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Rheumatology Advance Access originally published online on March 19, 2008
Rheumatology 2008 47(5):617-621; doi:10.1093/rheumatology/ken054
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Associations between gout tophus and polymorphisms 869T/C and –509C/T in transforming growth factor β1 gene

S.-J. Chang1, C.-J. Chen2, F.-C. Tsai3,4, H.-M. Lai2, P.-C. Tsai5, M.-H. Tsai4 and Y.-C. Ko1

1Department of Public Health, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, 2Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Department of Radiology, Long Cyuan Veterans Hospital, PingTung, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung and 5Graduate Institute of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan.

Correspondence to: S.-J. Chang, 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
 
Objectives. To investigate the associations between gout tophus and polymorphisms 869T/C and –509C/T in TGF-β1 gene.

Methods. The polymorphisms 869T/C and –509C/T were determined in 73 gout patients and 114 healthy controls among male Taiwanese using the PCR–restriction fragment length polymorphism method. Each patient was matched with 1–2 controls by age within 1–2 yrs. The tophus number was measured from all the patients’ arms and legs.

Results. Neither 869T/C nor –509C/T showed a significant association between patients and controls in the proportions of genotypes, allele frequency or dominant and recessive models. The mean number of tophi for all patients was 1.53 ± 3.44, showing a significant difference in distribution among the genotypes at polymorphism 869T/C (P = 0.006), but not those in polymorphism –509C/T (P > 0.05). Those carrying genotype CC at polymorphism 869T/C have a mean number of tophi 0.35 (± 1.11), which is significantly lower than those carrying genotype TT (3.73 ± 4.67; P < 0.05). Those with genotype TT at polymorphism 869T/C also had 11.06 times the likelihood of having at least one tophus compared with the genotype CC after adjustment of hyperuricaemia (95% CI = 1.84, 66.36; P = 0.009). However, except for the tophus number, these two polymorphisms did not show any significant association with the clinical characteristics or biochemical markers.

Conclusions. The polymorphism 869T/C in TGF-β1 gene has a significant association with the occurrence of tophus in gout patients.

KEY WORDS: Tophus, TGF, Gout, Polymorphism


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Gout is a condition characterized by the deposition of monosodium urate (MSU) crystals in the joints or soft tissue. There are four phases involved in gout disease including asymptomatic hyperuricaemia, acute gouty arthritis, intercritical gout and chronic tophaceous gout. During the acute phase, three components are involved in the activation of vascular endothelial cells, leading to vasodilatation: increased blood flow, increased permeability to plasma proteins and the recruitment of leucocytes into the tissue [1]. The monocytes and immature macrophages take a key role in the acute phase, secreting TNF-{alpha}, IL-1β, IL-6 and IL-8, and promoting secondary neutrophils captured by endothelial cells under physiological flow in response to MSU crystal uptake [2–6]. Meanwhile, while the monocytes differentiate to macrophages, the differentiated macrophages play an anti-inflammatory role in terminating an acute attack by ingesting MSU crystals without pro-inflammatory cytokine secretion or endothelial cell activation [2, 7]. The macrophages also take a phagocytosis of apoptotic neutrophils, and promote the production of TGF-β to inhibit the responsiveness of the endothelial cells to IL-1β and TNF-{alpha}, and suppress the pro-inflammatory cytokine production [1, 8, 9].

High levels of TGF-β1 have been demonstrated in the synovial fluid of patients with acute gout [10], and administration of TGF-β1 also significantly reduced leucocyte infiltration into the joint after injecting with MSU crystals [11]. Further study has identified TGF-β1 as a suppressor of monocytes-derived cytokine secretion, endothelial cell adhesion molecule expression and leucocyte adhesion in MSU crystal-induced inflammation [9], and it has also been implicated in the regulation of leucocyte and vascular endothelial cell activation [12]. Obviously, TGF-β1 is considered to be an important mediator in regulating inflammation by suppressing monocytes and endothelial cell pro-inflammatory function.

Even in the absence of clinical intervention, the acute gouty arthritis usually resolves within a few days, meaning that an anti-inflammatory reaction will be invoked after the acute phase. However, MSU crystals can persist in joints following acute inflammation and they have been identified within mononuclear cells in synovial fluid [13–15]. Gouty tophi are granulomas of mono- and multi-nucleated macrophages surrounding a core of debris and MSU crystals [16], and the development of the tophus is a dynamic process with a low-level continuous recruitment, pro-inflammatory activation, maturation and turnover of monocyte-macrophages [17]; therefore, we hypothesize that if a down-regulation of inflammatory activity was not terminated completely by the mediation of TGF-β1 released by the differentiated macrophages, the inflammation process and neutrophil infiltration will continue, thus the tophus, i.e. macrophages, debris and MSU crystals surrounded by dense connective tissue, may be expected to be observed in the intercritical gout or chronic tophaceous gout phases.

The gene encoding TGF-β1 is located on chromosome 19q13 [18]. Five polymorphisms were found in the TGF-β1 gene, including –988C/A (rs1800820), –800G/A (rs1800468), –509C/T (rs1800469), 869T/C (rs1982073; Leu10/Pro10; T29->C) and 915G/C (rs1800471) [19–21]. Those polymorphisms were not distributed similarly among different populations or diseases [22]; only two polymorphisms with different alleles, –509C/T and 869T/C, are found in Taiwanese [20]. Since no variant was observed in the other three polymorphisms among Taiwanese, we chose the two polymorphisms, –509C/T and 869T/C, to explore the relationship associated with the occurrence of tophus in gout patients among Taiwanese.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
This study was designed as a cross-sectional study, and all the participants were male. Each gout patient was matched with 1–3 controls and within 2 yrs of their age. Blood samples during fasting were drawn from all participants in 2004 and 2005. The process and design for this study was approved by the Human Research Ethics Committee of Kaohsiung Medical University and Kaohsiung Chang-Gung Memorial Hospital and informed consent was obtained from all patients and controls. A total of 73 gout patients were enrolled from Kaohsiung Chang-Gung Memorial Hospital, and 114 healthy controls were enrolled from a community clinic in southern Taiwan. All the gout patients were diagnosed by a clinical rheumatism physician according to the criteria defined by the ARA [23], and all the healthy controls were also diagnosed to be free from gout.

We collected the clinical features from the patients, and measured all the participants for Glutamyl oxaloacetic transaminase (GOT), Glutamyl pyruvic transaminase (GPT), creatinine, uric acid, total cholesterol (TC), and triglycerides (TG) in the plasma by an automated multichannel chemistry analyser (Toshiba 200, Tokyo). The tophus number was measured from all the patients’ arms and legs for whom, along with palpable tophus and the age of gout onset, duration of gout history and attack frequency by gout during last year were also measured to explore the associations with polymorphisms 869T/C and –509C/T in the TGF-β1 gene. Hyperuricaemia is defined as the uric acid levels ≥7 mg/dl.

The genomic DNA was prepared from peripheral blood leucocytes. The polymorphism 869T/C located at codon 10 and polymorphism –509C/T located in the promoter region of TGF-β1 gene were identified by PCR and restriction fragment length polymorphism (RFLP) methods [24, 25]. The primers used in the PCR procedure for 869T/C were 5'-CTC CGG GCT GCG GCT GCA GCC-3' for forward, and 5'-CGG GAC CTC CCC CTG GCT CG-3' for reverse; and the primers for –509C/T were 5'-CAGAC TCTAG AGACT GTCAG-3' for forward, and 5'-GTC ACC AGA G AA AGA GGA C-3' for reverse. The temperature in 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 61°C for 30 s (869T/C) and at 55°C for 30 s (–509C/T) and extension at 72°C for 45 s; and a final extension at 72°C for 7 min and the samples were maintained at a final 4°C. PvuII and Bsu36I were used as the restriction enzymes for polymorphisms 869T/C and –509C/T, respectively in the RFLP method.

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 duration of gout history and age of gout onset between those with and without tophus among the gout patients. The gout patients’ clinical characteristics, including duration of gout disease, uric acid, TC, TG and creatinine, were tested by analysis of variance (ANOVA) among different genotypes at polymorphisms 869T/C and –509C/T. The differences in the mean tophus number and attack frequency during last years were analysed by Kruskal–Wallis test, and a Dunn posterior test was used for posterior comparisons. The chi-square test was used to detect the Hardy–Weinberg equilibrium (HWE) for polymorphisms 869T/C and –509C/T among the control group.

The odds ratios (ORs) and 95% CI were used to assess the strength of relationship in the inherited models, genotype and allele distribution of polymorphisms 869T/C and –509C/T between the patient groups and controls, and between those with tophus among gout patients, and the P-value was estimated by chi-square test. A logistic regression was used to detect the association in the genotype distribution of the above two polymorphisms with the occurrence of tophus for controlling of hyperuricaemia. As a measure for linkage disequilibrium (LD) between the genotyped polymorphisms 869T/C and –509C/T, D', the coefficient of LD, and r2 were estimated in the patients and controls [26]. Haplotype frequencies were estimated in the two polymorphisms, 869T/C and –509C/T, and we also used the ORs and 95% CI to estimate the haplotype association risk between those with without tophus among gout patients. If the P-value was <0.05 or the range of 95% CI did not include unity, the difference was considered to be statistically significant. The PHASE program (V2.1) was used for haplotype frequencies estimation, and SAS software (V9.13) was used for the statistical analysis.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
A total of 187 male subjects participated in this study during 2004–05, comprising of 73 gout patients and 114 healthy controls. The mean age for all participants was 57.78 ± 11.10 yrs, and there was no significant difference between gout patients and controls (58.41 ± 11.03 vs 57.36 ± 11.17, respectively; P = 0.532). The HWE of polymorphisms 869T/C and –509C/T were estimated in the control group, and the results showed both polymorphisms were in HWE (P = 0.192 for 869T/C; P = 0.358 for –509C/T).

Table 1 lists the association of polymorphisms 869T/C and –509C/T in genotypes, allele frequency and dominant and recessive models between gout patients and controls. For the polymorphism 869T/C, the genotype CT and TT did not show a significant association with gout disease compared with general genotype CC (OR = 0.99; 95% CI = 0.51, 1.90; P = 0.963 for genotype CT; OR = 1.08; 95% CI = 0.43, 2.72; P = 0.877 for genotype TT). Neither the polymorphism 869T/C nor –509C/T showed any significant association between patients and controls in genotypes, allele frequency or dominant and recessive models (Table 1).


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  		TABLE 1. The associations in the distributions of genotypes, allele frequency, dominant and recessive models of two polymorphisms (869T/C and –509C/T) in TGF gene between gout patients and controls

 
The associations between clinical characteristics and genotypes at polymorphisms 869T/C and –509C/T among gout patients are listed in Table 2. The clinical data including duration of gout history, age of gout onset, tophus numbers, attack frequency during last year and uric acid, TC, TG and creatinine levels in plasma. For all patients, the mean tophus number was 1.53 ± 3.44, which showed a significantly different distribution among the different genotypes at polymorphism 869T/C (P = 0.006). For those carrying genotype CC at polymorphism 869T/C, the mean tophus number was 0.35 (± 1.11), significantly lower than that for genotype TT (3.73 ± 4.67; P < 0.05). However, the duration of gout history, age of gout onset, number of attacks during last year, as well as uric acid, TC, TG and creatinine levels did not show the same significant difference between different genotypes among polymorphism 869T/C (all P > 0.05). Regarding the polymorphism –509C/T, the mean tophus number in those with genotype TT was 0.78 (± 1.99); the mean number was lower compared with those with genotype CC (4.40 ± 7.00), but this did not show a significant association (P = 0.252). None of the aforementioned clinical characteristics showed any significant association with the different genotypes of polymorphism –509C/T (all P > 0.05).


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  		TABLE 2. The associations between clinical characteristics and genotypes at polymorphisms 869T/C and –509C/T in TGF gene among gout patients

 
We dichotomized the tophus number into zero and equal or more than one in order to explore the associations with different genotypes or inherited models among polymorphisms 869T/C and –509C/T (Table 3). The duration of gout history and age of gout onset after adjustment of hyperuricaemia are also listed in Table 3 to show the associations with the occurrence of tophus. The results showed that those experiencing tophus had a mean gout history of 11.48 yrs (± 7.00), which was not significantly different from those without tophus (9.49 ± 5.23, P = 0.102), and the age of gout onset also showed no significant association with the occurrence of tophus (48.52 ± 10.51 for those with tophus vs 48.11 ± 12.48 for those without tophus, P = 0.757). Regarding the polymorphism 869T/C after adjustment of hyperuricaemia, when compared with the genotype CC, the genotype TT showed a strong association with the status of tophus (OR = 11.06; 95% CI = 1.84–66.36; P = 0.009); the genotype CT showed little significant association (OR = 3.78; 95% CI = 0.94–15.16; P = 0.061). In the analysis of allele frequency among the polymorphism 869T/C, the allele 869T showed a significant association with the tophus occurrence compared with allele 869C (OR = 2.70; 95% CI = 1.32, 5.54; P = 0.007). The dominant and recessive models of polymorphism 869T/C also showed the same significant association between these two tophus groups (P ≤ 0.05; Table 3). Concerning the polymorphism –509C/T, there was no statistical evidence to show the same significant association between tophus occurrence and genotypes, allele frequency or dominant and recessive models after adjustment of hyperuricaemia (all P > 0.05).


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  		TABLE 3. The ORs and 95% CIs of the tophaceous occurrence associated with polymorphisms 869T/C and –509C/T after adjustment of hyperuricaemia

 
The haplotypes of polymorphisms –509C/T and 869T/C are estimated and listed in Table 4. Most of subjects were of haplotype –509T/869C, so we used this haplotype as baseline, and compared the others with it. The results showed that those carrying allele 869T (haplotypes –509T/869T and –509C/869T) had significant associations with the tophus occurrence (OR = 3.38; 95% CI = 1.19, 9.54 for haplotype –509T/869T; OR = 2.64; 95% CI = 1.15, 6.07 for haplotype –509C/869T). However, those with haplotype –509C/869C did not show the same significant difference (OR = 1.23; 95% CI = 0.34, 4.38; P = 0.752). This means that only the polymorphism 869T/C had a significant association with occurrence of tophus. Table 5 lists the LD between polymorphisms –509C/T and 869T/C among gout patients and controls. The LD was observed, especially in the control group, that the coefficient of LD, D', for those gout patients and controls are 0.620 and 0.873, respectively, and the r2-values are 0.334 and 0.762, respectively.


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  		TABLE 4. The OR and 95% CI between estimated number of haplotypes of polymorphisms –509C/T and 869T/C and tophus number among gout patients

 

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  		TABLE 5. The LD between polymorphisms –509C/T and 869T/C among gout patients and controls

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
TGF-β1 is released by macrophages with a capacity of inhibiting pro-inflammatory monocyte and endothelial cell activation [1, 9]. This inhibiting reaction may act in conjunction with phagocytosis of apoptotic neutrophils by macrophages to prevent further leucocyte trafficking into the synovial tissues during the resolution phase of an acute attack of gout [8]. From the genotype and haplotype analysis on the polymorphisms –509C/T and 869T/C in TGF-β1 gene, we demonstrated a significant association between polymorphism 869T/C and the occurrence of tophus, but this was not the case with polymorphism –509C/T. It is our hypothesis that under the dysfunction of TGF-β1, caused by carrying allele 869T, the inflammatory action may not be terminated absolutely, with the result that the endothelial cell activation and neutrophil infiltration would not be completely blocked; thus, activation of leucocytes and chronic inflammation would persist and a tophus would be synthesized after a long period.

The attack frequency of gout would also be expected to be more frequent in those carrying allele 869T, because under the dysfunction of TGF-β1, the pro-inflammatory reaction would not be completely blocked. Since all the patients were selected from the hospital, and all of them were under treatment, the attack frequency may be distorted during the period of medical treatment with the effect that the observed attack frequency did not reflect the actual one. In our study, we did not find a significant association between the attack frequency during the last year and either of the polymorphisms of 869T/C and –509C/T. This association should be further identified by selecting patients from the community who are not currently under treatment.

Our study shows that those carrying allele 869T have higher mean tophus numbers, and that there is a significant association between tophus number and polymorphism 869T/C. The polymorphism 869T/C gives rise to a Leu->Pro polymorphism at amino acid residue 10 in the signal peptide, which allows export of the newly synthesized protein across the membranes of the endoplasmic reticulum [27]. In several previous studies, allele 869T or genotype 869TT have been reported to be associated with reduced production of TGF-β1 protein [20, 28–30]. The reduction in protein production may be resulted from the lower export efficiency influenced by the allele 869T. The development of tophus is a dynamic process with a low-level continuous recruitment of leucocytes, pro-inflammatory activation, maturation and turnover of monocyte-macrophages, and chronic tophaceous gout usually develops after years of acute intermittent gout. Therefore, we speculate that the allele 869T might be associated with lower production of TGF-β1, and this may result in chronic inflammation for a long time after the acute gout phase, which is correlated with the development of tophus. In our study, since we have no TGF-β1 levels to show the association between the TGF-β1 levels and development of tophus, the interpretation for our results is limited. We explore the associations between the polymorphism –509C/T and occurrence of tophus by genotype and haplotype analysis, and none of the results show a significant difference in statistics between polymorphism –509C/T and tophus occurrence. Only the polymorphism 869T/C was found to show significant association with the gouty tophus in our study, and a linked disequilibrium was observed between these two polymorphisms that may be the consequence of the polymorphism –509C/T that did not show the same significant association with occurrence of tophus.

The genotype distributions of polymorphisms 869T/C and –509C/T in our controls show no significant differences when compared with the controls in other studies [20, 24, 31]; our results also showed that the genotype distributions of polymorphisms 869T/C and –509C/T in the controls are in HWE, which means our data are comparable with other studies and there are no serious concerns about the genetic structure of this sample.

Our previous report had found an independent association between polymorphism –863C/A in TNF-{alpha} gene and gout disease [32], but it did not show the same significant association with the occurrence of tophus. That fact is not unexpected since the TNF-{alpha} was demonstrated to be involved in endothelial activation, recruitment and activation of leucocytes in the acute gout phase, not in the chronic tophaceous phase [1]. Additionally, the TGF-β1 function was shown to suppress the endothelial activation and to inhibit the pro-inflammatory cytokine production after the acute phase [1], and we are interested in the development of tophus, which is related with the chronic inflammation. It is also within our expectation that our results showed that those carrying allele 869T have higher mean tophus number than those with allele 869C, but the same significant association did not exist with the gout disease. Khalil et al. [31] showed that the genotype TT at polymorphism –509C/T in TGF-β1 was more prevalent in relation to the patients with severe proteinuria in a Caucasian population and that disease also resulted in significant higher levels of serum creatinine which strong correlated with the development of gout disease. Some studies also showed that those patients with rheumatic heart disease or RA have a lower frequency of genotype CC at polymorphism –509C/T and a higher frequency of allele 869T [24, 33]. However, in our study, the proportions of genotypes or allelic frequency at polymorphisms 869T/C and –509C/T in TGF-β1 gene did not show a significant difference between gout patients and controls.

The most reliable method of diagnosis for tophus is invasive needle aspiration and identification of crystals on polarizing microscopy, which on demonstrating the presence of MSU crystals in aspirated joint fluid or tophus is considered the gold standard [34]. However, the usefulness of ultrasonography for diagnosing gout can detect tophaceous material more precisely in gouty metatarsophalangeal joints, even in those without palpable tophus [35]. The tophus number may be underestimated in our study without the usefulness of ultrasonography, but it can really reflect the tophus status in general gout patients.

In summary, we have seen a significantly higher mean tophus number among gout patients in those carrying genotype TT at polymorphism 869T/C in TGF-β1 gene compared with those carrying genotype CC, but we did not see the same significant association in gout patients with polymorphism –509C/T. Besides, neither polymorphism 869T/C nor –509C/T had a significant association in the genotype distributions with the occurrence of gout disease.

Formula

Disclosure statement: The authors have declared no conflicts of interest.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 20 October 2007; revised version accepted 23 January 2008.
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H. R. SCHUMACHER, W. TAYLOR, L. EDWARDS, R. GRAINGER, N. SCHLESINGER, N. DALBETH, F. SIVERA, J. SINGH, R. EVANS, R. W. WALTRIP, et al.
Outcome Domains for Studies of Acute and Chronic Gout
J Rheumatol, October 1, 2009; 36(10): 2342 - 2345.
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