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Rheumatology Advance Access originally published online on October 15, 2007
Rheumatology 2007 46(11):1662-1666; doi:10.1093/rheumatology/kem235
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The polymorphism -863C/A in tumour necrosis factor-{alpha} gene contributes an independent association to gout

S.-J. Chang, P.-C. Tsai1, C.-J. Chen2, H.-M. Lai2 and Y.-C. Ko

Department of Public Health, Faculty of Medicine, College of Medicine, 1Institute of Public Health, College of Health Science, Kaohsiung Medical University and 2Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan

Correspondence to: S.-J. Chang, PhD, Department of Public Health, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Kaohsiung 807, Taiwan. E-mail: changsj{at}kmu.edu.tw


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. To investigate the associations between polymorphisms in the promoter of the tumour necrosis factor-{alpha} (TNF-{alpha}) gene and gout.

Methods. The polymorphisms -308G/A and -863C/A in the TNF-{alpha} gene were determined in 106 gout patients and 159 healthy controls among male Taiwanese using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. The biochemical markers, including Glutamic-oxaloacetic transaminase (GOT), Glutamic-pyruvic transaminase (GPT), uric acid, creatinine, total cholesterol (TC), triglycerides (TG), body mass index (BMI) and hypertension, as well as alcohol consumption were measured.

Results. The gout patients had 9.43% (10/106) with genotype AA at polymorphism -863C/A showing a significantly higher fraction than controls (0.63%; 1/159, P < 0.001). The crude results also showed that the gout patients had significantly higher portions of abnormal GOT, GPT, creatinine, TC, TG, alcohol consumption, hypertension and hyperuricaemia than controls (P < 0.05), but the -308G/A, BMI and genotype CA at -863C/A did not show the same significant difference (P > 0.05). After adjustment by a stepwise logistic regression method, the hyperuricaemia, creatinine, GPT, TG and alcohol consumption as well as genotype AA at polymorphism -863C/A were found to be significantly associated with gout.

Conclusion. The genotype AA at polymorphism -863C/A in a recessive model showed a significant association with developing gout independent of hyperuricaemia, abnormal creatinine, higher TG, GPT and alcohol consumption.

KEY WORDS: Gout, Tumour necrosis factor, Hyperuricaemia, Creatinine


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Gout is a disease caused by urate deposition around joint areas. The factors associated with gout are most often found in age, sex, hyperuricaemia, creatinine, triglycerides (TG), obesity, hypertension and heavy alcohol use [1–5]. Although hyperuricaemia is the most important and direct factor to cause gout and gout incidence increases with increased levels of serum uric acid [6, 7], only ~5–20% of those with hyperuricaemia had symptoms with gout, and 90% of these were in gout-free status [8]. Some factors besides hyperuricaemia may be considered to contribute towards the development of gouty arthritis. To date, it is realized that the inflammation response is the key factor for onset of gout as well as hyperuricaemia. The inflammatory reaction in gout includes initiation of the acute attack, leucocyte recruitment, amplification and subsequent resolution [9]. The reaction of crystal-induced mast cell degranulation may play a key role in initiating inflammation [10]. In addition, Meng et al. [11] reported that tumour necrosis factor-{alpha} (TNF-{alpha}), released by mast cells, is an important substance for pro-inflammatory reaction, which may contribute to the promotion of the inflammatory process.

In our previous study, we showed that Taiwanese aborigines had higher gout prevalence than non-aborigines [1]. Another study also showed the heritability of gout was 90% [12], and it has been hypothesized that gout develops with a genetic component [13–15] and is inherited by polygenes [16, 17]. Regarding the association between inflammation reaction and candidate genes, such as the TNF-{alpha} gene [18], many studies have shown that different genotypes in the TNF-{alpha} gene have a relationship with the onset or severity of rheumatoid arthritis (RA) [19–21]. The polymorphism -308G/A in the TNF-{alpha} gene was shown to contribute to the severity for RA in Mexicans [20, 22]; and this polymorphism was also shown to have a protective effect against RA in HLA-DR4-negative patients among the Taiwanese [23]; but other studies did not show any significant association between polymorphism -308G/A and RA [24, 25]. Moreover, another polymorphism, -863C/A, in the TNF-{alpha} gene was shown to have no significant association with RA [23].

Many studies have investigated the association between the TNF-{alpha} gene and RA; however, even though those patients with RA and gout had the same inflammation reaction, to our knowledge, there was little evidence that the polymorphisms in the TNF-{alpha} gene were associated with gout. Here, we report the associations between two polymorphisms (-308 G/A and -863C/A) in the TNF-{alpha} gene, as well as biochemical markers and developing gout among male Taiwanese.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
This study was designed as a cross-sectional study, all the participants were male, and we matched one patient with 1–2 gout-free controls by age in a range of 3 yrs. Blood samples during fasting were drawn from all participants in 2004 and 2005. The process and design for this study was approved by the hospital Human Research Ethics Committee and informed consent was obtained from each patient. A total of 106 gout patients were enrolled from Kaohsiung Chang-Gung Memorial Hospital, and 159 healthy controls were enrolled from a community clinic. All the gout patients were diagnosed by a clinical physician, and all the healthy controls were also diagnosed to be free from gout.

Biochemical data measurement
We measured all the participants for Glutamic-oxaloacetic transaminase (GOT), Glutamic-pyruvic transaminase (GPT), creatinine, uric acid, total cholesterol (TC) and TG in the plasma by an automated multichannel chemistry analyser (Toshiba 200), and measured the systolic and diastolic blood pressure by sphygmomanometer. Hypertension was defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure of ≥90 mmHg or under treatment. The body mass index (BMI) was measured by the body weight over the body height in metres (kg/m2); and hyperuricaemia was defined as uric acid ≥7.7 mg/dl. The GOT, GPT, TC, TG and creatinine were dichotomous according to the clinical criteria. Alcohol consumption was rated as having consumed or currently consuming vs never having consumed.

TNF-{alpha} promoter polymorphism sites determination
The polymorphisms -308G/A and -863C/A in the promoter region of the TNF-{alpha} gene were identified by a Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method [26, 27]. The primers used in the PCR procedure were 5'-AGCAATAGGTTTTGAGGGCCAT for forward and 5'-GG GACACACAAGCATCAAG for reverse for -308G/A; and 5'-GGCTCTGAGGAATGGGTTAC for forward and 5'-CTACATGGCCCTGTCTTCGTTACG for reverse for -863C/A [23]. The underlined nucleotides are mismatched. NcoI and TaiI were used as the restriction enzyme for polymorphisms -308G/A and -863C/A, respectively. The temperature in the PCR procedure for initial denaturation was 95°C for 5 min; followed by 30 cycles of denaturation at 95°C for 30 s, annealing at 59°C for 30 s (-308G/A) and at 62°C for 30 s (-863C/A) and extension at 72°C for 40 s; and a final extension at 72°C for 7 min and the samples were maintained at a final 4°C.

Statistics
Student's t-test was used to test for a significant difference in the mean age between gout patients and controls, and in the mean values of clinical characteristics among different genotypes at polymorphism -308G/A. An analysis of variance (ANOVA) was used to detect the mean differences between the genotypes at polymorphism -863C/A and clinical characteristics among gout patients, including duration of gout, age of onset and biochemical markers. The Kruskal–Wallis test was used to detect the means difference for number of tophi and the frequency of attacks during the last year. The chi-squared test was used to reveal rate differences in categories in biochemical data, alcohol consumption and BMI between gout patients and controls, and it was also used to detect the Hardy–Weinberg equilibrium for polymorphisms -308G/A and -863C/A among the control group.

The odds ratios (OR) and 95% confidence intervals (95% CI) were used to assess the strength of relationship in the inherited model, genotype and allele distribution of -308G/A and -863C/A between the patient groups and controls, and the P-value was estimated by chi-squared test. An adjusted OR and 95% CI estimated by stepwise logistic regression was used to delineate the covariant factors associated with the development of gout when the factors showed a significant association in the crude analysis. If the P-value was less than 0.05 or the range of 95% CI did not include unity, the difference was considered to be statistically significant. SAS software (V9.13) was used for the statistical analysis.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
A total of 265 male subjects participated in this study—106 gout patients and 159 healthy controls. The mean age of all the participants was 52.37 ± 14.00 yrs old, and there was no significant difference between gout patients and controls in age (52.18 ± 13.42 vs 52.50 ± 14.41, respectively; P = 0.854). The associations between demographic data, biochemical data and gout are listed in Table 1. The results showed that gout patients had significantly higher portions of abnormal GOT, GPT, creatinine, TC, TG, alcohol consumption, hypertension and hyperuricaemia than healthy controls (Table 1, P < 0.05). The BMI did not show the same significant difference (P = 0.156).


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  		TABLE 1. Baseline characteristics and clinical data of gout patients and controls

 
Table 2 lists the clinical characteristics distributed in different genotypes at polymorphisms -308G/A and -863C/A among gout patients. Since there was only one patient with genotype AA at polymorphism -308G/A, this patient was omitted from the table. The clinical characteristics include duration of gout, age of onset, number of tophi, frequency of attacks during last year, uric acid levels, TC, TG and creatinine levels in serum. The results showed that those with different genotypes at polymorphisms -308G/A and -863C/A did not have a significant difference in the mean values of the aforementioned clinical factors (all P > 0.05; Table 2).


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  		TABLE 2. The associations between clinic characteristics and genotypes at polymorphisms -308G/A and -863C/A among gout paients

 
Table 3 lists the distributions of genotypes, alleles, dominant and recessive models among polymorphisms -308G/A and -863C/A and shows their associations with gout. Both of these polymorphisms in the control group showed genetic distribution in the Hardy–Weinberg equilibrium ({chi}2 = 1.80 for polymorphism -308G/A, {chi}2 = 0.56 for polymorphism -863C/A, both P-values>0.05). Regarding the genotype GG at polymorphism -308G/A, most of the patients and controls with this genotype (81.13 and 82.39%, respectively) showed no significant difference compared with the genotypes GA and AA between gout patients and controls (OR = 1.16 for genotype GA, OR = 0.51 for genotype AA, both P > 0.05). The allele distribution and neither the dominant nor the recessive models showed significant associations at polymorphism -308G/A between gout patients and controls (P > 0.05). Concerning the polymorphism -863C/A, most participants had the genotype CC (65.09% for patients and 78.62% for controls); those with genotype AA revealed a significant association between gout patients and controls compared with genotype CC, and thus those with genotype AA showed an increased risk 18.12-fold to get gout disease compared with those with CC (OR = 18.12, 95% CI = 2.27–144.51; P < 0.001; Table 3). However, the heterozygous genotype CA did not show a significant association between patients and controls when compared with genotype CC (OR = 1.48, 95% CI = 0.82–2.67, P = 0.189). The allele A, dominant model (CA/AA vs CC) and recessive model (AA vs CC/CA) also showed significant difference at polymorphism -863C/A between gout patients and controls (P < 0.05), and the result also revealed that the recessive model showed a higher risk of developing gout than the dominant model (OR = 14.46 for recessive genotype vs OR = 1.97 for dominant genotype).


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  		TABLE 3. The associations in the distributions of genotypes, allele frequency, dominant and recessive models for two polymorphisms (-308G/A and -863C/A) in the TNF-{alpha} gene between gout patients and controls

 
A stepwise logistic regression model was used to analyse the covariate effects which have been shown to have a significant association with the occurrence of gout in a crude analysis; the factors entered included hypertension, hyperuricaemia, creatinine, GOT, GPT, alcohol consumption, TC, TG and polymorphism -863C/A (Table 4). The results showed that hyperuricaemia (OR = 6.10, 95% CI = 2.64–14.07), creatinine (OR = 3.72, 95% CI = 1.83–7.56), GPT (OR = 2.80, 95% CI = 1.36–7.79), alcohol consumption (OR = 2.60, 95% CI = 1.21–5.60), TG (OR = 3.94, 95% CI = 2.03–7.65) as well as genotype AA at polymorphism -863C/A (OR = 13.46, 95% CI = 1.31–138.79) had significant associations with gout (all P < 0.05), but hypertension, GOT, TC and genotype CA at polymorphism -863C/A did not show the same significant difference (P > 0.05). That is to say that the occurrence of gout was more related to those with genotype AA at polymorphism -863C/A, hyperuricaemia, abnormal values of creatinine, GPT and TG, and to those who had or were currently consuming alcohol.


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  		TABLE 4. The adjusted ORs and 95% CI for the factors associated with gout

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
This study explored the factors associated with gout in male Taiwanese. The factors included in this study were biochemical markers, such as uric acid, creatinine, TC, TG, GOT and GPT, as well as alcohol consumption behaviour and the genetic component involved in the inflammation reaction. Among the participants in this study, none was a Taiwanese aborigine, although Taiwanese aborigines have been demonstrated to be a population with a higher prevalence of gout and to have a suspected gene in chromosome 4 [15]. Our results showed that many factors were significantly associated with gout independently, such as hyperuricaemia, alcohol consumption, abnormal values of creatinine, GPT and TG, and the polymorphism -863C/A in the TNF-{alpha} gene. The biochemical markers and alcohol consumption were found to be associated significantly with gout in this study and these results are in consistent with the other studies [2, 3, 5]. Our results also showed a significant association between the genotype AA at polymorphism -863C/A and development of gout even after adjustment for the aforementioned biochemical markers. This result adds further evidence to the hypothesis that the onset of gout may be caused by a TNF-{alpha} genetic component independent of hyperuricaemia or abnormal creatinine, GPT and TG.

Many reports have demonstrated that some cytokines, in particular TNF-{alpha} and interleukin-1-ß (IL-1ß), IL-6 and IL-8, may have a major role in the pathogenesis of joint diseases. The TNF-{alpha} is a cytokine and was demonstrated to have a wide range of pro-inflammatory activities [28, 29]. It is produced primarily by monocytes and macrophages [30], although significant amounts are also secreted by several other cell types. Several studies have shown that the polymorphisms in the TNF-{alpha} gene had different TNF levels and were associated with different diseases [23, 25, 31], but the associations between TNF-{alpha} production and TNF promoter polymorphisms also remain controversial. Wilson et al. [31] showed that TNF-{alpha} -308A is a much stronger transcriptional activator than TNF-{alpha} -308G in the human B-cell line, and polymorphism -308G/A has direct effects on TNF gene regulation. However, Uglialoro et al. [32] showed that the polymorphism -308G/A did not affect TNF-{alpha} gene expression in activated lymphocytes. In the Abdallah et al. [33] study, polymorphism -308A was related to the lower plasma TNF-{alpha} level, but this was not significant. Another study also showed that polymorphism -308A was associated with RA, systemic lupus erythematosus and primary Sjögren's syndrome, but that polymorphism -308G was associated with tuberculosis [25]. Yen et al. [23] performed a study among the Taiwanese, which showed polymorphism -308G/A had a protective association with RA patients only in those who were HLA-DR4-negative.

Although the demographic characteristics of our sample population in the control group may have no significant difference from that of Dr Yen's study since all of them came from southern Taiwanese, the polymorphism -308G/A in our study did not show any significant difference in association with the onset of gout, even although this polymorphism has been demonstrated to contribute to RA. The allele A dominant and recessive models at polymorphism -863C/A showed strong associations with the development of gout and the recessive model also showed more association than the dominant model. This finding demonstrates that a recessive model was preferred at polymorphism -863C/A to have a better association with gout.

Many reports have demonstrated that some cytokines, in particular TNF-{alpha} and IL-1ß, IL-6 and IL-8, may have a major role in the pathogenesis of chronic inflammatory arthritis or joint diseases [34–37]. In the clinical setting, TNF-{alpha} can induce endothelial adherence and activation of granulocytes [38], and it can stimulate fibroblast growth via platelet-derived growth factor [39]. Other systemic inflammatory properties of TNF-{alpha} include the induction of fever, stimulation of acute phase protein production [40] and neutrophil accumulation [30]. Among the gout patients, the granulomas composed of mono- and multi-nucleated macrophages enclosing deposits of monosodium urate (MSU) microcrystals represent the histological hallmark of gout tophi. Macrophages are the pivotal effectors of inflammation, the activity which may result in phagocytosis and degradation of foreign bodies, and synthesis of pro-inflammatory cytokines [41, 42]. Recently, it has been demonstrated that macrophages undergo apoptosis in foreign bodies with a central necrosis, such as those seen in cases with tuberculosis, rheumatoid nodules and granuloma annulare [43–45]. From the phagocytosis and degradation of foreign bodies among gout patients, we infer that both macrophages and cytokines are involved, and if one is insufficient, the MSU microcrystals will be exposed and cause the acute syndrome. Here we suggest that genotype AA at polymorphism -863C/A in the TNF-{alpha} gene has a stronger association for developing gout but the polymorphism -308A/G does not. This phenomenon may be due to a lack of TNF-{alpha} level in the serum, which was supported by the result of Skoog et al. [27] who showed that the carriers of the -863A allele have a significantly lower TNF-{alpha} level, but no significant difference was found in -308A/G polymorphism with the TNF-{alpha} levels.

In summary, we report a result with genetic and environmental effects on the risk of developing gout. Our conclusion is that gout has a strong association with hyperuricaemia, alcohol consumption, creatinine, GPT and TG levels as well as with the polymorphism -863C/A in the TNF-{alpha} gene. Since all the biochemical markers had already been identified previously to have had an association with the onset of gout, here we showed a genetic component related to gout by which the polymorphism -863C/A had a strong independent association with the development of gout and a recessive model is suggested.

Formula


   Acknowledgments
 
Disclosure Statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 11 May 2007; revised version accepted 3 August 2007.
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S.-J. Chang, C.-J. Chen, F.-C. Tsai, H.-M. Lai, P.-C. Tsai, M.-H. Tsai, and Y.-C. Ko
Associations between gout tophus and polymorphisms 869T/C and -509C/T in transforming growth factor {beta}1 gene
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