Abstract
Objectives: FAS plays a critical role in the extrinsic apoptosis pathway in autoimmune diseases. Previous studies investigating the association between FAS gene −670 A/G and −1377 G/A polymorphisms and the risk of autoimmune diseases reported controversial results. We performed the meta-analysis to evaluate the possible association. Methods: Relevant studies were identified by searching the PubMed, Embase, CNKI, and Wanfang databases up to December 2018. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to determine the association. Results: A total of 43 articles including 67 studies (52 studies for FAS −670 A/G and 15 studies for −1377 G/A) were included in the meta-analysis. Our meta-analysis showed that the FAS −670 A/G polymorphism was associated with the risk of autoimmune diseases (GG vs. GA: OR = 1.079, 95% CI = 1.004–1.160, P=0.038), especially in Caucasians (GG vs. GA: OR = 1.12, 95% CI = 1.03–1.23, P=0.012), Asians (G vs. A: OR = 0.89, 95% CI = 0.83–0.96, P=0.002), systemic lupus erythematosus (SLE) (G vs. A: OR = 0.85, 95% CI = 0.77–0.94, P=0.001), multiple sclerosis (MS) (GG+GA vs. AA: OR = 0.83, 95% CI = 0.70–0.99, P=0.043), systemic sclerosis (SSc) (GG vs. GA: OR = 1.20, 95% CI = 1.07–1.36, P=0.003) and Hashimoto’s thyroiditis (HT) (G vs. A: OR = 1.45, 95% CI = 1.10–1.90, P=0.008); the FAS −1377 G/A polymorphism was associated with the risk of autoimmune diseases (A vs. G: OR = 1.11, 95% CI = 1.03–1.20, P=0.008), especially in Asians (A vs. G: OR = 1.15, 95% CI = 1.05–1.25, P=0.002) and high quality studies (A vs. G: OR = 1.14, 95% CI = 1.05–1.24, P=0.002). Conclusion: This meta-analysis demonstrated that the FAS –670A/G and –1377 G/A polymorphisms were associated with the risk of autoimmune diseases.
Introduction
Autoimmune diseases are chronic disorders characterized by the loss of immune tolerance to self-antigens, leading to immune-mediated tissue destruction. They affect 4–5% of adults, the majority of whom are women [1]. Co-occurrence of distinct autoimmune diseases within a single family and genome-wide association studies (GWASs) support the hypothesis that these diseases share common genetic risk factors [2–6]. The etiology of autoimmune diseases is attributed to complex interactions of genetics, epigenetics, and environmental factors that remain to be elucidated [7–12].
FAS (also known as APO-1, CD95, or TNFSF6) is a cell surface receptor that belongs to the tumor necrosis factor (TNF) receptor superfamily [13]. FAS is widely expressed in normal human tissues. To maintain self-tolerance, the binding of FAS-ligand (FASL) to FAS on the cell surface initiates the extrinsic apoptosis pathway [14]; thus, autoreactive lymphocytes are normally eliminated. However, abnormal apoptosis may lead to a failure to eliminate autoreactive lymphocytes, which can induce the appearance and development of autoimmune diseases [15]. The FAS gene is located on chromosome 10q24.1 in humans and is highly polymorphic [16]. In some individuals, there is an A to G substitution at position 670 and a G to A substitution at position 1377 in the FAS promoter region [17]. The FAS −670 A/G and −1377 G/A polymorphisms may destroy signal transducer and activator of transcription protein 1 (STAT1) and stimulatory protein 1 (SP1) transcription factor binding sites, resulting in reduced promoter activity and FAS expression [18]. Abnormal apoptosis mediated by the FASL interaction with the FAS receptor is involved in the pathogenesis of several autoimmune diseases and cancers [19].
Many studies have investigated the relationship between the FAS −670 A/G rs1800682 and −1377 G/A rs2234767 polymorphisms and the risk of autoimmune diseases [15,17,20–60], including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), autoimmune hepatitis (AIH), alopecia areata (AA), lupus nephritis (LN), systemic sclerosis (SSc), primary Sjögren’s syndrome (pSS), Hashimoto’s thyroiditis (HT), Guillain–Barré syndrome (GBS), primary biliary cirrhosis (PBC), vitiligo, Graves’ disease (GD), type 1 diabetes mellitus (T1D), idiopathic aplastic anemia (IAA), juvenile idiopathic arthritis (JIA), and spondyloarthropathies (SPA). However, previous results have been controversial, perhaps due to small sample sizes and low statistical power. Meta-analysis could provide more reliable results, enabling the inclusion of a larger sample size and enhanced statistical power by combining the results of independent eligible studies. Seven previous meta-analyses [43,61–66] have analyzed the association between the FAS −670 A/G or −1377 G/A polymorphisms and some autoimmune diseases. However, these studies only analyzed SLE, RA, LN, SSc, pSS, JIA, SPA, and AIH and did not include all autoimmune diseases. Furthermore, previous meta-analyses [63,65] including several studies [25,30,31,40] contained some errors when extracting the data. Thus, in the present study, we aimed to perform a meta-analysis to investigate whether the FAS −670 A/G or −1377 G/A polymorphisms is associated with autoimmune diseases risk by including 23 new articles, consisting of 33 studies [15,17,22,27–30,32–35,37,41,43–45,50,52–55,59,60] on SLE, MS, pSS, AA, PBC, HT, GBS, LN, vitiligo, T1D, IAA, and GD and correcting the errors in the previous meta-analyses. To our knowledge, this is the most comprehensive meta-analysis to assess the association of an FAS polymorphisms with the risk of autoimmune diseases, including SLE, RA, MS, AIH, LN, SSc, AA, pSS, HT, GBS, PBC, vitiligo, GD, T1D, IAA, JIA, and SPA.
Methods
This meta-analysis was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 checklist [67].
Literature search
Literature published in English and Chinese was retrieved from the PubMed, Embase, CNKI, and Wanfang databases up to December 2018. The search strategy used the following medical subject heading (MeSH) terms combined with text words: ‘FAS or TNFRSF6 or CD95 or APO-1 or rs1800682 or rs2234767’, ‘polymorphism, genetic or polymorphisms or polymorphism or variant or mutation’ and ‘autoimmune diseases or autoimmune disease or autoimmunity’. A manual search of the reference lists was also performed to identify additional articles.
Inclusion and exclusion criteria
Studies meeting all the following criteria were included in the analysis: (1) evaluation of the association between the FAS −670 A/G or −1377 G/A polymorphisms and autoimmune diseases risk; (2) available and sufficient genotype data to calculate the odds ratio (OR) with 95% confidence interval (CI); and (3) a case–control study design.
Studies were excluded if they met the following criteria: (1) containing overlapping data; (2) not containing genotype data from the cases and controls; and (3) reviews, case reports, abstracts, letters, animal experiments and meta-analyses.
Data extraction
Two investigators independently assessed and extracted data from all included studies. Discrepancies were resolved by discussion. The following data were collected from each study: disease type, first author, year of publication, country, ethnicity, genotyping method, sample sizes of cases and controls, genotype frequencies in cases and controls, and P-value of test for Hardy–Weinberg equilibrium (HWE) in controls.
Quality evaluation
The methodological quality of the included studies was assessed independently by two investigators using the Newcastle–Ottawa scale (NOS) score [68]. The NOS score ranges from 0 to 9 and encompasses three components, including selection, comparability, and exposure. A study with score greater than or equal to 6 was considered of high methodological quality. Discrepancies were resolved by discussion.
Statistical analysis
The chi-square test was applied to examine whether the observed genotype frequencies in controls conformed to HWE, and P<0.05 was considered to deviate from HWE. The ORs with their 95% CIs were used to assess the strength of associations between the FAS −670 A/G and −1377 G/A polymorphisms and autoimmune diseases. The statistical significance of the pooled ORs was determined by the Z test. The allelic (FAS −670 A/G: G vs. A; FAS −1377 G/A: A vs. G), homozygous (FAS −670 A/G: GG vs. AA; FAS −1377 G/A: AA vs. GG), heterozygous (FAS −670 A/G: GG vs. GA; FAS −1377 G/A: AA vs. AG), dominant (FAS −670 A/G: GG + GA vs. AA; FAS −1377 G/A: AA+AG vs. GG), and recessive (FAS −670 A/G: GG vs. GA+ AA; FAS −1377 G/A: AA vs. AG+GG) models were examined. The between-studies heterogeneity was assessed by Q test and quantified by I2 test [69]. When P≥0.1 or I2 < 50%, there was no heterogeneity, and pooled OR estimates were combined using the fixed-effects model (Mantel–Haenszel method); otherwise, the random-effects model (Mantel–Haenszel method) was used to combine summary data [70]. To detect the main sources of heterogeneity, subgroup analyses were performed by ethnicity, disease type and quality score. Sensitivity analysis was carried out by excluding studies deviating from HWE to assess the stability of the meta-analysis. Egger’s test was used to assess publication bias [71]. If there was publication bias, we recalculated the adjusted ORs using the trim-and-fill method [72] to evaluate the possible impact of publication bias. The trim-and-fill method was used to impute hypothetical missing studies. For significant results observed in the current meta-analysis, the false-positive report probability (FPRP) test was utilized to examine positive associations. An FPRP threshold of 0.5 and a prior probability of 0.1 were set to detect an OR of 0.67/1.50 (protective/risk effects) for an association with the tested genotypes. FPRP values less than 0.5 were considered as noteworthy associations [73]. All statistical analyses were conducted using Stata 15 software (Stata Corporation, College Station, TX, U.S.A.). Results with P<0.05 were considered significant.
Trial sequential analysis
Traditional meta-analysis may yield type I errors due to dispersed data or repetitive significance testing when new studies are added to it [74,75]. Trial sequential analysis (TSA) was used to minimize the risk of type I errors by calculating required information size (RIS) (meta-analysis sample size) and adjusted threshold for statistical significance [76]. TSA was performed by using TSA software 0.9.5.10 Beta (http://www.ctu.dk/tsa/) in the allelic model with the overall included studies by setting an overall type I error of 5%, power of 80%, relative risk reduction (RRR) of 20%, and control event proportion [77]. If the cumulative Z-curve crosses the trial sequential monitoring boundary or the RIS line, a reliable and conclusive evidence has been reached and further studies are not needed. Otherwise, more studies are needed to reach a firm conclusion.
Results
Characteristics of the included studies
A flowchart of the selection of eligible articles is presented in Figure 1. The initial search identified 2552 articles through the search strategy, and a total of 43 articles [15,17,20–60], consisting of 67 studies comprising 13340 patients and 14547 controls, were finally included in the meta-analysis according to the inclusion and exclusion criteria. Fifty-two studies examined the FAS −670 A/G polymorphism, and 15 studies examined the FAS −1377 G/A polymorphism. The characteristics of the articles included in the meta-analysis are summarized in Table 1.
Flow diagram of the study selection process
Disease type . | Polymorphism . | Author . | Year . | Country . | Ethnicity . | Genotyping method . | Sample size (case/control) . | Case (GG/GA/AA) . | Control (GG/GA/AA) . | HWE . | NOS . | ||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
. | . | . | . | . | . | . | . | . | . | . | P-value . | score . | . | . | . |
SLE | FAS −670A/G | Bollain et al. | 2014 | Mexico | Mestizos | PCR-RFLP | 43/54 | 16 | 13 | 14 | 14 | 12 | 28 | <0.001 | 5 |
Moudi et al. | 2013 | Iran | Caucasian | PCR-RFLP | 106/149 | 17 | 55 | 34 | 39 | 73 | 37 | 0.808 | 7 | ||
Molin et al. | 2012 | Germany | Caucasian | PCR | 46/96 | 8 | 21 | 17 | 34 | 51 | 11 | 0.213 | 4 | ||
Lu et al. | 2012 | China | Asian | PCR | 552/718 | 96 | 237 | 219 | 138 | 326 | 254 | 0.070 | 6 | ||
Pradhan et al. | 2012 | India | Indian | PCR-RFLP | 70/70 | 11 | 37 | 22 | 21 | 42 | 7 | 0.036 | 6 | ||
Arasteh et al. | 2010 | Iran | Caucasian | ASO-PCR | 249/212 | 74 | 93 | 82 | 58 | 98 | 56 | 0.273 | 7 | ||
Xu et al. | 2004 | China | Asian | PCR-RFLP | 103/110 | 15 | 59 | 29 | 23 | 61 | 26 | 0.249 | 5 | ||
Kanemitsu et al. | 2002 | Japan | Asian | AS-PCR, PCR-SSCP | 109/140 | 25 | 49 | 35 | 50 | 64 | 26 | 0.492 | 5 | ||
Lee et al. | 2001 | Korea | Asian | PCR-RFLP | 87/87 | 13 | 47 | 27 | 13 | 48 | 26 | 0.230 | 5 | ||
Huang et al. | 1999 | Australia | Caucasian | PCR-RFLP | 79/86 | 20 | 21 | 38 | 20 | 22 | 44 | <0.001 | 4 | ||
MS | FAS −670A/G | Mohammadzadeh et al. | 2012 | Iran | Caucasian | PCR-RFLP | 107/112 | 22 | 37 | 48 | 18 | 50 | 44 | 0.551 | 8 |
Kantarci et al. | 2004 | U.S.A. | Caucasian | PCR-RFLP | 218/441 | 37 | 108 | 73 | 86 | 234 | 121 | 0.154 | 8 | ||
Lucas et al. | 2004 | Spain | Caucasian | PCR | 320/218 | 68 | 177 | 75 | 44 | 113 | 61 | 0.525 | 7 | ||
Niino et al. | 2002 | Japan | Asian | PCR-RFLP | 114/121 | 23 | 65 | 26 | 25 | 63 | 33 | 0.614 | 7 | ||
van Veen et al. | 2002 | Netherlands | Caucasian | PCR | 383/206 | 80 | 185 | 118 | 42 | 118 | 46 | 0.036 | 6 | ||
Huang et al. | 2000 | Australia | Caucasian | PCR-RFLP | 124/183 | 22 | 58 | 44 | 40 | 97 | 46 | 0.407 | 7 | ||
RA | FAS −670A/G | Yıldır et al. | 2013 | Turkey | Caucasian | TaqMan | 100/101 | 20 | 45 | 35 | 22 | 40 | 39 | 0.063 | 7 |
Kobak et al. | 2012 | Turkey | Caucasian | PCR-RFLP | 101/105 | 24 | 50 | 27 | 14 | 52 | 39 | 0.608 | 5 | ||
Mohammadzadeh et al. | 2011 | Iran | Caucasian | PCR | 120/112 | 17 | 64 | 39 | 18 | 50 | 44 | 0.551 | 4 | ||
Lee et al. | 2001 | Korea | Asian | PCR-RFLP | 87/87 | 16 | 38 | 33 | 13 | 48 | 26 | 0.230 | 5 | ||
Huang et al. | 1999 | Australia | Caucasian | PCR-RFLP | 185/86 | 32 | 105 | 48 | 22 | 44 | 20 | 0.825 | 4 | ||
Coakley et al. | 1999 | U.S.A. | Caucasian | PCR | 18/128 | 4 | 8 | 6 | 31 | 61 | 36 | 0.607 | 4 | ||
AIH | FAS −670A/G | Ngu et al. | 2013 | New Zealand | Caucasian | PCR | 77/455 | 19 | 35 | 23 | 107 | 214 | 134 | 0.232 | 5 |
Su et al. | 2012 | China | Asian | PCR-RFLP | 48/68 | 5 | 24 | 19 | 20 | 30 | 18 | 0.335 | 6 | ||
Agarwal et al. | 2007 | U.S.A. | Caucasian | PCR | 149/172 | 35 | 75 | 39 | 32 | 84 | 56 | 0.960 | 4 | ||
Hiraide et al. | 2005 | Japan | Asian | PCR | 72/130 | 14 | 31 | 27 | 40 | 63 | 27 | 0.811 | 4 | ||
LN | FAS −670A/G | Bollain et al. | 2014 | Mexico | Mestizos | PCR-RFLP | 24/54 | 8 | 9 | 7 | 14 | 12 | 28 | <0.001 | 5 |
Pradhan et al. | 2012 | India | Indian | PCR-RFLP | 35/70 | 7 | 16 | 12 | 21 | 42 | 7 | 0.036 | 6 | ||
Xu et al. | 2004 | China | Asian | PCR-RFLP | 62/110 | 9 | 34 | 19 | 23 | 61 | 26 | 0.249 | 5 | ||
Lee et al. | 2001 | Korea | Asian | PCR-RFLP | 26/87 | 4 | 12 | 10 | 13 | 48 | 26 | 0.230 | 5 | ||
SSc | FAS −670A/G | Liakouli et al. | 2013 | Italy | Caucasian | PCR | 350/232 | 65 | 158 | 127 | 60 | 120 | 52 | 0.586 | 8 |
Broen et al. | 2009 | Europe, U.S.A. | Caucasian | TaqMan | 2565/2855 | 616 | 1205 | 744 | 586 | 1455 | 814 | 0.168 | 7 | ||
Broen et al. | 2009 | U.S.A. | Hispanic | TaqMan | 159/137 | 46 | 80 | 33 | 41 | 71 | 25 | 0.552 | 7 | ||
Broen et al. | 2009 | U.S.A. | African | TaqMan | 176/194 | 93 | 68 | 15 | 96 | 83 | 15 | 0.613 | 7 | ||
AA | FAS −670A/G | Seleit et al. | 2018 | Egypt | Caucasian | PCR | 60/40 | 14 | 37 | 9 | 4 | 23 | 13 | 0.181 | 8 |
Kalkan et al. | 2013 | Turkey | Caucasian | PCR-RFLP | 118/118 | 0 | 81 | 37 | 13 | 65 | 40 | 0.077 | 7 | ||
Fan et al. | 2010 | China | Asian | PCR | 84/84 | 13 | 35 | 36 | 13 | 49 | 22 | 0.099 | 6 | ||
pSS | FAS −670A/G | Treviño-Talavera et al. | 2014 | Mexico | Amerindian | PCR-RFLP | 77/84 | 25 | 32 | 20 | 22 | 42 | 20 | 0.996 | 4 |
Mullighan et al. | 2004 | Australia | Caucasian | PCR | 101/108 | 17 | 54 | 30 | 21 | 54 | 33 | 0.897 | 4 | ||
Bolstad et al. | 2000 | Norway | Caucasian | PCR | 70/72 | 26 | 26 | 18 | 12 | 39 | 21 | 0.394 | 5 | ||
HT | FAS −670A/G | Erdogan et al. | 2016 | Turkey | Caucasian | PCR-RFLP | 112/112 | 31 | 57 | 24 | 15 | 56 | 41 | 0.547 | 8 |
Inoue et al. | 2016 | Japan | Asian | PCR-RFLP | 117/80 | 33 | 53 | 31 | 20 | 37 | 23 | 0.510 | 6 | ||
GBS | FAS −670A/G | Islam et al. | 2018 | Japan | Asian | PCR | 300/300 | 51 | 114 | 135 | 45 | 126 | 129 | 0.125 | 7 |
Geleijns et al. | 2005 | Netherlands | Caucasian | PCR | 272/212 | 67 | 129 | 76 | 42 | 114 | 56 | 0.243 | 5 | ||
PBC | FAS −670A/G | Su et al. | 2012 | China | Asian | PCR-RFLP | 19/68 | 5 | 7 | 7 | 20 | 30 | 18 | 0.335 | 6 |
Hiraide et al. | 2005 | Japan | Asian | PCR | 96/130 | 30 | 37 | 29 | 40 | 63 | 27 | 0.811 | 4 | ||
vitiligo | FAS −670A/G | Li et al. | 2008 | China | Asian | PCR | 750/756 | 101 | 364 | 285 | 108 | 363 | 285 | 0.660 | 7 |
GD | FAS −670A/G | Inoue et al. | 2016 | Japan | Asian | PCR-RFLP | 146/80 | 41 | 61 | 44 | 20 | 37 | 23 | 0.510 | 6 |
T1D | FAS −670A/G | Sahin et al. | 2012 | Turkey | Caucasian | PCR | 85/80 | 13 | 46 | 26 | 10 | 40 | 30 | 0.551 | 7 |
IAA | FAS −670A/G | Rehman et al. | 2018 | Pakistan | Caucasian | PCR | 170/222 | 13 | 105 | 52 | 26 | 47 | 149 | <0.001 | 7 |
JIA | FAS −670A/G | Donn et al. | 2002 | U.K. | Caucasian | PCR-RFLP | 342/255 | 79 | 177 | 86 | 48 | 139 | 68 | 0.122 | 4 |
SPA | FAS −670A/G | Lee et al. | 2001 | Korea | Asian | PCR | 54/84 | 11 | 27 | 16 | 13 | 46 | 25 | 0.279 | 5 |
Case (AA/AG/GG) | Control (AA/AG/GG) | ||||||||||||||
SLE | FAS −1377A/G | Arasteh et al. | 2010 | Iran | Caucasian | ASO-PCR | 249/212 | 3 | 43 | 203 | 6 | 54 | 152 | 0.652 | 7 |
Kanemitsu et al. | 2002 | Japan | Asian | AS-PCR, PCR-SSCP | 109/140 | 25 | 42 | 42 | 33 | 62 | 45 | 0.202 | 5 | ||
Huang et al. | 2000 | Australia | Caucasian | PCR | 86/90 | 3 | 21 | 62 | 2 | 22 | 66 | 0.917 | 7 | ||
RA | FAS −1377A/G | Zhu et al. | 2016 | China | Asian | MALDI-TOFMS | 615/839 | 68 | 284 | 246 | 85 | 357 | 389 | 0.817 | 7 |
Yıldır et al. | 2013 | Turkey | Caucasian | TaqMan | 100/101 | 0 | 26 | 74 | 2 | 18 | 81 | 0.411 | 7 | ||
pSS | FAS −1377A/G | Mullighan et al. | 2004 | Australia | Caucasian | PCR | 101/108 | 4 | 14 | 83 | 1 | 19 | 88 | 0.982 | 4 |
Bolstad et al. | 2000 | Norway | Caucasian | PCR | 70/72 | 2 | 18 | 50 | 1 | 18 | 53 | 0.702 | 5 | ||
GBS | FAS −1377A/G | Islam et al. | 2018 | Japan | Asian | PCR | 300/300 | 12 | 105 | 183 | 9 | 93 | 198 | 0.627 | 7 |
Geleijns et al. | 2005 | Netherlands | Caucasian | PCR | 272/212 | 3 | 61 | 208 | 1 | 40 | 171 | 0.406 | 5 | ||
Vitiligo | FAS −1377A/G | Li et al. | 2008 | China | Asian | PCR | 750/756 | 100 | 378 | 272 | 82 | 346 | 328 | 0.514 | 7 |
IAA | FAS −1377A/G | Rehman et al. | 2018 | Pakistan | Caucasian | PCR | 170/222 | 26 | 23 | 121 | 31 | 39 | 152 | <0.001 | 7 |
HT | FAS −1377A/G | Inoue et al. | 2016 | Japan | Asian | PCR-RFLP | 123/87 | 26 | 61 | 36 | 13 | 40 | 34 | 0.826 | 6 |
GD | FAS −1377A/G | Inoue et al. | 2016 | Japan | Asian | PCR-RFLP | 160/87 | 27 | 78 | 55 | 13 | 40 | 34 | 0.826 | 6 |
AIH | FAS −1377A/G | Hiraide et al. | 2005 | Japan | Asian | PCR | 74/98 | 13 | 28 | 33 | 25 | 39 | 34 | 0.051 | 4 |
AA | FAS −1377A/G | Fan et al. | 2010 | China | Asian | PCR | 84/84 | 12 | 32 | 40 | 7 | 42 | 35 | 0.252 | 6 |
Disease type . | Polymorphism . | Author . | Year . | Country . | Ethnicity . | Genotyping method . | Sample size (case/control) . | Case (GG/GA/AA) . | Control (GG/GA/AA) . | HWE . | NOS . | ||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
. | . | . | . | . | . | . | . | . | . | . | P-value . | score . | . | . | . |
SLE | FAS −670A/G | Bollain et al. | 2014 | Mexico | Mestizos | PCR-RFLP | 43/54 | 16 | 13 | 14 | 14 | 12 | 28 | <0.001 | 5 |
Moudi et al. | 2013 | Iran | Caucasian | PCR-RFLP | 106/149 | 17 | 55 | 34 | 39 | 73 | 37 | 0.808 | 7 | ||
Molin et al. | 2012 | Germany | Caucasian | PCR | 46/96 | 8 | 21 | 17 | 34 | 51 | 11 | 0.213 | 4 | ||
Lu et al. | 2012 | China | Asian | PCR | 552/718 | 96 | 237 | 219 | 138 | 326 | 254 | 0.070 | 6 | ||
Pradhan et al. | 2012 | India | Indian | PCR-RFLP | 70/70 | 11 | 37 | 22 | 21 | 42 | 7 | 0.036 | 6 | ||
Arasteh et al. | 2010 | Iran | Caucasian | ASO-PCR | 249/212 | 74 | 93 | 82 | 58 | 98 | 56 | 0.273 | 7 | ||
Xu et al. | 2004 | China | Asian | PCR-RFLP | 103/110 | 15 | 59 | 29 | 23 | 61 | 26 | 0.249 | 5 | ||
Kanemitsu et al. | 2002 | Japan | Asian | AS-PCR, PCR-SSCP | 109/140 | 25 | 49 | 35 | 50 | 64 | 26 | 0.492 | 5 | ||
Lee et al. | 2001 | Korea | Asian | PCR-RFLP | 87/87 | 13 | 47 | 27 | 13 | 48 | 26 | 0.230 | 5 | ||
Huang et al. | 1999 | Australia | Caucasian | PCR-RFLP | 79/86 | 20 | 21 | 38 | 20 | 22 | 44 | <0.001 | 4 | ||
MS | FAS −670A/G | Mohammadzadeh et al. | 2012 | Iran | Caucasian | PCR-RFLP | 107/112 | 22 | 37 | 48 | 18 | 50 | 44 | 0.551 | 8 |
Kantarci et al. | 2004 | U.S.A. | Caucasian | PCR-RFLP | 218/441 | 37 | 108 | 73 | 86 | 234 | 121 | 0.154 | 8 | ||
Lucas et al. | 2004 | Spain | Caucasian | PCR | 320/218 | 68 | 177 | 75 | 44 | 113 | 61 | 0.525 | 7 | ||
Niino et al. | 2002 | Japan | Asian | PCR-RFLP | 114/121 | 23 | 65 | 26 | 25 | 63 | 33 | 0.614 | 7 | ||
van Veen et al. | 2002 | Netherlands | Caucasian | PCR | 383/206 | 80 | 185 | 118 | 42 | 118 | 46 | 0.036 | 6 | ||
Huang et al. | 2000 | Australia | Caucasian | PCR-RFLP | 124/183 | 22 | 58 | 44 | 40 | 97 | 46 | 0.407 | 7 | ||
RA | FAS −670A/G | Yıldır et al. | 2013 | Turkey | Caucasian | TaqMan | 100/101 | 20 | 45 | 35 | 22 | 40 | 39 | 0.063 | 7 |
Kobak et al. | 2012 | Turkey | Caucasian | PCR-RFLP | 101/105 | 24 | 50 | 27 | 14 | 52 | 39 | 0.608 | 5 | ||
Mohammadzadeh et al. | 2011 | Iran | Caucasian | PCR | 120/112 | 17 | 64 | 39 | 18 | 50 | 44 | 0.551 | 4 | ||
Lee et al. | 2001 | Korea | Asian | PCR-RFLP | 87/87 | 16 | 38 | 33 | 13 | 48 | 26 | 0.230 | 5 | ||
Huang et al. | 1999 | Australia | Caucasian | PCR-RFLP | 185/86 | 32 | 105 | 48 | 22 | 44 | 20 | 0.825 | 4 | ||
Coakley et al. | 1999 | U.S.A. | Caucasian | PCR | 18/128 | 4 | 8 | 6 | 31 | 61 | 36 | 0.607 | 4 | ||
AIH | FAS −670A/G | Ngu et al. | 2013 | New Zealand | Caucasian | PCR | 77/455 | 19 | 35 | 23 | 107 | 214 | 134 | 0.232 | 5 |
Su et al. | 2012 | China | Asian | PCR-RFLP | 48/68 | 5 | 24 | 19 | 20 | 30 | 18 | 0.335 | 6 | ||
Agarwal et al. | 2007 | U.S.A. | Caucasian | PCR | 149/172 | 35 | 75 | 39 | 32 | 84 | 56 | 0.960 | 4 | ||
Hiraide et al. | 2005 | Japan | Asian | PCR | 72/130 | 14 | 31 | 27 | 40 | 63 | 27 | 0.811 | 4 | ||
LN | FAS −670A/G | Bollain et al. | 2014 | Mexico | Mestizos | PCR-RFLP | 24/54 | 8 | 9 | 7 | 14 | 12 | 28 | <0.001 | 5 |
Pradhan et al. | 2012 | India | Indian | PCR-RFLP | 35/70 | 7 | 16 | 12 | 21 | 42 | 7 | 0.036 | 6 | ||
Xu et al. | 2004 | China | Asian | PCR-RFLP | 62/110 | 9 | 34 | 19 | 23 | 61 | 26 | 0.249 | 5 | ||
Lee et al. | 2001 | Korea | Asian | PCR-RFLP | 26/87 | 4 | 12 | 10 | 13 | 48 | 26 | 0.230 | 5 | ||
SSc | FAS −670A/G | Liakouli et al. | 2013 | Italy | Caucasian | PCR | 350/232 | 65 | 158 | 127 | 60 | 120 | 52 | 0.586 | 8 |
Broen et al. | 2009 | Europe, U.S.A. | Caucasian | TaqMan | 2565/2855 | 616 | 1205 | 744 | 586 | 1455 | 814 | 0.168 | 7 | ||
Broen et al. | 2009 | U.S.A. | Hispanic | TaqMan | 159/137 | 46 | 80 | 33 | 41 | 71 | 25 | 0.552 | 7 | ||
Broen et al. | 2009 | U.S.A. | African | TaqMan | 176/194 | 93 | 68 | 15 | 96 | 83 | 15 | 0.613 | 7 | ||
AA | FAS −670A/G | Seleit et al. | 2018 | Egypt | Caucasian | PCR | 60/40 | 14 | 37 | 9 | 4 | 23 | 13 | 0.181 | 8 |
Kalkan et al. | 2013 | Turkey | Caucasian | PCR-RFLP | 118/118 | 0 | 81 | 37 | 13 | 65 | 40 | 0.077 | 7 | ||
Fan et al. | 2010 | China | Asian | PCR | 84/84 | 13 | 35 | 36 | 13 | 49 | 22 | 0.099 | 6 | ||
pSS | FAS −670A/G | Treviño-Talavera et al. | 2014 | Mexico | Amerindian | PCR-RFLP | 77/84 | 25 | 32 | 20 | 22 | 42 | 20 | 0.996 | 4 |
Mullighan et al. | 2004 | Australia | Caucasian | PCR | 101/108 | 17 | 54 | 30 | 21 | 54 | 33 | 0.897 | 4 | ||
Bolstad et al. | 2000 | Norway | Caucasian | PCR | 70/72 | 26 | 26 | 18 | 12 | 39 | 21 | 0.394 | 5 | ||
HT | FAS −670A/G | Erdogan et al. | 2016 | Turkey | Caucasian | PCR-RFLP | 112/112 | 31 | 57 | 24 | 15 | 56 | 41 | 0.547 | 8 |
Inoue et al. | 2016 | Japan | Asian | PCR-RFLP | 117/80 | 33 | 53 | 31 | 20 | 37 | 23 | 0.510 | 6 | ||
GBS | FAS −670A/G | Islam et al. | 2018 | Japan | Asian | PCR | 300/300 | 51 | 114 | 135 | 45 | 126 | 129 | 0.125 | 7 |
Geleijns et al. | 2005 | Netherlands | Caucasian | PCR | 272/212 | 67 | 129 | 76 | 42 | 114 | 56 | 0.243 | 5 | ||
PBC | FAS −670A/G | Su et al. | 2012 | China | Asian | PCR-RFLP | 19/68 | 5 | 7 | 7 | 20 | 30 | 18 | 0.335 | 6 |
Hiraide et al. | 2005 | Japan | Asian | PCR | 96/130 | 30 | 37 | 29 | 40 | 63 | 27 | 0.811 | 4 | ||
vitiligo | FAS −670A/G | Li et al. | 2008 | China | Asian | PCR | 750/756 | 101 | 364 | 285 | 108 | 363 | 285 | 0.660 | 7 |
GD | FAS −670A/G | Inoue et al. | 2016 | Japan | Asian | PCR-RFLP | 146/80 | 41 | 61 | 44 | 20 | 37 | 23 | 0.510 | 6 |
T1D | FAS −670A/G | Sahin et al. | 2012 | Turkey | Caucasian | PCR | 85/80 | 13 | 46 | 26 | 10 | 40 | 30 | 0.551 | 7 |
IAA | FAS −670A/G | Rehman et al. | 2018 | Pakistan | Caucasian | PCR | 170/222 | 13 | 105 | 52 | 26 | 47 | 149 | <0.001 | 7 |
JIA | FAS −670A/G | Donn et al. | 2002 | U.K. | Caucasian | PCR-RFLP | 342/255 | 79 | 177 | 86 | 48 | 139 | 68 | 0.122 | 4 |
SPA | FAS −670A/G | Lee et al. | 2001 | Korea | Asian | PCR | 54/84 | 11 | 27 | 16 | 13 | 46 | 25 | 0.279 | 5 |
Case (AA/AG/GG) | Control (AA/AG/GG) | ||||||||||||||
SLE | FAS −1377A/G | Arasteh et al. | 2010 | Iran | Caucasian | ASO-PCR | 249/212 | 3 | 43 | 203 | 6 | 54 | 152 | 0.652 | 7 |
Kanemitsu et al. | 2002 | Japan | Asian | AS-PCR, PCR-SSCP | 109/140 | 25 | 42 | 42 | 33 | 62 | 45 | 0.202 | 5 | ||
Huang et al. | 2000 | Australia | Caucasian | PCR | 86/90 | 3 | 21 | 62 | 2 | 22 | 66 | 0.917 | 7 | ||
RA | FAS −1377A/G | Zhu et al. | 2016 | China | Asian | MALDI-TOFMS | 615/839 | 68 | 284 | 246 | 85 | 357 | 389 | 0.817 | 7 |
Yıldır et al. | 2013 | Turkey | Caucasian | TaqMan | 100/101 | 0 | 26 | 74 | 2 | 18 | 81 | 0.411 | 7 | ||
pSS | FAS −1377A/G | Mullighan et al. | 2004 | Australia | Caucasian | PCR | 101/108 | 4 | 14 | 83 | 1 | 19 | 88 | 0.982 | 4 |
Bolstad et al. | 2000 | Norway | Caucasian | PCR | 70/72 | 2 | 18 | 50 | 1 | 18 | 53 | 0.702 | 5 | ||
GBS | FAS −1377A/G | Islam et al. | 2018 | Japan | Asian | PCR | 300/300 | 12 | 105 | 183 | 9 | 93 | 198 | 0.627 | 7 |
Geleijns et al. | 2005 | Netherlands | Caucasian | PCR | 272/212 | 3 | 61 | 208 | 1 | 40 | 171 | 0.406 | 5 | ||
Vitiligo | FAS −1377A/G | Li et al. | 2008 | China | Asian | PCR | 750/756 | 100 | 378 | 272 | 82 | 346 | 328 | 0.514 | 7 |
IAA | FAS −1377A/G | Rehman et al. | 2018 | Pakistan | Caucasian | PCR | 170/222 | 26 | 23 | 121 | 31 | 39 | 152 | <0.001 | 7 |
HT | FAS −1377A/G | Inoue et al. | 2016 | Japan | Asian | PCR-RFLP | 123/87 | 26 | 61 | 36 | 13 | 40 | 34 | 0.826 | 6 |
GD | FAS −1377A/G | Inoue et al. | 2016 | Japan | Asian | PCR-RFLP | 160/87 | 27 | 78 | 55 | 13 | 40 | 34 | 0.826 | 6 |
AIH | FAS −1377A/G | Hiraide et al. | 2005 | Japan | Asian | PCR | 74/98 | 13 | 28 | 33 | 25 | 39 | 34 | 0.051 | 4 |
AA | FAS −1377A/G | Fan et al. | 2010 | China | Asian | PCR | 84/84 | 12 | 32 | 40 | 7 | 42 | 35 | 0.252 | 6 |
Meta-analysis results of the FAS −670 A/G and −1377 G/A polymorphisms and autoimmune diseases
A summary of the meta-analysis of the association between the FAS −670 A/G and −1377 G/A polymorphisms and autoimmune diseases is shown in Table 2. In the FAS −670 A/G polymorphism, a significant association between FAS −670 A/G and the risk of autoimmune diseases was observed under the heterozygous genetic model (GG vs. GA: OR = 1.079, 95% CI 1.004–1.160, P=0.038). In the FAS −1377 G/A polymorphism, our results indicated that FAS −1377 G/A polymorphism was associated with the risk of autoimmune diseases (A vs. G: OR = 1.11, 95% CI = 1.03–1.20, P=0.008; AA vs. GG: OR = 1.23, 95% CI = 1.03–1.47, P=0.024; AA+AG vs. GG: OR = 1.14, 95% CI = 1.02–1.26, P=0.015).
Polymorphism . | Categories . | Studies (n) . | Test of heterogeneity . | Test of associations . | Egger’s test . | Sensitivity analysis . | ||
---|---|---|---|---|---|---|---|---|
. | . | . | P-value . | I2 (%) . | OR (95% CI) . | P-value . | P-value . | P-value . |
FAS −670 A/G G vs. A | ||||||||
Overall | 52 | <0.001 | 65.9 | 0.99 (0.95, 1.03) | 0.493 | 0.222 | 0.295 | |
Caucasian | 27 | <0.001 | 71.5 | 1.03 (0.98, 1.08) | 0.241 | 0.973 | 0.418 | |
Asian | 18 | 0.225 | 19.2 | 0.89 (0.83, 0.96) | 0.002 | 0.147 | 0.002 | |
High quality | 28 | <0.001 | 70.9 | 0.98 (0.94, 1.03) | 0.446 | 0.314 | 0.427 | |
Low quality | 24 | <0.001 | 59.3 | 1.00 (0.93, 1.08) | 0.958 | 0.622 | 0.328 | |
SLE | 10 | <0.001 | 73.6 | 0.85 (0.77, 0.94) | 0.001 | 0.583 | <0.001 | |
RA | 6 | 0.264 | 22.6 | 1.04 (0.88, 1.23) | 0.675 | 0.772 | 0.675 | |
MS | 6 | 0.313 | 15.7 | 0.92 (0.82, 1.03) | 0.148 | 0.826 | 0.348 | |
AIH | 4 | 0.003 | 78.2 | 0.89 (0.74, 1.08) | 0.232 | 0.089 | 0.232 | |
LN | 4 | 0.041 | 63.6 | 0.82 (0.62, 1.08) | 0.159 | 0.531 | 0.201 | |
SSc | 4 | 0.002 | 80.2 | 1.01 (0.95, 1.09) | 0.707 | 0.419 | 0.707 | |
AA | 3 | 0.024 | 73.3 | 0.93 (0.72, 1.19) | 0.553 | 0.372 | 0.553 | |
pSS | 3 | 0.692 | 0.0 | 1.02 (0.76, 1.36) | 0.914 | 0.285 | 0.914 | |
HT | 2 | 0.082 | 67.0 | 1.45 (1.10, 1.90) | 0.008 | NA | 0.008 | |
GBS | 2 | 0.709 | 0.0 | 1.03 (0.87, 1.23) | 0.729 | NA | 0.729 | |
PBC | 2 | 0.828 | 0.0 | 0.82 (0.59, 1.14) | 0.240 | NA | 0.240 | |
FAS −670 A/G GG vs. AA | ||||||||
Overall | 52 | <0.001 | 59.1 | 0.96 (0.89, 1.04) | 0.288 | 0.104 | 0.375 | |
Caucasian | 27 | <0.001 | 63.8 | 1.03 (0.94, 1.14) | 0.524 | 0.519 | 0.368 | |
Asian | 18 | 0.225 | 19.2 | 0.81 (0.70, 0.94) | 0.005 | 0.196 | 0.005 | |
High quality | 28 | <0.001 | 62.6 | 0.95 (0.86, 1.04) | 0.244 | 0.078 | 0.556 | |
Low quality | 24 | <0.001 | 56.1 | 0.99 (0.85, 1.16) | 0.905 | 0.287 | 0.304 | |
SLE | 10 | <0.001 | 73.2 | 0.74 (0.61, 0.89) | 0.002 | 0.230 | <0.001 | |
RA | 6 | 0.263 | 22.7 | 1.05 (0.75, 1.48) | 0.762 | 0.930 | 0.762 | |
MS | 6 | 0.353 | 9.9 | 0.87 (0.69, 1.10) | 0.239 | 0.686 | 0.467 | |
AIH | 4 | 0.004 | 77.2 | 0.80 (0.56, 1.15) | 0.232 | 0.123 | 0.232 | |
LN | 4 | 0.036 | 65.0 | 0.68 (0.39, 1.18) | 0.173 | 0.843 | 0.226 | |
SSc | 4 | 0.002 | 79.1 | 1.04 (0.91, 1.19) | 0.567 | 0.342 | 0.567 | |
AA | 3 | 0.003 | 82.9 | 0.68 (0.36, 1.28) | 0.235 | 0.805 | 0.235 | |
pSS | 3 | 0.683 | 0.0 | 1.00 (0.56, 1.79) | 0.998 | 0.044 | 0.286 | |
HT | 2 | 0.062 | 71.4 | 2.05 (1.19, 3.54) | 0.010 | NA | 0.010 | |
GBS | 2 | 0.818 | 0.0 | 1.12 (0.79, 1.59) | 0.510 | NA | 0.510 | |
PBC | 2 | 0.913 | 0.0 | 0.69 (0.37, 1.28) | 0.234 | NA | 0.234 | |
FAS −670 A/G GG vs. GA | ||||||||
Overall | 52 | 0.018 | 31.4 | 1.079 (1.004, 1.160) | 0.038 | 0.087 | 0.006 | |
Caucasian | 27 | <0.001 | 54.4 | 1.12 (1.03, 1.23) | 0.012 | 0.008 | 0.001 | |
Asian | 18 | 0.835 | 0.0 | 0.99 (0.86, 1.14) | 0.905 | 0.991 | 0.905 | |
High quality | 28 | 0.003 | 47.3 | 1.07 (0.99, 1.17) | 0.096 | 0.022 | 0.028 | |
Low quality | 24 | 0.454 | 0.5 | 1.10 (0.95, 1.27) | 0.208 | 0.364 | 0.180 | |
SLE | 10 | 0.568 | 0.0 | 0.92 (0.77, 1.11) | 0.398 | 0.177 | 0.493 | |
RA | 6 | 0.276 | 20.9 | 0.96 (0.69, 1.31) | 0.781 | 0.497 | 0.781 | |
MS | 6 | 0.766 | 0.0 | 1.05 (0.85, 1.30) | 0.674 | 0.627 | 0.995 | |
AIH | 4 | 0.151 | 43.5 | 0.90 (0.64, 1.27) | 0.563 | 0.005 | 0.563 | |
LN | 4 | 0.910 | 0.0 | 0.83 (0.49, 1.39) | 0.471 | 0.142 | 0.621 | |
SSc | 4 | 0.243 | 28.2 | 1.20 (1.07, 1.36) | 0.003 | 0.201 | 0.003 | |
AA | 3 | 0.009 | 78.7 | 0.79 (0.44, 1.41) | 0.419 | 0.355 | 0.419 | |
pSS | 3 | 0.252 | 23.9 | 1.10 (0.66, 1.85) | 0.715 | 0.358 | 0.071 | |
HT | 2 | 0.267 | 18.9 | 1.52 (0.93, 2.50) | 0.098 | NA | 0.098 | |
GBS | 2 | 0.726 | 0.0 | 1.33 (0.96, 1.85) | 0.089 | NA | 0.089 | |
PBC | 2 | 0.809 | 0.0 | 1.23 (0.71, 2.16) | 0.461 | NA | 0.461 | |
FAS −670 A/G GG+GA vs. AA | ||||||||
Overall | 52 | <0.001 | 70.6 | 0.94 (0.89, 1.00) | 0.051 | 0.129 | 0.004 | |
Caucasian | 27 | <0.001 | 76.0 | 1.00 (0.93, 1.08) | 0.945 | 0.662 | 0.306 | |
Asian | 18 | 0.143 | 26.7 | 0.83 (0.74, 0.92) | 0.001 | 0.056 | 0.001 | |
High quality | 28 | <0.001 | 76.7 | 0.94 (0.88, 1.01) | 0.071 | 0.614 | 0.023 | |
Low quality | 24 | <0.001 | 60.1 | 0.95 (0.85, 1.08) | 0.445 | 0.500 | 0.050 | |
SLE | 10 | <0.001 | 74.3 | 0.78 (0.67, 0.90) | 0.001 | 0.374 | <0.001 | |
RA | 6 | 0.388 | 4.4 | 1.09 (0.85, 1.40) | 0.503 | 0.388 | 0.503 | |
MS | 6 | 0.080 | 49.1 | 0.83 (0.70, 0.99) | 0.043 | 0.752 | 0.261 | |
AIH | 4 | 0.026 | 67.6 | 0.87 (0.65, 1.15) | 0.330 | 0.170 | 0.330 | |
LN | 4 | <0.001 | 84.2 | 0.86 (0.57, 1.31) | 0.483 | 0.922 | 0.196 | |
SSc | 4 | 0.014 | 71.7 | 0.92 (0.82, 1.02) | 0.112 | 0.424 | 0.112 | |
AA | 3 | 0.009 | 78.5 | 0.95 (0.66, 1.39) | 0.804 | 0.666 | 0.804 | |
pSS | 3 | 0.741 | 0.0 | 0.98 (0.62, 1.54) | 0.921 | 0.964 | 0.874 | |
HT | 2 | 0.150 | 51.7 | 1.58 (1.03, 2.42) | 0.037 | NA | 0.037 | |
GBS | 2 | 0.988 | 0.0 | 0.92 (0.72, 1.19) | 0.536 | NA | 0.536 | |
PBC | 2 | 0.976 | 0.0 | 0.61 (0.36, 1.03) | 0.066 | NA | 0.066 | |
FAS −670 A/G GG vs. GA+AA | ||||||||
Overall | 52 | 0.003 | 38.8 | 1.04 (0.97, 1.11) | 0.294 | 0.083 | 0.142 | |
Caucasian | 27 | 0.001 | 52.7 | 1.10 (1.01, 1.19) | 0.035 | 0.175 | 0.011 | |
Asian | 18 | 0.694 | 0.0 | 0.91 (0.80, 1.04) | 0.162 | 0.541 | 0.162 | |
High quality | 28 | 0.005 | 45.3 | 1.03 (0.95, 1.12) | 0.457 | 0.019 | 0.226 | |
Low quality | 24 | 0.066 | 32.2 | 1.06 (0.93, 1.21) | 0.421 | 0.284 | 0.638 | |
SLE | 10 | 0.065 | 44.1 | 0.86 (0.72, 1.01) | 0.071 | 0.292 | 0.034 | |
RA | 6 | 0.237 | 26.4 | 0.99 (0.74, 1.34) | 0.962 | 0.627 | 0.962 | |
MS | 6 | 0.824 | 0.0 | 0.97 (0.80, 1.19) | 0.796 | 0.714 | 0.709 | |
AIH | 4 | 0.027 | 67.3 | 0.86 (0.63, 1.18) | 0.345 | 0.060 | 0.345 | |
LN | 4 | 0.895 | 0.0 | 0.71 (0.43, 1.15) | 0.162 | 0.193 | 0.303 | |
SSc | 4 | 0.028 | 67.2 | 1.14 (1.02, 1.28) | 0.022 | 0.275 | 0.022 | |
AA | 3 | 0.009 | 79.0 | 0.77 (0.44, 1.34) | 0.349 | 0.546 | 0.349 | |
pSS | 3 | 0.338 | 0.0 | 1.07 (0.66, 1.75) | 0.081 | 0.426 | 0.081 | |
HT | 2 | 0.122 | 58.1 | 1.68 (1.06, 2.68) | 0.029 | NA | 0.029 | |
GBS | 2 | 0.678 | 0.0 | 1.24 (0.91, 1.69) | 0.172 | NA | 0.172 | |
PBC | 2 | 0.787 | 0.0 | 0.99 (0.66, 1.75) | 0.960 | NA | 0.960 | |
FAS −1377 G/A A vs. G | ||||||||
Overall | 15 | 0.091 | 34.6 | 1.11 (1.03, 1.20) | 0.008 | 0.329 | 0.006 | |
Caucasian | 7 | 0.173 | 33.4 | 0.98 (0.82, 1.16) | 0.790 | 0.357 | 0.863 | |
Asian | 8 | 0.198 | 28.8 | 1.15 (1.05, 1.25) | 0.002 | 0.167 | 0.002 | |
High quality | 10 | 0.116 | 36.5 | 1.14 (1.05, 1.24) | 0.002 | 0.285 | 0.001 | |
Low quality | 5 | 0.293 | 19.2 | 0.96 (0.79, 1.18) | 0.711 | 0.588 | 0.711 | |
FAS −1377 G/A AA vs. GG | ||||||||
Overall | 15 | 0.452 | 0.0 | 1.23 (1.03, 1.47) | 0.024 | 0.878 | 0.020 | |
Caucasian | 7 | 0.459 | 0.0 | 1.06 (0.67, 1.66) | 0.816 | 0.752 | 0.881 | |
Asian | 8 | 0.353 | 10.0 | 1.27 (1.04, 1.54) | 0.018 | 0.511 | 0.018 | |
High quality | 10 | 0.702 | 0.0 | 1.31 (1.08, 1.59) | 0.007 | 0.234 | 0.005 | |
Low quality | 5 | 0.325 | 14.1 | 0.86 (0.54, 1.38) | 0.536 | 0.072 | 0.536 | |
FAS −1377 G/A AA vs. AG | ||||||||
Overall | 15 | 0.863 | 0.0 | 1.12 (0.93, 1.34) | 0.234 | 0.584 | 0.323 | |
Caucasian | 7 | 0.570 | 0.0 | 1.30 (0.76, 2.20) | 0.335 | 0.883 | 0.680 | |
Asian | 8 | 0.858 | 0.0 | 1.09 (0.90, 1.33) | 0.360 | 0.444 | 0.360 | |
High quality | 10 | 0.820 | 0.0 | 1.12 (0.92, 1.36) | 0.268 | 0.958 | 0.375 | |
Low quality | 5 | 0.507 | 0.0 | 1.11 (0.70, 1.77) | 0.662 | 0.166 | 0.662 | |
FAS −1377 G/A AA+AG vs. GG | ||||||||
Overall | 15 | 0.055 | 39.9 | 1.14 (1.02, 1.26) | 0.015 | 0.113 | 0.008 | |
Caucasian | 7 | 0.190 | 31.1 | 0.95 (0.78, 1.16) | 0.620 | 0.366 | 0.798 | |
Asian | 8 | 0.157 | 34.0 | 1.21 (1.07, 1.36) | 0.002 | 0.080 | 0.002 | |
High quality | 10 | 0.047 | 47.5 | 1.17 (1.05, 1.31) | 0.005 | 0.257 | 0.002 | |
Low quality | 5 | 0.402 | 0.7 | 0.96 (0.74, 1.23) | 0.727 | 0.560 | 0.727 | |
FAS −1377 G/A AA vs. AG+GG | ||||||||
Overall | 15 | 0.741 | 0.0 | 1.16 (0.98, 1.37) | 0.090 | 0.888 | 0.097 | |
Caucasian | 7 | 0.490 | 0.0 | 1.10 (0.70, 1.72) | 0.674 | 0.823 | 0.834 | |
Asian | 8 | 0.683 | 0.0 | 1.17 (0.97, 1.40) | 0.098 | 0.959 | 0.098 | |
High quality | 10 | 0.823 | 0.0 | 1.20 (0.99, 1.44) | 0.054 | 0.444 | 0.056 | |
Low quality | 5 | 0.392 | 2.5 | 0.96 (0.63, 1.47) | 0.848 | 0.120 | 0.848 |
Polymorphism . | Categories . | Studies (n) . | Test of heterogeneity . | Test of associations . | Egger’s test . | Sensitivity analysis . | ||
---|---|---|---|---|---|---|---|---|
. | . | . | P-value . | I2 (%) . | OR (95% CI) . | P-value . | P-value . | P-value . |
FAS −670 A/G G vs. A | ||||||||
Overall | 52 | <0.001 | 65.9 | 0.99 (0.95, 1.03) | 0.493 | 0.222 | 0.295 | |
Caucasian | 27 | <0.001 | 71.5 | 1.03 (0.98, 1.08) | 0.241 | 0.973 | 0.418 | |
Asian | 18 | 0.225 | 19.2 | 0.89 (0.83, 0.96) | 0.002 | 0.147 | 0.002 | |
High quality | 28 | <0.001 | 70.9 | 0.98 (0.94, 1.03) | 0.446 | 0.314 | 0.427 | |
Low quality | 24 | <0.001 | 59.3 | 1.00 (0.93, 1.08) | 0.958 | 0.622 | 0.328 | |
SLE | 10 | <0.001 | 73.6 | 0.85 (0.77, 0.94) | 0.001 | 0.583 | <0.001 | |
RA | 6 | 0.264 | 22.6 | 1.04 (0.88, 1.23) | 0.675 | 0.772 | 0.675 | |
MS | 6 | 0.313 | 15.7 | 0.92 (0.82, 1.03) | 0.148 | 0.826 | 0.348 | |
AIH | 4 | 0.003 | 78.2 | 0.89 (0.74, 1.08) | 0.232 | 0.089 | 0.232 | |
LN | 4 | 0.041 | 63.6 | 0.82 (0.62, 1.08) | 0.159 | 0.531 | 0.201 | |
SSc | 4 | 0.002 | 80.2 | 1.01 (0.95, 1.09) | 0.707 | 0.419 | 0.707 | |
AA | 3 | 0.024 | 73.3 | 0.93 (0.72, 1.19) | 0.553 | 0.372 | 0.553 | |
pSS | 3 | 0.692 | 0.0 | 1.02 (0.76, 1.36) | 0.914 | 0.285 | 0.914 | |
HT | 2 | 0.082 | 67.0 | 1.45 (1.10, 1.90) | 0.008 | NA | 0.008 | |
GBS | 2 | 0.709 | 0.0 | 1.03 (0.87, 1.23) | 0.729 | NA | 0.729 | |
PBC | 2 | 0.828 | 0.0 | 0.82 (0.59, 1.14) | 0.240 | NA | 0.240 | |
FAS −670 A/G GG vs. AA | ||||||||
Overall | 52 | <0.001 | 59.1 | 0.96 (0.89, 1.04) | 0.288 | 0.104 | 0.375 | |
Caucasian | 27 | <0.001 | 63.8 | 1.03 (0.94, 1.14) | 0.524 | 0.519 | 0.368 | |
Asian | 18 | 0.225 | 19.2 | 0.81 (0.70, 0.94) | 0.005 | 0.196 | 0.005 | |
High quality | 28 | <0.001 | 62.6 | 0.95 (0.86, 1.04) | 0.244 | 0.078 | 0.556 | |
Low quality | 24 | <0.001 | 56.1 | 0.99 (0.85, 1.16) | 0.905 | 0.287 | 0.304 | |
SLE | 10 | <0.001 | 73.2 | 0.74 (0.61, 0.89) | 0.002 | 0.230 | <0.001 | |
RA | 6 | 0.263 | 22.7 | 1.05 (0.75, 1.48) | 0.762 | 0.930 | 0.762 | |
MS | 6 | 0.353 | 9.9 | 0.87 (0.69, 1.10) | 0.239 | 0.686 | 0.467 | |
AIH | 4 | 0.004 | 77.2 | 0.80 (0.56, 1.15) | 0.232 | 0.123 | 0.232 | |
LN | 4 | 0.036 | 65.0 | 0.68 (0.39, 1.18) | 0.173 | 0.843 | 0.226 | |
SSc | 4 | 0.002 | 79.1 | 1.04 (0.91, 1.19) | 0.567 | 0.342 | 0.567 | |
AA | 3 | 0.003 | 82.9 | 0.68 (0.36, 1.28) | 0.235 | 0.805 | 0.235 | |
pSS | 3 | 0.683 | 0.0 | 1.00 (0.56, 1.79) | 0.998 | 0.044 | 0.286 | |
HT | 2 | 0.062 | 71.4 | 2.05 (1.19, 3.54) | 0.010 | NA | 0.010 | |
GBS | 2 | 0.818 | 0.0 | 1.12 (0.79, 1.59) | 0.510 | NA | 0.510 | |
PBC | 2 | 0.913 | 0.0 | 0.69 (0.37, 1.28) | 0.234 | NA | 0.234 | |
FAS −670 A/G GG vs. GA | ||||||||
Overall | 52 | 0.018 | 31.4 | 1.079 (1.004, 1.160) | 0.038 | 0.087 | 0.006 | |
Caucasian | 27 | <0.001 | 54.4 | 1.12 (1.03, 1.23) | 0.012 | 0.008 | 0.001 | |
Asian | 18 | 0.835 | 0.0 | 0.99 (0.86, 1.14) | 0.905 | 0.991 | 0.905 | |
High quality | 28 | 0.003 | 47.3 | 1.07 (0.99, 1.17) | 0.096 | 0.022 | 0.028 | |
Low quality | 24 | 0.454 | 0.5 | 1.10 (0.95, 1.27) | 0.208 | 0.364 | 0.180 | |
SLE | 10 | 0.568 | 0.0 | 0.92 (0.77, 1.11) | 0.398 | 0.177 | 0.493 | |
RA | 6 | 0.276 | 20.9 | 0.96 (0.69, 1.31) | 0.781 | 0.497 | 0.781 | |
MS | 6 | 0.766 | 0.0 | 1.05 (0.85, 1.30) | 0.674 | 0.627 | 0.995 | |
AIH | 4 | 0.151 | 43.5 | 0.90 (0.64, 1.27) | 0.563 | 0.005 | 0.563 | |
LN | 4 | 0.910 | 0.0 | 0.83 (0.49, 1.39) | 0.471 | 0.142 | 0.621 | |
SSc | 4 | 0.243 | 28.2 | 1.20 (1.07, 1.36) | 0.003 | 0.201 | 0.003 | |
AA | 3 | 0.009 | 78.7 | 0.79 (0.44, 1.41) | 0.419 | 0.355 | 0.419 | |
pSS | 3 | 0.252 | 23.9 | 1.10 (0.66, 1.85) | 0.715 | 0.358 | 0.071 | |
HT | 2 | 0.267 | 18.9 | 1.52 (0.93, 2.50) | 0.098 | NA | 0.098 | |
GBS | 2 | 0.726 | 0.0 | 1.33 (0.96, 1.85) | 0.089 | NA | 0.089 | |
PBC | 2 | 0.809 | 0.0 | 1.23 (0.71, 2.16) | 0.461 | NA | 0.461 | |
FAS −670 A/G GG+GA vs. AA | ||||||||
Overall | 52 | <0.001 | 70.6 | 0.94 (0.89, 1.00) | 0.051 | 0.129 | 0.004 | |
Caucasian | 27 | <0.001 | 76.0 | 1.00 (0.93, 1.08) | 0.945 | 0.662 | 0.306 | |
Asian | 18 | 0.143 | 26.7 | 0.83 (0.74, 0.92) | 0.001 | 0.056 | 0.001 | |
High quality | 28 | <0.001 | 76.7 | 0.94 (0.88, 1.01) | 0.071 | 0.614 | 0.023 | |
Low quality | 24 | <0.001 | 60.1 | 0.95 (0.85, 1.08) | 0.445 | 0.500 | 0.050 | |
SLE | 10 | <0.001 | 74.3 | 0.78 (0.67, 0.90) | 0.001 | 0.374 | <0.001 | |
RA | 6 | 0.388 | 4.4 | 1.09 (0.85, 1.40) | 0.503 | 0.388 | 0.503 | |
MS | 6 | 0.080 | 49.1 | 0.83 (0.70, 0.99) | 0.043 | 0.752 | 0.261 | |
AIH | 4 | 0.026 | 67.6 | 0.87 (0.65, 1.15) | 0.330 | 0.170 | 0.330 | |
LN | 4 | <0.001 | 84.2 | 0.86 (0.57, 1.31) | 0.483 | 0.922 | 0.196 | |
SSc | 4 | 0.014 | 71.7 | 0.92 (0.82, 1.02) | 0.112 | 0.424 | 0.112 | |
AA | 3 | 0.009 | 78.5 | 0.95 (0.66, 1.39) | 0.804 | 0.666 | 0.804 | |
pSS | 3 | 0.741 | 0.0 | 0.98 (0.62, 1.54) | 0.921 | 0.964 | 0.874 | |
HT | 2 | 0.150 | 51.7 | 1.58 (1.03, 2.42) | 0.037 | NA | 0.037 | |
GBS | 2 | 0.988 | 0.0 | 0.92 (0.72, 1.19) | 0.536 | NA | 0.536 | |
PBC | 2 | 0.976 | 0.0 | 0.61 (0.36, 1.03) | 0.066 | NA | 0.066 | |
FAS −670 A/G GG vs. GA+AA | ||||||||
Overall | 52 | 0.003 | 38.8 | 1.04 (0.97, 1.11) | 0.294 | 0.083 | 0.142 | |
Caucasian | 27 | 0.001 | 52.7 | 1.10 (1.01, 1.19) | 0.035 | 0.175 | 0.011 | |
Asian | 18 | 0.694 | 0.0 | 0.91 (0.80, 1.04) | 0.162 | 0.541 | 0.162 | |
High quality | 28 | 0.005 | 45.3 | 1.03 (0.95, 1.12) | 0.457 | 0.019 | 0.226 | |
Low quality | 24 | 0.066 | 32.2 | 1.06 (0.93, 1.21) | 0.421 | 0.284 | 0.638 | |
SLE | 10 | 0.065 | 44.1 | 0.86 (0.72, 1.01) | 0.071 | 0.292 | 0.034 | |
RA | 6 | 0.237 | 26.4 | 0.99 (0.74, 1.34) | 0.962 | 0.627 | 0.962 | |
MS | 6 | 0.824 | 0.0 | 0.97 (0.80, 1.19) | 0.796 | 0.714 | 0.709 | |
AIH | 4 | 0.027 | 67.3 | 0.86 (0.63, 1.18) | 0.345 | 0.060 | 0.345 | |
LN | 4 | 0.895 | 0.0 | 0.71 (0.43, 1.15) | 0.162 | 0.193 | 0.303 | |
SSc | 4 | 0.028 | 67.2 | 1.14 (1.02, 1.28) | 0.022 | 0.275 | 0.022 | |
AA | 3 | 0.009 | 79.0 | 0.77 (0.44, 1.34) | 0.349 | 0.546 | 0.349 | |
pSS | 3 | 0.338 | 0.0 | 1.07 (0.66, 1.75) | 0.081 | 0.426 | 0.081 | |
HT | 2 | 0.122 | 58.1 | 1.68 (1.06, 2.68) | 0.029 | NA | 0.029 | |
GBS | 2 | 0.678 | 0.0 | 1.24 (0.91, 1.69) | 0.172 | NA | 0.172 | |
PBC | 2 | 0.787 | 0.0 | 0.99 (0.66, 1.75) | 0.960 | NA | 0.960 | |
FAS −1377 G/A A vs. G | ||||||||
Overall | 15 | 0.091 | 34.6 | 1.11 (1.03, 1.20) | 0.008 | 0.329 | 0.006 | |
Caucasian | 7 | 0.173 | 33.4 | 0.98 (0.82, 1.16) | 0.790 | 0.357 | 0.863 | |
Asian | 8 | 0.198 | 28.8 | 1.15 (1.05, 1.25) | 0.002 | 0.167 | 0.002 | |
High quality | 10 | 0.116 | 36.5 | 1.14 (1.05, 1.24) | 0.002 | 0.285 | 0.001 | |
Low quality | 5 | 0.293 | 19.2 | 0.96 (0.79, 1.18) | 0.711 | 0.588 | 0.711 | |
FAS −1377 G/A AA vs. GG | ||||||||
Overall | 15 | 0.452 | 0.0 | 1.23 (1.03, 1.47) | 0.024 | 0.878 | 0.020 | |
Caucasian | 7 | 0.459 | 0.0 | 1.06 (0.67, 1.66) | 0.816 | 0.752 | 0.881 | |
Asian | 8 | 0.353 | 10.0 | 1.27 (1.04, 1.54) | 0.018 | 0.511 | 0.018 | |
High quality | 10 | 0.702 | 0.0 | 1.31 (1.08, 1.59) | 0.007 | 0.234 | 0.005 | |
Low quality | 5 | 0.325 | 14.1 | 0.86 (0.54, 1.38) | 0.536 | 0.072 | 0.536 | |
FAS −1377 G/A AA vs. AG | ||||||||
Overall | 15 | 0.863 | 0.0 | 1.12 (0.93, 1.34) | 0.234 | 0.584 | 0.323 | |
Caucasian | 7 | 0.570 | 0.0 | 1.30 (0.76, 2.20) | 0.335 | 0.883 | 0.680 | |
Asian | 8 | 0.858 | 0.0 | 1.09 (0.90, 1.33) | 0.360 | 0.444 | 0.360 | |
High quality | 10 | 0.820 | 0.0 | 1.12 (0.92, 1.36) | 0.268 | 0.958 | 0.375 | |
Low quality | 5 | 0.507 | 0.0 | 1.11 (0.70, 1.77) | 0.662 | 0.166 | 0.662 | |
FAS −1377 G/A AA+AG vs. GG | ||||||||
Overall | 15 | 0.055 | 39.9 | 1.14 (1.02, 1.26) | 0.015 | 0.113 | 0.008 | |
Caucasian | 7 | 0.190 | 31.1 | 0.95 (0.78, 1.16) | 0.620 | 0.366 | 0.798 | |
Asian | 8 | 0.157 | 34.0 | 1.21 (1.07, 1.36) | 0.002 | 0.080 | 0.002 | |
High quality | 10 | 0.047 | 47.5 | 1.17 (1.05, 1.31) | 0.005 | 0.257 | 0.002 | |
Low quality | 5 | 0.402 | 0.7 | 0.96 (0.74, 1.23) | 0.727 | 0.560 | 0.727 | |
FAS −1377 G/A AA vs. AG+GG | ||||||||
Overall | 15 | 0.741 | 0.0 | 1.16 (0.98, 1.37) | 0.090 | 0.888 | 0.097 | |
Caucasian | 7 | 0.490 | 0.0 | 1.10 (0.70, 1.72) | 0.674 | 0.823 | 0.834 | |
Asian | 8 | 0.683 | 0.0 | 1.17 (0.97, 1.40) | 0.098 | 0.959 | 0.098 | |
High quality | 10 | 0.823 | 0.0 | 1.20 (0.99, 1.44) | 0.054 | 0.444 | 0.056 | |
Low quality | 5 | 0.392 | 2.5 | 0.96 (0.63, 1.47) | 0.848 | 0.120 | 0.848 |
Stratification analyses by ethnicity, disease type, and quality score
Based on ethnicity, disease type, and quality score, we performed stratification analyses.
The results of the meta-analysis of the association between the FAS −670 A/G and −1377 G/A polymorphisms and autoimmune diseases risk stratified by ethnicity, disease type, and quality score are shown in Table 2.
On the basis of ethnicity, the stratified meta-analysis showed an association between FAS −670 A/G polymorphism and the risk of autoimmune diseases in Caucasians (GG vs. GA: OR = 1.12, 95% CI 1.03–1.23, P=0.012) and Asians (G vs. A: OR = 0.89, 95% CI 0.83–0.96, P=0.002) but not in other ethnic groups. The association between FAS −1377 G/A polymorphism and the risk of autoimmune diseases was observed in Asians (A vs. G: OR = 1.15, 95% CI 1.05–1.25, P=0.002) but not in Caucasians.
On the basis of disease type, the stratified meta-analysis suggested that the FAS −670 A/G polymorphism might be associated with the risk of SLE (G vs. A: OR = 0.85, 95% CI 0.77–0.94, P=0.001), MS (GG+GA vs. AA: OR = 0.83, 95% CI 0.70–0.99, P=0.043), SSc (GG vs. GA: OR = 1.20, 95% CI 1.07–1.36, P=0.003), and HT (G vs. A: OR = 1.45, 95% CI 1.10–1.90, P=0.008). However, no association was observed between the FAS −670A/G polymorphism and the risk of RA, AIH, AA, pSS, GBS, PBC, or LN. For FAS −1377 G/A polymorphism, subgroup analysis was not performed owing to the limited study number.
On the basis of quality score, the stratified meta-analysis suggested that the FAS −670 A/G polymorphism might not be associated with autoimmune diseases in high- or low-quality studies. However, the association between FAS −1377 G/A polymorphism and the risk of autoimmune diseases was observed in high-quality studies (A vs. G: OR = 1.14, 95% CI 1.05–1.24, P=0.002) but not in low-quality studies.
Stratification analysis showed that ethnicity, disease type, and quality score might be the factors of heterogeneity across all studies of association between FAS −670 A/G polymorphism and autoimmune diseases risk, and quality score may be the factor of heterogeneity across all studies of association between FAS −1377 G/A polymorphism and autoimmune diseases risk.
Stratification analysis by ethnicity for SLE, RA, MS, AIH, LN, SSc, AA, and pSS
The associations between the FAS −670 A/G polymorphism and SLE, RA, MS, AIH, LN, SSc, AA, and pSS are summarized in Table 3 (for FAS −1377 G/A polymorphism, subgroup analysis was not performed owing to the limited study number). An association between the FAS −670 A/G polymorphism and the risk of autoimmune diseases was observed in Asian patients with SLE (G vs. A: OR = 0.84, 95% CI 0.74–0.95, P=0.007) or AIH (G vs. A: OR = 0.55, 95% CI 0.40–0.76, P<0.001) and in Caucasian patients with SLE (G vs. A: OR = 0.80, 95% CI 0.67–0.96, P=0.015), MS (GG+GA vs. AA: OR = 0.80, 95% CI 0.66–0.96, P=0.018), or SSc (GG vs. GA: OR = 1.22, 95% CI 1.07–1.39, P=0.003). However, no significant risk was found in any specific ethnicity for RA, LN, AA, or pSS.
Diseases . | FAS −670A/G polymorphism . | Population . | Studies (n) . | Test of heterogeneity . | Test of associations . | Egger’s test P-value . | Power analysis (%) . | Sensitivity analysis value . | ||
---|---|---|---|---|---|---|---|---|---|---|
. | . | . | . | P-value . | I2 (%) . | OR (95% CI) . | P-value . | . | . | . |
SLE | ||||||||||
G vs. A | Caucasian | 4 | 0.017 | 70.7 | 0.80 (0.67, 0.96) | 0.015 | 0.634 | 73.1 | 0.015 | |
Asian | 4 | 0.296 | 18.9 | 0.84 (0.74, 0.95) | 0.007 | 0.634 | 80.2 | 0.007 | ||
GG vs. AA | Caucasian | 4 | 0.011 | 73.2 | 0.68 (0.49, 0.94) | 0.021 | 0.279 | 63.9 | 0.021 | |
Asian | 4 | 0.209 | 33.9 | 0.71 (0.55, 0.92) | 0.010 | 0.545 | 72.9 | 0.010 | ||
GG vs. GA | Caucasian | 4 | 0.130 | 46.9 | 0.96 (0.70, 1.31) | 0.797 | 0.288 | 5.1 | 0.797 | |
Asian | 4 | 0.848 | 0.0 | 0.93 (0.72, 1.18) | 0.537 | 0.600 | 13.7 | 0.537 | ||
GG+GA vs. AA | Caucasian | 4 | 0.027 | 67.4 | 0.70 (0.54, 0.92) | 0.011 | 0.442 | 81.6 | 0.011 | |
Asian | 4 | 0.091 | 53.6 | 0.77 (0.63, 0.93) | 0.007 | 0.581 | 76.7 | 0.007 | ||
GG vs. GA+AA | Caucasian | 4 | 0.056 | 60.4 | 0.84 (0.63, 1.12) | 0.228 | 0.272 | 19.2 | 0.228 | |
Asian | 4 | 0.767 | 0.0 | 0.83 (066, 1.05) | 0.118 | 0.551 | 40.4 | 0.118 | ||
RA | ||||||||||
G vs. A | Caucasian | 5 | 0.197 | 33.7 | 1.06 (0.88, 1.27) | 0.520 | 0.838 | 5.7 | 0.149 | |
GG vs. AA | Caucasian | 5 | 0.169 | 37.8 | 1.07 (0.74, 1.55) | 0.723 | 0.956 | 8.6 | 0.250 | |
GG vs. GA | Caucasian | 5 | 0.309 | 16.6 | 0.88 (0.62, 1.24) | 0.471 | 0.633 | 21.4 | 0.941 | |
GG+GA vs. AA | Caucasian | 5 | 0.568 | 0.0 | 1.19 (0.90, 1.56) | 0.221 | 0.376 | 27.6 | 0.103 | |
GG vs. GA+AA | Caucasian | 5 | 0.178 | 36.5 | 0.95 (0.69, 1.32) | 0.764 | 0.737 | 10.1 | 0.764 | |
MS | ||||||||||
G vs. A | Caucasian | 5 | 0.282 | 20.9 | 0.90 (0.80, 1.02) | 0.095 | 0.863 | 23.3 | 0.242 | |
GG vs. AA | Caucasian | 5 | 0.296 | 18.6 | 0.84 (0.66, 1.08) | 0.172 | 0.981 | 10.4 | 0.356 | |
GG vs. GA | Caucasian | 5 | 0.678 | 0.0 | 1.07(0.85, 1.34) | 0.576 | 0.410 | 17.7 | 0.899 | |
GG+GA vs. AA | Caucasian | 5 | 0.103 | 48.1 | 0.80 (0.66, 0.96) | 0.018 | 0.754 | 49.9 | 0.139 | |
GG vs. GA+AA | Caucasian | 5 | 0.703 | 0.0 | 0.97 (0.79, 1.20) | 0.809 | 0.710 | 5.0 | 0.716 | |
LN | ||||||||||
G vs. A | Asian | 2 | 0.796 | 0.0 | 0.79 (0.55, 1.14) | 0.201 | NA | 19.7 | 0.201 | |
GG vs. AA | Asian | 2 | 0.634 | 0.0 | 0.62 (0.28, 1.35) | 0.226 | NA | 18.7 | 0.226 | |
GG vs. GA | Asian | 2 | 0.480 | 0.0 | 0.83 (0.40, 1.72) | 0.621 | NA | 6.7 | 0.621 | |
GG+GA vs. AA | Asian | 2 | 0.964 | 0.0 | 0.69 (0.40, 1.21) | 0.196 | NA | 21.3 | 0.196 | |
GG vs. GA+AA | Asian | 2 | 0.528 | 0.0 | 0.75 (0.37, 1.49) | 0.407 | NA | 10.3 | 0.407 | |
SSc | ||||||||||
G vs. A | Caucasian | 2 | <0.001 | 93.3 | 1.01 (0.94, 1.09) | 0.688 | NA | 6.3 | 0.688 | |
GG vs. AA | Caucasian | 2 | <0.001 | 92.8 | 1.05 (0.91, 1.22) | 0.476 | NA | 84.1 | 0.476 | |
GG vs. GA | Caucasian | 2 | 0.056 | 72.6 | 1.22 (1.07, 1.39) | 0.003 | NA | 10.3 | 0.003 | |
GG+GA vs. AA | Caucasian | 2 | 0.001 | 90.5 | 0.92 (0.82, 1.03) | 0.137 | NA | 33.6 | 0.137 | |
GG vs. GA+AA | Caucasian | 2 | 0.003 | 88.4 | 1.15 (1.02, 1.30) | 0.021 | NA | 64.5 | 0.021 | |
AIH | ||||||||||
G vs. A | Caucasian | 2 | 0.368 | 0.0 | 1.14 (0.91, 1.43) | 0.265 | NA | 13.4 | 0.265 | |
Asian | 2 | 0.786 | 0.0 | 0.55 (0.40, 0.76) | <0.001 | NA | 95.9 | <0.001 | ||
GG vs. AA | Caucasian | 2 | 0.369 | 0.0 | 1.29 (0.82, 2.02) | 0.276 | NA | 5.9 | 0.276 | |
Asian | 2 | 0.591 | 0.0 | 0.31 (0.16, 0.60) | <0.001 | NA | 51.7 | <0.001 | ||
GG vs. GA | Caucasian | 2 | 0.776 | 0.0 | 1.16 (0.76, 1.75) | 0.489 | NA | 13.1 | 0.489 | |
Asian | 2 | 0.230 | 30.7 | 0.54 (0.29, 1.00) | 0.051 | NA | 95.4 | 0.051 | ||
GG+GA vs. AA | Caucasian | 2 | 0.369 | 0.0 | 1.17 (0.82, 1.68) | 0.384 | NA | 12.6 | 0.384 | |
Asian | 2 | 0.658 | 0.0 | 0.48 (0.29, 0.79) | 0.004 | NA | 84.2 | 0.004 | ||
GG vs. GA+AA | Caucasian | 2 | 0.560 | 0.0 | 1.20 (0.82, 1.77) | 0.350 | NA | 8.5 | 0.350 | |
Asian | 2 | 0.303 | 5.7 | 0.44 (0.25, 0.78) | 0.005 | NA | 84.3 | 0.005 | ||
AA | ||||||||||
G vs. A | Caucasian | 2 | 0.021 | 81.2 | 1.06 (0.78, 1.45) | 0.703 | NA | 9.7 | 0.703 | |
GG vs. AA | Caucasian | 2 | 0.001 | 91.1 | 0.75 (0.32, 1.74) | 0.496 | NA | 25.0 | 0.496 | |
GG vs. GA | Caucasian | 2 | 0.002 | 89.3 | 0.50 (0.22, 1.10) | 0.086 | NA | 5.2 | 0.086 | |
GG+GA vs. AA | Caucasian | 2 | 0.118 | 59.2 | 1.39 (0.87, 2.23) | 0.172 | NA | 34.0 | 0.172 | |
GG vs. GA+AA | Caucasian | 2 | 0.001 | 90.1 | 0.61 (0.29, 1.32) | 0.211 | NA | 15.2 | 0.211 | |
pSS | ||||||||||
G vs. A | Caucasian | 2 | 0.096 | 64.0 | 1.19 (0.88, 1.60) | 0.252 | NA | 20.7 | 0.252 | |
GG vs. AA | Caucasian | 2 | 0.097 | 63.7 | 1.40 (0.77, 2.55) | 0.273 | NA | 32.5 | 0.273 | |
GG vs. GA | Caucasian | 2 | 0.015 | 83.0 | 1.49 (0.87, 2.56) | 0.144 | NA | 24.4 | 0.144 | |
GG+GA vs. AA | Caucasian | 2 | 0.783 | 0.0 | 1.10 (0.69, 1.74) | 0.694 | NA | 6.8 | 0.694 | |
GG vs. GA+AA | Caucasian | 2 | 0.020 | 81.7 | 1.49 (0.89, 2.47) | 0.128 | NA | 34.0 | 0.128 |
Diseases . | FAS −670A/G polymorphism . | Population . | Studies (n) . | Test of heterogeneity . | Test of associations . | Egger’s test P-value . | Power analysis (%) . | Sensitivity analysis value . | ||
---|---|---|---|---|---|---|---|---|---|---|
. | . | . | . | P-value . | I2 (%) . | OR (95% CI) . | P-value . | . | . | . |
SLE | ||||||||||
G vs. A | Caucasian | 4 | 0.017 | 70.7 | 0.80 (0.67, 0.96) | 0.015 | 0.634 | 73.1 | 0.015 | |
Asian | 4 | 0.296 | 18.9 | 0.84 (0.74, 0.95) | 0.007 | 0.634 | 80.2 | 0.007 | ||
GG vs. AA | Caucasian | 4 | 0.011 | 73.2 | 0.68 (0.49, 0.94) | 0.021 | 0.279 | 63.9 | 0.021 | |
Asian | 4 | 0.209 | 33.9 | 0.71 (0.55, 0.92) | 0.010 | 0.545 | 72.9 | 0.010 | ||
GG vs. GA | Caucasian | 4 | 0.130 | 46.9 | 0.96 (0.70, 1.31) | 0.797 | 0.288 | 5.1 | 0.797 | |
Asian | 4 | 0.848 | 0.0 | 0.93 (0.72, 1.18) | 0.537 | 0.600 | 13.7 | 0.537 | ||
GG+GA vs. AA | Caucasian | 4 | 0.027 | 67.4 | 0.70 (0.54, 0.92) | 0.011 | 0.442 | 81.6 | 0.011 | |
Asian | 4 | 0.091 | 53.6 | 0.77 (0.63, 0.93) | 0.007 | 0.581 | 76.7 | 0.007 | ||
GG vs. GA+AA | Caucasian | 4 | 0.056 | 60.4 | 0.84 (0.63, 1.12) | 0.228 | 0.272 | 19.2 | 0.228 | |
Asian | 4 | 0.767 | 0.0 | 0.83 (066, 1.05) | 0.118 | 0.551 | 40.4 | 0.118 | ||
RA | ||||||||||
G vs. A | Caucasian | 5 | 0.197 | 33.7 | 1.06 (0.88, 1.27) | 0.520 | 0.838 | 5.7 | 0.149 | |
GG vs. AA | Caucasian | 5 | 0.169 | 37.8 | 1.07 (0.74, 1.55) | 0.723 | 0.956 | 8.6 | 0.250 | |
GG vs. GA | Caucasian | 5 | 0.309 | 16.6 | 0.88 (0.62, 1.24) | 0.471 | 0.633 | 21.4 | 0.941 | |
GG+GA vs. AA | Caucasian | 5 | 0.568 | 0.0 | 1.19 (0.90, 1.56) | 0.221 | 0.376 | 27.6 | 0.103 | |
GG vs. GA+AA | Caucasian | 5 | 0.178 | 36.5 | 0.95 (0.69, 1.32) | 0.764 | 0.737 | 10.1 | 0.764 | |
MS | ||||||||||
G vs. A | Caucasian | 5 | 0.282 | 20.9 | 0.90 (0.80, 1.02) | 0.095 | 0.863 | 23.3 | 0.242 | |
GG vs. AA | Caucasian | 5 | 0.296 | 18.6 | 0.84 (0.66, 1.08) | 0.172 | 0.981 | 10.4 | 0.356 | |
GG vs. GA | Caucasian | 5 | 0.678 | 0.0 | 1.07(0.85, 1.34) | 0.576 | 0.410 | 17.7 | 0.899 | |
GG+GA vs. AA | Caucasian | 5 | 0.103 | 48.1 | 0.80 (0.66, 0.96) | 0.018 | 0.754 | 49.9 | 0.139 | |
GG vs. GA+AA | Caucasian | 5 | 0.703 | 0.0 | 0.97 (0.79, 1.20) | 0.809 | 0.710 | 5.0 | 0.716 | |
LN | ||||||||||
G vs. A | Asian | 2 | 0.796 | 0.0 | 0.79 (0.55, 1.14) | 0.201 | NA | 19.7 | 0.201 | |
GG vs. AA | Asian | 2 | 0.634 | 0.0 | 0.62 (0.28, 1.35) | 0.226 | NA | 18.7 | 0.226 | |
GG vs. GA | Asian | 2 | 0.480 | 0.0 | 0.83 (0.40, 1.72) | 0.621 | NA | 6.7 | 0.621 | |
GG+GA vs. AA | Asian | 2 | 0.964 | 0.0 | 0.69 (0.40, 1.21) | 0.196 | NA | 21.3 | 0.196 | |
GG vs. GA+AA | Asian | 2 | 0.528 | 0.0 | 0.75 (0.37, 1.49) | 0.407 | NA | 10.3 | 0.407 | |
SSc | ||||||||||
G vs. A | Caucasian | 2 | <0.001 | 93.3 | 1.01 (0.94, 1.09) | 0.688 | NA | 6.3 | 0.688 | |
GG vs. AA | Caucasian | 2 | <0.001 | 92.8 | 1.05 (0.91, 1.22) | 0.476 | NA | 84.1 | 0.476 | |
GG vs. GA | Caucasian | 2 | 0.056 | 72.6 | 1.22 (1.07, 1.39) | 0.003 | NA | 10.3 | 0.003 | |
GG+GA vs. AA | Caucasian | 2 | 0.001 | 90.5 | 0.92 (0.82, 1.03) | 0.137 | NA | 33.6 | 0.137 | |
GG vs. GA+AA | Caucasian | 2 | 0.003 | 88.4 | 1.15 (1.02, 1.30) | 0.021 | NA | 64.5 | 0.021 | |
AIH | ||||||||||
G vs. A | Caucasian | 2 | 0.368 | 0.0 | 1.14 (0.91, 1.43) | 0.265 | NA | 13.4 | 0.265 | |
Asian | 2 | 0.786 | 0.0 | 0.55 (0.40, 0.76) | <0.001 | NA | 95.9 | <0.001 | ||
GG vs. AA | Caucasian | 2 | 0.369 | 0.0 | 1.29 (0.82, 2.02) | 0.276 | NA | 5.9 | 0.276 | |
Asian | 2 | 0.591 | 0.0 | 0.31 (0.16, 0.60) | <0.001 | NA | 51.7 | <0.001 | ||
GG vs. GA | Caucasian | 2 | 0.776 | 0.0 | 1.16 (0.76, 1.75) | 0.489 | NA | 13.1 | 0.489 | |
Asian | 2 | 0.230 | 30.7 | 0.54 (0.29, 1.00) | 0.051 | NA | 95.4 | 0.051 | ||
GG+GA vs. AA | Caucasian | 2 | 0.369 | 0.0 | 1.17 (0.82, 1.68) | 0.384 | NA | 12.6 | 0.384 | |
Asian | 2 | 0.658 | 0.0 | 0.48 (0.29, 0.79) | 0.004 | NA | 84.2 | 0.004 | ||
GG vs. GA+AA | Caucasian | 2 | 0.560 | 0.0 | 1.20 (0.82, 1.77) | 0.350 | NA | 8.5 | 0.350 | |
Asian | 2 | 0.303 | 5.7 | 0.44 (0.25, 0.78) | 0.005 | NA | 84.3 | 0.005 | ||
AA | ||||||||||
G vs. A | Caucasian | 2 | 0.021 | 81.2 | 1.06 (0.78, 1.45) | 0.703 | NA | 9.7 | 0.703 | |
GG vs. AA | Caucasian | 2 | 0.001 | 91.1 | 0.75 (0.32, 1.74) | 0.496 | NA | 25.0 | 0.496 | |
GG vs. GA | Caucasian | 2 | 0.002 | 89.3 | 0.50 (0.22, 1.10) | 0.086 | NA | 5.2 | 0.086 | |
GG+GA vs. AA | Caucasian | 2 | 0.118 | 59.2 | 1.39 (0.87, 2.23) | 0.172 | NA | 34.0 | 0.172 | |
GG vs. GA+AA | Caucasian | 2 | 0.001 | 90.1 | 0.61 (0.29, 1.32) | 0.211 | NA | 15.2 | 0.211 | |
pSS | ||||||||||
G vs. A | Caucasian | 2 | 0.096 | 64.0 | 1.19 (0.88, 1.60) | 0.252 | NA | 20.7 | 0.252 | |
GG vs. AA | Caucasian | 2 | 0.097 | 63.7 | 1.40 (0.77, 2.55) | 0.273 | NA | 32.5 | 0.273 | |
GG vs. GA | Caucasian | 2 | 0.015 | 83.0 | 1.49 (0.87, 2.56) | 0.144 | NA | 24.4 | 0.144 | |
GG+GA vs. AA | Caucasian | 2 | 0.783 | 0.0 | 1.10 (0.69, 1.74) | 0.694 | NA | 6.8 | 0.694 | |
GG vs. GA+AA | Caucasian | 2 | 0.020 | 81.7 | 1.49 (0.89, 2.47) | 0.128 | NA | 34.0 | 0.128 |
Abbreviation: NA, not available.
Publication bias
The Egger’s test was performed to assess the publication bias under all genetic models of the meta-analysis and the results are shown in Table 2. For the FAS −670 A/G polymorphism, the results from Egger’s tests indicated evidence for publication bias in the homozygous model for pSS, heterozygous models for Caucasians, AIH and high-quality studies, and recessive models for high-quality studies (P=0.044, 0.008, 0.005, 0.022, and 0.019, respectively). After adjustment by the trim-and-fill method, the ORs corrected for publication bias were not qualitatively different for the five models (OR = 1.30, 95% CI = 0.79–2.13, P=0.298; OR = 1.13, 95% CI = 1.03–1.23, P=0.007; OR = 0.92, 95% CI = 0.65–1.30, P=0.636; OR = 1.09, 95% CI = 1.00–1.18, P=0.052; and OR = 1.04, 95% CI = 0.96–1.13, P=0.323, respectively). No publication bias was found among the studies regarding the association between Fas −1377 G/A polymorphism and autoimmune diseases risk (all P>0.05). Therefore, the presence of publication bias did not influence the stability of the results. In addition, the results concerning association between FAS −670 A/G polymorphism and SLE, RA, MS, AIH, LN, SSc, AA, and pSS stratified by ethnicity did not show any evidence of publication bias (Table 3).
Sensitivity analysis
The genotype frequencies in the controls of five articles [22,31,51,52,55] deviated significantly from the HWE, which could cause potential bias. To check the robustness of our results, sensitivity analysis was performed by excluding these five HWE-deviating studies. The corresponding results of the sensitivity analysis are provided in Tables 2 and 3. The results showed that the overall OR changed only under the dominant model (P=0.051 vs. 0.004) after excluding the HWE-deviating studies, but the association between the FAS −670 A/G polymorphism and autoimmune diseases risk was not qualitatively altered under the heterozygous model (P=0.038 vs. 0.006), illustrating that the meta-analysis results were stable. In the stratification analysis by ethnicity, the results in Caucasians and Asians did not change when the HWE-deviating studies were excluded. In the stratification analysis by disease type, the OR changed only under the recessive model (P=0.071 vs. 0.034) after excluding the HWE-deviating studies from the analysis of SLE, but the association between the FAS −670 A/G polymorphism and SLE risk was not qualitatively altered under the allelic model (P=0.001 vs. <0.001). However, the association between FAS −670 A/G and MS risk was materially altered under the dominant model (P=0.043 vs. 0.261) after excluding the HWE-deviating studies. Similarly, a change was observed in the analysis of Caucasian patients with MS under the dominant model (P=0.018 vs. 0.139). In the stratification analysis by quality score, the association between FAS −670 A/G and high-quality studies was materially altered under the heterozygous and dominant model (P=0.096 vs. 0.028; P=0.071 vs. 0.023) after excluding the HWE-deviating studies. Additionally, the results of the association between FAS −1377 G/A and autoimmune diseases risk did not change when the HWE-deviating studies were excluded in five models.
FPRP analysis results
The FPRP values were calculated for the main significant associations and the results are shown in Table 4. For a prior probability of 0.1, the FPRP values indicated that four genetic models (FAS −670 A/G: GG vs. GA; FAS −1377 G/A: A vs. G; FAS −1377 G/A: AA vs. GG; FAS −1377 G/A: AA+AG vs. GG) of the FAS −670 A/G and −1377 G/A polymorphisms were truly associated with an increased risk of autoimmune diseases (FPRP = 0.262, 0.073, 0.173, and 0.085, respectively). Furthermore, with regard to the FAS −670 A/G polymorphism, noteworthy results were found in Asians, Caucasians, SLE, HT, SSc, and MS. Regarding the FAS −1377 G/A polymorphism, a positive association was observed in Asians and high-quality studies.
Genotype . | Population . | Studies (n) . | OR (95% CI) . | P-value1 . | Statistical power2 . | Prior probability . | ||||
---|---|---|---|---|---|---|---|---|---|---|
. | . | . | . | . | . | 0.25 . | 0.1 . | 0.01 . | 0.001 . | 0.0001 . |
FAS −670 A/G G vs. A | ||||||||||
Asian | 18 | 0.89 (0.83, 0.96) | 0.003 | 1.000 | 0.0083 | 0.0223 | 0.2023 | 0.718 | 0.962 | |
SLE | 10 | 0.85 (0.77, 0.94) | 0.002 | 1.000 | 0.0053 | 0.0143 | 0.1333 | 0.608 | 0.939 | |
HT | 2 | 1.45 (1.10, 1.90) | 0.007 | 0.597 | 0.0343 | 0.0963 | 0.539 | 0.922 | 0.992 | |
FAS −670 A/G GG vs. AA | ||||||||||
Asian | 18 | 0.81 (0.70, 0.94) | 0.006 | 0.995 | 0.0163 | 0.0483 | 0.3553 | 0.847 | 0.982 | |
SLE | 10 | 0.74 (0.61, 0.89) | 0.001 | 0.866 | 0.0053 | 0.0143 | 0.1373 | 0.615 | 0.941 | |
HT | 2 | 2.05 (1.19, 3.54) | 0.010 | 0.131 | 0.1863 | 0.4073 | 0.883 | 0.987 | 0.999 | |
FAS −670 A/G GG vs. GA | ||||||||||
Overall | 52 | 1.079 (1.004, 1.160) | 0.040 | 1.000 | 0.1063 | 0.2623 | 0.796 | 0.975 | 0.997 | |
Caucasian | 27 | 1.12 (1.03, 1.23) | 0.018 | 1.000 | 0.0513 | 0.1383 | 0.637 | 0.947 | 0.994 | |
SSc | 4 | 1.20 (1.07, 1.36) | 0.004 | 1.000 | 0.0133 | 0.0373 | 0.2993 | 0.811 | 0.977 | |
FAS −670 A/G GG+GA vs. AA | ||||||||||
Asian | 18 | 0.83 (0.74, 0.92) | <0.001 | 1.000 | 0.0013 | 0.0033 | 0.0373 | 0.2803 | 0.795 | |
SLE | 10 | 0.78 (0.67, 0.90) | <0.001 | 0.984 | 0.0023 | 0.0063 | 0.0633 | 0.4033 | 0.871 | |
MS | 6 | 0.83 (0.70, 0.99) | 0.038 | 0.993 | 0.1043 | 0.2583 | 0.792 | 0.975 | 0.997 | |
HT | 2 | 1.58 (1.03, 2.42) | 0.035 | 0.406 | 0.2083 | 0.4403 | 0.896 | 0.989 | 0.999 | |
FAS −670 A/G GG vs. GA+AA | ||||||||||
Caucasian | 27 | 1.10 (1.01, 1.19) | 0.018 | 1.000 | 0.0503 | 0.1363 | 0.634 | 0.946 | 0.994 | |
SSc | 4 | 1.14 (1.02, 1.28) | 0.027 | 1.000 | 0.0743 | 0.1933 | 0.725 | 0.964 | 0.996 | |
HT | 2 | 1.68 (1.06, 2.68) | 0.029 | 0.317 | 0.2183 | 0.4553 | 0.902 | 0.989 | 0.999 | |
FAS −1377 G/A A vs. G | ||||||||||
Overall | 15 | 1.11 (1.03, 1.20) | 0.009 | 1.000 | 0.0253 | 0.0733 | 0.4643 | 0.897 | 0.989 | |
Asian | 8 | 1.15 (1.05, 1.25) | 0.001 | 1.000 | 0.0033 | 0.0093 | 0.0923 | 0.504 | 0.911 | |
High quality | 10 | 1.14 (1.05, 1.24) | 0.002 | 1.000 | 0.0073 | 0.0203 | 0.1833 | 0.693 | 0.958 | |
FAS −1377 G/A AA vs. GG | ||||||||||
Overall | 15 | 1.23 (1.03, 1.47) | 0.023 | 0.985 | 0.0653 | 0.1733 | 0.696 | 0.959 | 0.996 | |
Asian | 8 | 1.27 (1.04, 1.54) | 0.015 | 0.955 | 0.0453 | 0.1253 | 0.610 | 0.940 | 0.994 | |
High quality | 10 | 1.31 (1.08, 1.59) | 0.007 | 0.915 | 0.0203 | 0.0583 | 0.4053 | 0.873 | 0.986 | |
FAS −1377 G/A AA+AG vs. GG | ||||||||||
Overall | 15 | 1.14 (1.02, 1.26) | 0.010 | 1.000 | 0.0303 | 0.0853 | 0.505 | 0.911 | 0.990 | |
Asian | 8 | 1.21 (1.07, 1.36) | 0.001 | 1.000 | 0.0043 | 0.0123 | 0.1213 | 0.581 | 0.933 | |
High quality | 10 | 1.17 (1.05, 1.31) | 0.005 | 1.000 | 0.0193 | 0.0553 | 0.3913 | 0.866 | 0.985 |
Genotype . | Population . | Studies (n) . | OR (95% CI) . | P-value1 . | Statistical power2 . | Prior probability . | ||||
---|---|---|---|---|---|---|---|---|---|---|
. | . | . | . | . | . | 0.25 . | 0.1 . | 0.01 . | 0.001 . | 0.0001 . |
FAS −670 A/G G vs. A | ||||||||||
Asian | 18 | 0.89 (0.83, 0.96) | 0.003 | 1.000 | 0.0083 | 0.0223 | 0.2023 | 0.718 | 0.962 | |
SLE | 10 | 0.85 (0.77, 0.94) | 0.002 | 1.000 | 0.0053 | 0.0143 | 0.1333 | 0.608 | 0.939 | |
HT | 2 | 1.45 (1.10, 1.90) | 0.007 | 0.597 | 0.0343 | 0.0963 | 0.539 | 0.922 | 0.992 | |
FAS −670 A/G GG vs. AA | ||||||||||
Asian | 18 | 0.81 (0.70, 0.94) | 0.006 | 0.995 | 0.0163 | 0.0483 | 0.3553 | 0.847 | 0.982 | |
SLE | 10 | 0.74 (0.61, 0.89) | 0.001 | 0.866 | 0.0053 | 0.0143 | 0.1373 | 0.615 | 0.941 | |
HT | 2 | 2.05 (1.19, 3.54) | 0.010 | 0.131 | 0.1863 | 0.4073 | 0.883 | 0.987 | 0.999 | |
FAS −670 A/G GG vs. GA | ||||||||||
Overall | 52 | 1.079 (1.004, 1.160) | 0.040 | 1.000 | 0.1063 | 0.2623 | 0.796 | 0.975 | 0.997 | |
Caucasian | 27 | 1.12 (1.03, 1.23) | 0.018 | 1.000 | 0.0513 | 0.1383 | 0.637 | 0.947 | 0.994 | |
SSc | 4 | 1.20 (1.07, 1.36) | 0.004 | 1.000 | 0.0133 | 0.0373 | 0.2993 | 0.811 | 0.977 | |
FAS −670 A/G GG+GA vs. AA | ||||||||||
Asian | 18 | 0.83 (0.74, 0.92) | <0.001 | 1.000 | 0.0013 | 0.0033 | 0.0373 | 0.2803 | 0.795 | |
SLE | 10 | 0.78 (0.67, 0.90) | <0.001 | 0.984 | 0.0023 | 0.0063 | 0.0633 | 0.4033 | 0.871 | |
MS | 6 | 0.83 (0.70, 0.99) | 0.038 | 0.993 | 0.1043 | 0.2583 | 0.792 | 0.975 | 0.997 | |
HT | 2 | 1.58 (1.03, 2.42) | 0.035 | 0.406 | 0.2083 | 0.4403 | 0.896 | 0.989 | 0.999 | |
FAS −670 A/G GG vs. GA+AA | ||||||||||
Caucasian | 27 | 1.10 (1.01, 1.19) | 0.018 | 1.000 | 0.0503 | 0.1363 | 0.634 | 0.946 | 0.994 | |
SSc | 4 | 1.14 (1.02, 1.28) | 0.027 | 1.000 | 0.0743 | 0.1933 | 0.725 | 0.964 | 0.996 | |
HT | 2 | 1.68 (1.06, 2.68) | 0.029 | 0.317 | 0.2183 | 0.4553 | 0.902 | 0.989 | 0.999 | |
FAS −1377 G/A A vs. G | ||||||||||
Overall | 15 | 1.11 (1.03, 1.20) | 0.009 | 1.000 | 0.0253 | 0.0733 | 0.4643 | 0.897 | 0.989 | |
Asian | 8 | 1.15 (1.05, 1.25) | 0.001 | 1.000 | 0.0033 | 0.0093 | 0.0923 | 0.504 | 0.911 | |
High quality | 10 | 1.14 (1.05, 1.24) | 0.002 | 1.000 | 0.0073 | 0.0203 | 0.1833 | 0.693 | 0.958 | |
FAS −1377 G/A AA vs. GG | ||||||||||
Overall | 15 | 1.23 (1.03, 1.47) | 0.023 | 0.985 | 0.0653 | 0.1733 | 0.696 | 0.959 | 0.996 | |
Asian | 8 | 1.27 (1.04, 1.54) | 0.015 | 0.955 | 0.0453 | 0.1253 | 0.610 | 0.940 | 0.994 | |
High quality | 10 | 1.31 (1.08, 1.59) | 0.007 | 0.915 | 0.0203 | 0.0583 | 0.4053 | 0.873 | 0.986 | |
FAS −1377 G/A AA+AG vs. GG | ||||||||||
Overall | 15 | 1.14 (1.02, 1.26) | 0.010 | 1.000 | 0.0303 | 0.0853 | 0.505 | 0.911 | 0.990 | |
Asian | 8 | 1.21 (1.07, 1.36) | 0.001 | 1.000 | 0.0043 | 0.0123 | 0.1213 | 0.581 | 0.933 | |
High quality | 10 | 1.17 (1.05, 1.31) | 0.005 | 1.000 | 0.0193 | 0.0553 | 0.3913 | 0.866 | 0.985 |
Chi-square test was used to calculate the genotype frequency distributions.
Statistical power was calculated using the number of observations in the subgroup and the OR and P-values in this table.
The level of FPRP threshold was set at 0.5 and noteworthy findings are presented.
TSA results
In the TSA of association of FAS −670 A/G polymorphism and autoimmune diseases risk, the cumulative Z-curve neither crossed conventional boundary nor trial sequential monitoring boundary, however, the sample size reached RIS (3365) in allelic model (Figure 2A). In the TSA of association of FAS −1377 G/A polymorphism and autoimmune diseases risk, the sample size also reached RIS (4387) and the cumulative Z-curve crossed the conventional boundary, although the cumulative Z-curve did not cross trial sequential monitoring boundary in allelic model (Figure 2B). The TSA results indicated that the cumulative evidence was reliable and sufficient, and no additional studies were required.
Trial sequential analyses of the associations between FAS polymorphisms and autoimmune diseases risk
Discussion
Our results showed that ethnicity, disease type, and quality score may be the factors of heterogeneity across all studies of association between FAS −670 A/G polymorphism and autoimmune diseases, and quality score may be the factor of heterogeneity across all studies of association between FAS −1377 G/A polymorphism and autoimmune diseases. In the ethnicity stratification analysis, the results of our meta-analysis revealed diverse associations between the FAS −670 A/G and −1377 G/A polymorphisms and various autoimmune diseases in different ethnic groups. The findings indicated that the FAS gene polymorphisms might play different roles in different ethnic groups. This suggests that ethnic differences may be involved in the genetic backgrounds of these patients. There are several possible explanations for such an ethnic discrepancy. First, different populations usually have different patterns of linkage disequilibrium. The FAS −670 A/G and −1377 G/A polymorphisms may be in close linkage with different nearby causal variants in different populations. Second, the FAS −670 A/G and −1377 G/A polymorphisms may interact with environmental and genetic factors or combined effects among different ethnicities. Furthermore, lifestyle factors such as alcohol consumption, cigarette smoking, nutritional status, and menopausal status may also explain this discrepancy. Finally, study numbers and sample sizes were relatively small in the stratification analysis by ethnicity, which may have resulted in inadequate statistical power to detect associations between the FAS −670 A/G and −1377 G/A polymorphisms and autoimmune diseases.
In the disease-type stratification analysis, the FAS −670 G allele was associated with an increased risk of SSc and HT and with a decreased risk of SLE, MS, and AIH (in Asians) but was not associated with other autoimmune diseases. These findings may reflect differences in the risks of various autoimmune diseases due to differences in environmental and genetic backgrounds. The present results indicate that the FAS −670 G allele is associated with a decreased risk of SLE, MS, and AIH (in Asians), which conflicts with a previous finding that the FAS −670 G allele in the FAS promoter was associated with an increased risk of autoimmune diseases [22,78]. One possible mechanism by which this allele may reduce the risk of SLE, MS, and AIH (in Asians) is by a reduction in soluble FAS (sFAS). The FAS protein exists in two isoforms, one a transmembrane protein and the other a soluble protein. sFAS expression is highly regulated at the mRNA transcript level [79,80]. Transcription of both FAS and sFAS is driven by the same gene promoter [22], with alternative splicing of the FAS mRNA resulting in a variant that lacks exon 6, which encodes the transmembrane domain of FAS [81]. Plasma sFAS, an antiapoptotic molecule, has been found to block apoptosis in autoreactive lymphocytes by competing with FAS for FASL or soluble FASL binding in SLE, MS, and AIH (in Asians) [79,82–85]. Similarly, this may explain why the FAS −670 G allele was associated with an increased risk of autoimmune diseases in Caucasians and with a decreased risk in Asians. For FAS −1377 G/A polymorphism, subgroup analysis was not performed owing to the limited study number. The FAS −1377 G/A polymorphism occurs at the consensus sequence of transcription factor SP1 binding site in the silencer region [48]. The FAS −1377 A allele may destroy SP1 transcription factor binding sites, resulting in reduced promoter activity and FAS expression [18]. Abnormal apoptosis mediated by the FASL interaction with the FAS receptor is involved in the pathogenesis of several autoimmune diseases [19].
We performed a meta-analysis of data from patients diagnosed with autoimmune diseases (SLE, MS, RA, AIH, LN, SSc, AA, pSS, HT, GBS, PBC, vitiligo, GD, T1D, IAA, JIA, and SPA) and healthy controls. This meta-analysis differs from the seven previous meta-analyses [43,61–66] because the present study included 33 more studies (consisting of new studies with same and different disease types) [15,17,22,27–30,32–35,37,41,43–45,50,52–55,59,60] and yielded several novel and distinct findings. One previous meta-analysis [62] including SLE, RA, SSc, pSS, JIA, and SPA demonstrated that the FAS −670 A/G polymorphism might be associated with the risk of rheumatic disease, especially in Asians, SLE and RA, and the FAS −1377 G/A polymorphism was associated with SLE risk. Compared with this meta-analysis, our meta-analysis focused on overall autoimmune diseases risk and showed that FAS −670 A/G polymorphism was associated with autoimmune diseases risk in Caucasians, MS, SSc and HT; and the FAS −1377 G/A polymorphism was associated with autoimmune diseases risk in Asians and high quality studies, which were different from the previous meta-analyses. One meta-analysis [43] showed that the FAS −670 A/G polymorphism may be associated with SLE risk in the Chinese population. Two meta-analyses [64,66] suggested that the FAS −670 A/G and −1377 G/A polymorphisms was associated with the risk of SLE, stratification by ethnicity indicated an association between the FAS −670 A/G and SLE in Asian populations. Two meta-analyses [61,63] showed that the FAS −670 A/G polymorphism was not associated with the risk of RA. One meta-analysis [65] suggested that the FAS −670 A/G polymorphism was not associated with the risk of AIH. These six meta-analyses focused on the association between FAS polymorphism and a single disease (SLE, RA, or AIH). Compared with these meta-analyses, our meta-analysis covered overall autoimmune diseases, and subgroup analyses were performed by ethnicity, disease type, and quality score, thereby yielding several novel and distinct findings. Furthermore, some previous meta-analyses [63,65] including several studies [25,30,31,40] made some errors when extracting the data. Thus, we here added 33 new studies [15,17,22,27–30,32–35,37,41,43–45,50,52–55,59,60] on SLE, MS, pSS, AA, PBC, HT, GBS, LN, vitiligo, T1D, IAA, and GD and corrected the previous errors, providing more reliable results. In addition, FPRP test was performed to support that the evidence of our results was robust and sufficiently conclusive, and the result of TSA showed that there was sufficient evidence and much larger sample size to support these conclusions, thereby increasing the statistical power. We strongly believe that our findings can help resolve many of the controversies of the association of FAS polymorphism and autoimmune diseases.
Sensitivity analysis are generally performed to assess the robustness of meta-analyses by excluding and including HWE-deviating studies from genetic association studies, which is a recommended approach [86]. Probable explanations for deviation from HWE include nonrandom mating, population stratification, selection bias, genotyping error, inbreeding, genetic drift, chance, differential survival of marker carriers, or combinations of these reasons [87]. However, key empirical evidence does not support a strong association between estimates of genetic effect and deviations from HWE [88]. Nonetheless, the findings of our meta-analysis should be interpreted with caution in the case of material alterations in results after excluding the HWE-deviating studies.
The present study has several limitations that should be considered when interpreting the conclusions. First, only case–control studies were considered for inclusion. Selection bias and unmeasured confounding can occur at both the design and analysis stages of observational studies. Second, this analysis only included articles published in English and Chinese; this may reduce the credibility of the results because of language bias [89]. Third, our study only analyzed a single locus, single nucleotide polymorphism (SNP) −670 A/G and −1377 G/A in the FAS gene and did not investigate associations between genetic haplotypes containing the FAS −670 A/G and −1377 G/A polymorphisms and the risk of autoimmune diseases because of inadequate haplotype data. It is unknown whether other genetic mutations contribute to changes in the expression or function of the FAS gene. For uncovering the genetic causes of disease, haplotypes provide more information and have a greater influence than genotypes and single SNPs. Fourth, most studies included in our analysis were performed in the Caucasian and Asian populations; therefore, our results may apply only to these ethnic groups. Additional studies of other ethnicities are needed. Fifth, autoimmune diseases are multifactorial diseases caused by interactions between genetic and environmental factors, meaning that the FAS −670 A/G and −1377 G/A polymorphisms may only partially influence the pathogenesis of autoimmune diseases; this may lead to bias in the present results. Finally, the findings of our meta-analysis should be interpreted with caution in the case of heterogeneity observed under some genetic models.
Translating information of genetic associations into clinical diagnostics would help with improved understanding of the autoimmune diseases’ etiology. Establishing evidence-based medical evidence of genetic susceptibility to autoimmune diseases risk might facilitate the preventive and therapeutic strategies, which has a beneficial clinical utility for not only clinicians and researchers but also patients.
In summary, our meta-analysis suggested that the FAS −670 A/G polymorphism might be associated with the risk of autoimmune diseases, especially in Caucasians and Asians, SLE, MS, SSc, and HT. Moreover, the FAS −670 A/G polymorphism might be associated with the risk of autoimmune diseases in Asian patients with SLE or AIH and Caucasian patients with SLE, MS, or SSc. The FAS −1377 G/A/ polymorphism might be associated with the risk of autoimmune diseases, specifically for Asians and high quality studies. Stratification analysis showed that ethnicity, disease type and quality score might be the factors of heterogeneity across all studies of association between FAS −670 A/G polymorphism and autoimmune diseases risk, and quality score might be the factor of heterogeneity across all studies of association between FAS −1377 G/A polymorphism and autoimmune diseases risk.
Author Contribution
Y.C. conceived and designed the meta-analysis. Y.H. and Y.C. performed the literature search and study selection. H.Y. and Y.H. extracted the data. Y.C. performed the quality evaluation and statistical analysis. H.Y. and Y.C. wrote the paper. Y.C. performed language correction and manuscript revision.
Competing Interests
The authors declare that there are no competing interests associated with the manuscript.
Funding
The authors declare that there are no sources of funding to be acknowledged.
Abbreviations
- AA
alopecia areata
- AIH
autoimmune hepatitis
- CI
confidence interval
- FASL
FAS-ligand
- FPRP
false-positive report probability
- GBS
Guillain–Barré syndrome
- GD
Graves’ disease
- HT
Hashimoto’s thyroiditis
- HWE
Hardy–Weinberg equilibrium
- IAA
idiopathic aplastic anemia
- JIA
juvenile idiopathic arthritis
- LN
lupus nephritis
- MS
multiple sclerosis
- NOS
Newcastle–Ottawa scale
- OR
odds ratio
- PBC
primary biliary cirrhosis
- pSS
primary Sjögren’s syndrome
- RA
rheumatoid arthritis
- RIS
required information size
- sFAS
soluble FAS
- SLE
systemic lupus erythematosus
- SNP
single nucleotide polymorphism
- SPA
spondyloarthropathy
- SP1
stimulatory protein 1
- SSc
systemic sclerosis
- TNF
tumor necrosis factor
- TSA
trial sequential analysis
- T1D
type 1 diabetes mellitus