vitiligo
As shown in Table 1, the frequencies of the GG, AG, and AA genotypes for the FAS1377 G4A polymorphism were 36.3, 50.4, and 13.3%, respectively, among the cases, and 43.4,
45.8, and 10.8%, respectively, among the controls. The difference was statistically significant (P ¼ 0.015). A statistically significantly increased risk of vitiligo was associated with FAS1377 AA (adjusted OR, 1.49; 95% CI, 1.07–2.08) and FAS1377 AG (adjusted OR, 1.31; 95% CI, 1.05–1.63), compared with 1377 GG. The frequency of the combined 1377 A variant genotype (AG þ AA) was significantly higher among cases (63.7%) than among controls (56.6%) (P ¼ 0.007) and was associated with a significant increase in risk of vitiligo (adjusted OR, 1.35; 95% CI, 1.09–1.66). For FAS670 A4G, the frequencies of the AA, AG, and GG genotypes among the cases were 38.0, 48.5, and 13.5%, respectively, and 37.7, 48.1, and 14.3%, respectively, among the controls. However, the difference was not statistically significant (P ¼ 0.899). The observed genotype frequencies of FAS among the controls were in agreement with the Hardy–Weinberg equilibrium (P ¼ 0.514 for 1377 G4A; and P ¼ 0.660 for 670 A4G). The frequencies of the TT, CT, and CC genotypes for FASLG844 T4C were 5.1, 33.3, and 61.6%, respectively, among the cases, and 6.8, 33.1, and 60.1%, respectively, among the controls. However, the data for FASLG844 were disregarded because of disagreement with the Hardy–Weinberg equilibrium (w2-test: P ¼ 0.032), so we did not carry out further statistical analysis for this set. Consistent with the genotypic distributions of FAS1377 G4A, the frequency of the FAS1377 variant A allele was significantly higher among cases than among controls (0.385 and 0.337, respectively, P ¼ 0.007). Similarly, the frequency of the FAS670 variant A allele was higher among cases than among controls (0.623 and 0.617, respectively), but the difference was not statistically significant (P ¼ 0.763). On the basis of these data, we assumed that the minor 1377 A and
Table 1. Genotypic frequencies of FAS polymorphisms in cases and controls and their associations with risk of vitiligo Controls (n=756)1
Cases (n=750) n
%
n
%
P2
GG
272
36.3
328
43.4
0.015
1.00 (reference)
1.00 (reference)
AG
378
50.4
346
45.8
—
1.32 (1.06–1.64)
1.31 (1.05–1.63)
AA
100
13.3
82
10.8
—
1.47 (1.05–2.05)
1.49 (1.07–2.08)
AG+AA
478
63.7
428
56.6
0.006
1.35 (1.09–1.66)
1.35 (1.09–1.66)
A allele
—
38.5
—
33.7
0.007
—
—
GG
101
13.5
108
14.3
0.899
1.00 (reference)
1.00 (reference)
AG
364
48.5
363
48.1
—
1.07 (0.79–1.46)
1.07 (0.79–1.46)
AA
285
38.0
285
37.7
—
1.07 (0.78–1.47)
1.07 (0.78–1.47)
AG+AA
649
86.5
648
85.7
0.708
1.07 (0.80–1.44)
1.07 (0.80–1.44)
A allele
—
62.3
—
61.7
0.763
—
—
Genotypes
Crude OR (95% CI)
Adjusted OR (95% CI)3
FAS1377
FAS670
CI, confidence interval; OR, odds ratio. 1 The observed genotype frequencies among the controls were in agreement with the Hardy–Weinberg equilibrium (w2=0.426, P=0.514 for 1377 G4A; w2=0.194, P=0.660 for 670 A4G). Data of FASLG844 were excluded because of disagreement with the Hardy–Weinberg equilibrium (w2=4.587, P=0.032). 2 Two–sided w2-test for distributions of either genotype or allele frequencies between the cases and controls. 3 ORs were obtained from a multivariate logistic regression model with adjustment for age and sex.
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M Li et al. Polymorphism of FAS Gene and Risk of Vitiligo
670 A were putative risk alleles, which we used for the analysis of risk associated with combined genotypes, as described below. Association between FAS haplotypes and combined genotype and vitiligo risk
Further analysis showed that the two FAS polymorphisms were in linkage disequilibrium (D0 ¼ 0.784, Po0.001), suggesting a possible combined effect of the two FAS polymorphisms or risk haplotypes. As shown in Table 2, there were four possible FAS haplotypes derived from the known genotypes, and the overall distributions of FAS haplotypes between the cases and controls were statistically different (Po0.001). The FASAA haplotype frequency was significantly different between cases and controls (6.5 and 2.4%, respectively; Po0.001). Moreover, when the FASGG haplotype was used as the reference, the AA haplotype was associated with a significantly higher vitiligo risk (adjusted OR, 3.29; 95% CI, 2.05–5.29). Next, we combined the two FAS variant genotypes on the basis of the established putative risk genotype. When the combined genotype FAS1377 (GG)/670 (AG þ AA) was used as the reference, we found that only those who carried the 1377 (AG þ AA)/670 (AG þ AA) genotype had a higher vitiligo risk (adjusted OR, 1.44; 95% CI, 1.15–1.79). We obtained five genotypes according to the number of risk alleles (that is, 1377 A and 670 A). The genotypes with one and two variants (that is, 1377 A and 670 A) were less common among the cases (10.1 and 77.3%, respectively) than among the controls (13.2 and 81.9%, respectively), and these differences were statistically significant (Po0.001). When these five genotypes were dichotomized into two groups (that is, 0–2 vs 3–4 variants) on the
basis of the number of risk alleles, their distributions differed significantly between the cases and controls (Po0.001). Consistently, when the genotypes with 0–2 variants were used as the reference, it was found that the risk of vitiligo increased significantly (adjusted OR, 2.87; 95% CI, 1.90–4.32). Finally, we performed a stratified analysis with FAS1377 GG genotype vs FAS1377 (AG þ AA) genotype. The increased risk was more pronounced among subgroups with the following characteristics: age420 years (adjusted OR, 1.43; 95% CI, 1.07–1.92), female (adjusted OR, 1.53; 95% CI, 1.12–2.10), non-segmental (adjusted OR, 1.32; 95% CI, 1.07–1.62), onset agep20 years (adjusted OR, 1.36; 95% CI, 1.05–1.77), and without family history (adjusted OR, 1.33; 95% CI, 1.07–1.65) (data not shown). DISCUSSION In this hospital-based case–control study, we investigated the associations of the FAS1377 G4A, 670 A4G, and FASLG844 T4C polymorphisms with risk of vitiligo in Han Chinese populations. Compared with the previously published data, our results were similar to the frequencies found in other Chinese controls but different from the frequencies of non–Hispanic white populations (Stuck et al., 2003; Krippl et al., 2004; Li et al., 2006a, b), which indicated that the genotype distributions of the FAS and FASLG polymorphisms vary with ethnicity. Data for FASLG844 were not taken into account due to disagreement with the Hardy–Weinberg equilibrium, most likely caused by an insufficient number of samples, as for smaller frequencies of the susceptibility allele in controls, a larger sample size is needed (Hattersley and McCarthy, 2005). The FAS670 A4G polymorphisms did not affect the risk of vitiligo. However, we found a statistically significant
Table 2. Frequencies of the FAS haplotypes and combined genotypes among the cases and controls and their associations with risk of vitiligo Cases (n=1,500 alleles) FAS haplotype
1
n
Controls (n=1,512 alleles)
%
n
%
P2
Crude OR (95% CI)
Adjusted OR (95% CI)3
GG
86
5.8
106
7.1
0.173
1.00 (reference)
1.00 (reference)
GA
1,029
68.6
1,039
68.7
0.975
1.22 (0.91–1.64)
1.23 (0.91–1.65)
AG
287
19.1
330
21.8
0.073
1.07 (0.77–1.48)
1.08 (0.78–1.50)
AA
98
6.5
37
2.4
o0.001
3.27 (2.03–5.24)
3.29 (2.05–5.29)
Combined genotypes
FAS1377 G4A
Cases (n=750)
Controls (n=756)
n (%)
n (%)
FAS670 A4G
0.009
GG
AG+AA
267 (35.6)
325 (43.0)
1.00 (reference)
1.00 (reference)
GG
GG
5 (0.7)
3 (0.4)
2.03 (0.48–8.57)
2.02 (0.48–8.57)
AG+AA
GG
96 (12.8)
105 (13.9)
1.11 (0.81–1.53)
1.11 (0.81–1.53)
AG+AA
AG+AA
382 (50.9)
323 (42.7)
1.44 (1.16–1.79)
1.44 (1.15–1.79)
CI, confidence interval; OR, odds ratio. 1 Po0.001 for the differences in haplotype allele distributions between cases and controls. Linkage disequilibrium analysis: D 0 =0.784, Po0.001. 2 Two-sided w2-test for distributions of either genotypic or allelic frequencies between cases and controls. 3 ORs were obtained from a multivariate logistic regression model, with adjustment for age and sex.
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M Li et al. Polymorphism of FAS Gene and Risk of Vitiligo
increased risk of vitiligo to be associated with FAS1377 G4A. In the association studies, analyzing more than one polymorphism or more than one gene involved in the same causal pathway appears to be more efficient than analyzing a single polymorphism or a single gene. When we analyzed the effects of these two FAS polymorphisms together in the context of haplotypes, we found that the genotypes with more than two risk alleles were associated with an increased risk of vitiligo, suggesting that these variants may have additive effects on the risk for this disease. When we explored the possible effects on clinical progression of vitiligo by FAS1377 gene polymorphisms, significantly higher vitiligo risks were found among subgroups with the following characteristics: age420 years, female, non-segmental, onset agep20 years, and without family history. This suggests that FAS1377 gene polymorphisms may have a greater effect on these subgroups. The differences may be due to the reduction in the number of observations in some strata or may reflect true susceptible subgroups. Further exploration is needed to determine whether the effects found here are an aberration, and what the exact mechanisms underlying such effects are. To the best of our knowledge, this is the first study designed to investigate the associations between FAS and FASLG polymorphisms and risk of vitiligo. The FAS receptor is widely expressed in a variety of tissues, whereas the expression of FASLG is restricted to the cells within the immune system, such as activated T lymphocytes and natural killer cells. Defective FAS function may favor autoimmunity by slowing down cell apoptosis and/or inducing exposure of abnormal amounts of apoptosis-related antigens (Dianzani et al., 2003). The increased risk associated with the FAS1377 A allele has been reported in other types of diseases, such as acute myeloid leukemia (Sibley et al., 2003) and cervical cancer (Lai et al., 2003). In addition, several association studies have reported that FAS and FASLG polymorphisms are associated with the risk of some autoimmune diseases (Mullighan et al., 2004; Geleijns et al., 2005; Nolsøe et al., 2005; Agarwal et al., 2007). These studies support our finding that polymorphisms potentially influencing the functions of FAS and FASLG are likely to be associated with the risk of vitiligo. Stimulatory protein 1 is an important transcriptional activator (Pugh and Tjian, 1990), and the transcriptional activation of signal transducer and activator of transcription 1 may depend on the concomitant stimulatory protein 1 binding (Look et al., 1995). The polymorphisms FAS1377 G4A and FAS670 A4G destroy the stimulatory protein 1 and signal transducer and activator of transcription 1 protein-binding elements, respectively, and thus diminish promoter activity and decrease FAS expression. Given the roles of the FAS/FASLG system in the apoptosis of T lymphocytes, it is biologically plausible that the FAS and FASLG polymorphisms may modulate the risk of autoimmune diseases, including vitiligo. Thus, we combined the genetic and immunologic etiology of vitiligo and speculated that the effects of the FAS variants on risk of vitiligo were likely due to the variant-mediated reduction in the apoptosis of T lymphocytes, whose increasing amount led to subsequent autoimmune destruction of melanocytes.
However, this hypothesis needs to be tested in further studies. We also considered the possibility of polymorphic FAS expression in melanocytes and proposed a direct effect of high FAS expression on melanocyte apoptosis. Exactly how the FAS variants may influence the risk of vitiligo remains unknown, but these variants could be either functional or in linkage disequilibrium with other, not yet tested, functional variants involved in the etiology of vitiligo. In summary, we provide evidence that FAS polymorphisms may influence the risk and clinical progression of vitiligo in Han Chinese populations. A statistically significantly increased risk of vitiligo was associated with the FAS1377 AA and FAS1377 AG genotypes compared with the 1377 GG genotype, but no evident risk was associated with the FAS670 G4A polymorphism. In the combined analysis of the two variant alleles of FAS, the genotypes with 3–4 risk alleles were associated with an increased risk of vitiligo compared with those having 0–2 variants. The combined risk genotypes FAS1377 (AG þ AA) were associated with a significantly higher risk of vitiligo, which was more pronounced among vitiligo patients with the following characteristics: age420 years, female, non-segmental, onset agep20 years, and without family history. Nevertheless, better-designed and larger prospective studies are needed to confirm these findings, and more detailed environmental exposure data are necessary to further test potential gene–environment interactions. MATERIALS AND METHODS Study population The study subjects were recruited from Xijing Hospital between August 2005 and January 2006. Only Han Chinese (more than 90% of the population of China) subjects were included. The controls were persons who came for health examinations and were frequency-matched to the cases by age (±5 years), sex, and ethnicity. All subjects were examined and diagnosed by dermatologists. We used a standard questionnaire to obtain demographic and characteristic information. The response rate among patients and controls approached for participation was approximately 90% for both. Active vitiligo was defined as the appearance of new lesions or enlargement of existing lesions in the 3 months before presentation. After the history and clinical examination, vitiligo was classified as segmental and non-segmental (Dave et al., 2002). Segmental vitiligo was diagnosed if it followed a dermatomal distribution. After signing informed consent forms, each subject donated 2 ml of blood, which was collected in heparinized tubes and used for genomic DNA extraction. The research protocol was designed and performed according to the Declaration of Helsinki Principles and was approved by the ethics review board of Fourth Military University.
Genotyping Genomic DNA was extracted from cell pellets by using a blood genomic DNA purification kit. We used the PCR-restriction fragment length polymorphism method to determine the FAS1377 G4A, 670 A4G, and FASLG844 T4C polymorphisms, as described previously (Li et al., 2006a). More than 10% of the samples were randomly selected and genotyped again by the same method to test the discrepancy rate, and the results were 100% concordant. www.jidonline.org 2823
M Li et al. Polymorphism of FAS Gene and Risk of Vitiligo
Statistical analysis We used w2-test to evaluate the differences in frequency distributions of selected demographic variables and each allele and genotype of the FAS and FASLG polymorphisms between the cases and controls. Unconditional univariate and multivariate logistic regression analyses were performed to obtain ORs for risk of vitiligo and their 95% CIs. Multivariate adjustments were made for age and sex. The 2LD software was used to calculate the D0 value for linkage disequilibrium between the two FAS polymorphisms (Zapata et al., 2001; Zhao, 2004), and the PHASE software (version 2.0.2; University of Washington, Seattle, WA) was used to reconstruct the haplotypes for each subject on the basis of known genotypes (Stephens et al., 2001; Stephens and Donnelly, 2003). The association between the combined genotypes of the FAS polymorphisms and risk of vitiligo was also evaluated. The genotype data were further stratified by subgroups according to age, sex, stage, type, onset age, and family history. Statistical significance was established at a P-value of 0.05. All tests were two-sided for statistical significance and conducted by using SAS software (version 8.2; SAS Institute Inc., Cary, NC). CONFLICT OF INTEREST The authors state no conflict of interest.
Lai HC, Sytwu HK, Sun CA, Yu MH, Yu CP, Liu HS et al. (2003) Single nucleotide polymorphism at Fas promoter is associated with cervical carcinogenesis. Int J Cancer 103:221–5 Lambe T, Leung JC, Bouriez-Jones T, Silver K, Makinen K, Crockford TL et al. (2006) CD4 T lymphocytes-dependent autoimmunity against a melanocyte neoantigen induces spontaneous vitiligo and depends upon Fas–Fas ligand interactions. J Immunol 177:3055–62 Li C, Larson D, Zhang Z, Liu Z, Strom SS, Gershenwald JE et al. (2006a) Polymorphisms of the FAS and FAS ligand genes associated with risk of cutaneous malignant melanoma. Pharmacogenetics and Genomics 16: 253–63 Li C, Wu W, Liu J, Qian L, Li A, Yang K et al. (2006b) Functional polymorphisms in the promoter regions of the FAS and FAS ligand genes and risk of bladder cancer in south China: a case–control analysis. Pharmacogenetics and Genomics 16:245–51 Look DC, Pelletier MR, Tidwell RM, Roswit WT, Holtzman MJ (1995) Stat1 depends on transcriptional synergy with Sp1. J Biol Chem 270: 30264–7 Mullighan CG, Heatley S, Lester S, Rischmuelle M, Gordon TP, Bardy PG (2004) Fas gene promoter polymorphisms in primary Sjo¨gren’s syndrome. Ann Rheum Dis 63:98–101 Nolsøe RL, Kelly JA, Pociot F, Moser KL, Kristiansen OP, Mandrup-Poulsen T et al. (2005) Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia. Genes Immun 6:699–706 Prc´ic´ S, Duran V, Poljacki M (2002) Vitiligo in childhood. Med Pregl 55: 475–80 Pugh BF, Tjian R (1990) Mechanism of transcriptional activation by Sp1: evidence for coactivators. Cell 61:1187–97
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