TGF-beta1 Gene Polymorphisms Research Articles

The involvement of IL‐10, IL‐6, IFN‐γ, TNF‐α and TGF‐β gene polymorphisms among Turkish lung cancer patients

Several genes encoding different cytokines may play crucial roles in host susceptibility to lung cancer, since cytokine production capacity varies among individuals and depends on cytokine gene polymorphisms. The association between cytokine gene polymorphisms with primary lung carcinoma was investigated. DNA samples were obtained from a Turkish population of 44 patients with primary lung cancer, and 59 healthy control subjects. All genotyping (IFN-gamma, TGF-beta1, TNF-alpha, IL-6 and IL-10) experiments were performed using sequence-specific primers (SSP)-PCR. When compared to the healthy controls, the frequencies of high/intermediate producing genotypes of IL-10 and low producing genotype of TNF-alpha were significantly more common in the patient group. It is noteworthy that lung cancer patients with the TGF-beta T/T genotype in codon 10 had statistically longer survival compared to those having the C/C genotype (Kaplan-Meier survival function test, log rank significance = 0.014). These results suggest that IL-10, TNF-alpha and TGF-beta1 gene polymorphisms may affect host susceptibility to lung cancer and the outcome of the patients.

Arg25Pro polymorphism of transforming growth factor-β1 and its role in the pathogenesis of essential hypertension in Russian population of the Central Chernozem Region

We studied the relationship between Arg25Pro polymorphism of TGFbeta1 gene and predisposition to essential hypertension in the Russian population of Central Chernozem Region (n=402). An association was found between 25Pro allele and 25ArgPro genotype with low risk of essential hypertension in male individuals.

Analysis of common transforming growth factor beta‐1 gene polymorphisms in gastric and duodenal ulcer disease: Pilot study

Transforming growth factor-beta1 (TGF-beta1) has been shown to be an important cytokine that plays a role in cell proliferation, differentiation, tissue injury repair and ulcer healing. The purpose of this pilot study was to investigate if common polymorphisms Leu10Pro, Arg25Pro and C-509T within the TGF-beta1 gene are associated with susceptibility to gastric and duodenal ulcer disease in Russians. Blood samples from 377 unrelated patients with gastric and duodenal ulcer disease and 226 sex- and age-matched healthy controls were used to determine TGF-beta1 gene polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Leu10Pro substitution in the signal peptide of TGF-beta1 has been found to be associated with susceptibility to gastric ulcer (odds ratio [OR] 1.76, 95% confidence interval [CI] 1.12-2.77). A genotype combination of 10Leu/Leu x 25Arg/Arg x -509C/C was also associated with susceptibility to gastric ulcer disease (OR 1.81, P = 0.01). In addition, the frequency of a combination of genotypes 10Pro/Pro x 25Arg/Pro x -509C/T was statistically lower in patients with duodenal ulcer than in controls (OR 0.42, P = 0.05). A significant difference (P = 0.04) in the distribution of rare haplotypes of the TGF-beta1 gene between patients with duodenal ulcer and healthy controls has been found. Polymorphism Leu10Pro was in positive linkage disequilibrium with C-509T polymorphism (coefficient D = 0.191; P < 0.0001). These findings indicate that the Leu10Pro and C-509T polymorphisms may be involved in the modulation of expression of the TGF-beta1 gene, and therefore a predisposition to peptic ulcer disease could be linked to particular alleles of this gene. In particular, a possible role of TGF-beta1 in the pathogenesis of gastric ulcer disease is discussed.

The challenge of renal function in heart transplant children

Renal dysfunction may occur after pediatric heart transplantation and impacts on long-term prognosis. This study aims to review the incidence and mechanisms of chronic nephropathy following heart transplantation, and suggest therapeutic directions. The proportion of pediatric heart-transplant recipients with impaired renal function varies from 22 to 57%, and end-stage renal failure from 3 to 10%, depending on the method used for estimating the glomerular filtration rate. The pathophysiology of renal dysfunction is in part due to calcineurin inhibitor-induced renal vasoconstriction, through activation of the intrarenal renin-angiotensin system, TGF-beta1 upregulation and TGF-beta1 gene polymorphisms. Overproduction of angiotensin II, associated with angiotensin-converting-enzyme genotype, might be associated with poor prognosis and pharmacological factor gene polymorphisms, and may contribute to variation of calcineurine inhibitor exposure in the kidney. Strategies to prevent renal dysfunction include reducing calcineurine inhibitor exposure or delaying calcineurine inhibitor administration from the early post-transplant period. Calcium channel blockers and angiotensin-converting-enzyme inhibitors, blockade of angiotensin II, or anti-TGF-beta1 antibodies might limit nephrotoxicity. No accurate marker can predict the potential of renal lesions to develop. Lowering calcineurine inhibitors levels with immunosuppressive agents that are either less nephrotoxic or non-nephrotoxic should be formally studied. Of high interest is the impact of genetic polymorphism on the development of renal dysfunction.

Cytokine Gene Polymorphisms Are Not Associated With Bronchiolitis Obliterans Syndrome or Survival After Lung Transplant

Cytokine polymorphisms are inconsistently associated with transplant rejection and other adverse outcomes. To address this controversy, we evaluated cytokine single nucleotide polymorphisms (SNPs) in a lung transplant cohort. All patients who underwent lung transplantation from 1993 to 1998 and had post-transplant survival of at least 6 months were included in the initial analysis. Subjects were genotyped for: TNF-alpha -308 G/A; IFN-gamma +874 A/T; TGF-beta1 +869 T/C and +915 G/C; IL-10 -1082 A/G, -819 C/T and -592 C/A; and IL-6 -174 G/C. End-points were onset of broncholitis obliterans syndrome (BOS) and survival. In the cohort, 78 subjects, with an overall mean +/- SE survival 2,339 +/- 117 days, had no correlation between onset of BOS1, BOS2 or survival with TNF-alpha, IFN-gamma, TGF-beta1 or IL-10 gene polymorphisms. However, IL-6 polymorphisms GG or GC were associated with an earlier onset of BOS1 (p = 0.039), BOS2 (p = 0.021), and decreased overall post-transplant survival (p = 0.038). A second cohort of more recent lung transplant recipients did not validate an association between IL-6 polymorphisms and earlier onset of BOS1 (p = 0.70), BOS2 (p = 0.54) or overall post-transplant survival (p = 0.25). Polymorphisms of TNF-alpha, IFN-gamma, TGF-beta1, IL-10 and IL-6 do not appear to influence the onset of BOS or graft survival in recipients.

Association between the polymorphism of TGF-beta1 gene promoter (-509C>T) and idiopathic chronic urticaria.

Idiopathic Chronic Urticaria (ICU), the most common form (70-80%) of chronic urticaria is supposed to have immune basis causes. It is speculated that the promoter polymorphism of TGF-Beta1 gene may be involved in ICU. This condition is thought to affect at least 0.1% of the population and often can be severe and difficult to treat. A total of 40 patients with ICU and 41 normal subjects were studied. DNA was extracted from whole blood and TGF-Beta1 promoter -509C>T polymorphism was determined by PCR-RFLP method. Out of the 40 patients with ICU, 11 (27.5%) had CC, 26 (65%) had CT and 3 (7.5%) had TT genotypes. A higher proportion of case subjects with the C allele (CT type or CC type) was found compared with the T allele. These results do suggest an influence of genetic variability at the promoter of TGF-Beta1 gene (-509C>T) on the occurrence of ICU. This polymorphism has been shown as a useful genetic change in our study. Further work is required to confirm this result.

Association between a TGF β1 promoter polymorphism and rhinosinusitis in aspirin-intolerant asthmatic patients

Rhinosinusitis is highly associated with aspirin-intolerant asthma (AIA). The risk of aspirin intolerance is higher in people with rhinosinusitis than in those without it. Recently, the role of transforming growth factor beta1 (TGFbeta1) in the pathogenesis of chronic rhinosinusitis has come under investigation. The goal of this study was to evaluate the association of TGFbeta1 gene polymorphism with an AIA phenotype in the Korean population. A promoter polymorphism of the TGFbeta1 gene, TGFbeta1-509C>T, and a coding polymorphism (L10P), were genotyped in 203 patients with AIA, 324 patients with aspirin-tolerant asthma (ATA), and 456 normal controls (NC). Serum TGFbeta1 levels were determined by ELISA. The TGFbeta1-509C>T polymorphism was not significantly associated with the AIA phenotype; however, a significant association with the prevalence of rhinosinusitis in AIA (P=0.012), but not in ATA (P>0.05), was observed. When stratified by the presence of rhinosinusitis, the frequency of T allele carriers (CT or TT genotype) of TGFbeta1-509C>T was significantly higher in AIA (87.1%) compared to ATA (52.9%, P<0.001, OR=6.0, 95% CI=3.3-11.1). In addition, AIA patients carrying the TGFbeta1-509T allele showed a lower serum TGFbeta1 level compared to AIA patients carrying the TGFbeta1-509 CC genotype, especially when stratified by the presence of rhinosinusitis (P=0.002). Our results show that the TGFbeta1 polymorphisms are not associated with the AIA phenotype in the Korean population, but may contribute to the development of the AIA phenotype with rhinosinusitis.

Impact of TGFβ1 Gene Polymorphisms on Acute and Chronic Rejection in Pediatric Heart Transplant Allografts

The aim of this study was to assess the influence of IL-10 and TGFbeta1 gene polymorphisms on the development of acute rejection and coronary disease in pediatric heart transplant recipients. Patients were classified as either Rejectors or Nonrejectors. Coronary artery disease (CAD) was diagnosed by angiography or on macroscopic examination. Genotyping PCR-SSP were performed for IL-10 and TGFbeta1 (codon 10 and 25) in 111 patients. Thirty-nine were Rejectors and 31 developed CAD. The proportion of IL-10 low-producers was higher in Rejectors than in Nonrejectors (respectively 46% versus 22%, P=0.009). IL-10 gene polymorphism was not associated with CAD. TGFbeta1-codon10-25 high-producers were 92.3% in Rejectors and 75% in Nonrejectors (P=0.026), 93.5% in patients with CAD and 76.2% in patients free from CAD (P=0.037). TGFbeta1-codon25 high-production separately analyzed correlated with CAD (31/31 high-producers in CAD=100% versus 69/80 in noCAD patients=86.2%, P=0.03). TGFbeta1-codon10 gene polymorphisms were not associated with CAD. IL-10 low-producers have an increased risk of acute rejection. High-expressors of TGFbeta1-codon10-25 have an increased risk of acute rejection and CAD, while TGFbeta1-codon25 high-production is associated with coronary disease. Genetic polymorphism may reveal patients at high-risk in whom therapies and monitoring should be adjusted.

Genetic Polymorphisms in Patients with Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) is a family of clonal disorders characterized by dyshematopoiesis and susceptibility to acute myelogenous leukemia. Tumor necrosis factor-a (TNF-alpha) and transforming growth factor-beta (TGF-beta) are cytokines that play key roles in the pathogenesis of MDS. There have been several reports on the presence of genetic polymorphisms in the DNA sequence encoding the leader sequence of the TGF-beta protein, and in the -308 promoter region of TNF-alpha. The association between TNF-alpha and TGF-beta1 gene polymorphism and the susceptibility to MDS and the progression of the disease was investigated. As compared with healthy control subjects (n = 74), patients with MDS (n = 55) showed no significant deviations in genotype or allele frequencies of TNF-alpha. Similarly, there were no differences in the distribution of TNF-alpha genotypes between the MDS patients with only anemia (mild group) and those with bi- or pancytopenia (severe group). On the other hand the TT homozygosity at codon 10 in exon 1 of TGF-beta1 gene was associated with a severe degree of cytopenia [95% CI OR = 4.889, p = 0.0071]. These findings suggest that the investigated genetic polymorphisms do not predispose to the development of MDS, but that TGF-beta1 gene polymorphism may affect the disease progression.

ASSOCIATION OF TRANSFORMING GROWTH FACTOR-β1 GENE POLYMORPHISM WITH REFLUX NEPHROPATHY

Reflux nephropathy (RN) is recognized as a major cause of end stage renal failure in children and young adults. Transforming growth factor-beta1 (TGF-beta1) is a potent proinflammatory and fibrogenetic cytokine known to have a key role in the regulation of renal tissue fibrosis. We investigate genotype frequencies for polymorphisms of the TGF-beta1 gene at position -509, codon 10 and 25, and examine circulating levels of TGF-beta1 in patients with reflux nephropathy. Renal scaring was evaluated with 99technetium dimercapto-succinic acid renal scan. Genotyping was performed in 123 patients with severe to moderate reflux nephropathy and 58 controls for the position -509, the coding region at position 10 and 25 of the TGF-beta1 gene polymorphisms by polymerase chain reaction, gel analysis and appropriate restriction digest. TGF-beta1 serum levels were measured with standard ELISA technique. The genotype distribution of -509-CT was significantly increased in the RN group compared to controls, (82% vs 37%). Similarly, there was a significant increase in the CC Lue(10)-->Pro (codon 10) genotype (77% vs 27.5%, p <0.05), while TC Lue(10)-->Pro was significantly lower (7.3% vs 43%, p <0.05) in patients compared to controls. There was no significant difference in the Arg(25)-->Pro (codon 25) TGF-beta1 genotypes distribution between patients and controls. There were no statistically significant differences in the serum levels of TGF-beta1 in children with RN (4.2 +/- 0.3 mIU/ml) compared to controls (3.9 +/- 0.4 mIU/ml) (p >0.05). Patients with TGF-beta1 -509 and Lue(10)-->Pro gene polymorphisms may be at higher risk for reflux nephropathy.

Impact of cytokine gene polymorphism on cardiovascular risk in renal transplant recipients

Cardiovascular events are the leading causes of morbidity and mortality in renal transplant recipients (RTR). Given the role of inflammation in atherosclerosis, the contribution of functional polymorphisms of cytokines to cardiovascular diseases (CVD) was assessed in RTR in this study. Polymorphisms of tumour necrosis factor alpha (TNF-alpha) gene [-308 (G-->A), -238 (G-->A)], interleukin-10 (IL-10) gene [-1082(A-->G), -819 (T-->C), -592 (A-->C)], transforming growth factor beta 1 (TGF-beta1) gene [codon 10 (T-->C), codon 25 (G-->C)], carotis intima media thickness (CIMT), left ventricular mass index (LVMI), 24-h ambulatory blood pressure and serum lipoprotein homocysteine level, erythrocyte sedimentation rate, serum C-reactive protein (CRP) and serum fibrinogen level of RTR were determined. Seventy-two RTR (26 cadaveric allograft, 46 living-related allograft, 43 male, 29 female) were included in this study. LVMI were similar in TNF-alpha, IL-10 and TGF-beta1 genotypes. Right and left CIMT were higher in TT genotype (n = 16) than CT (n = 46) and CC (n = 10) genotypes of TGF-beta1 codon 10 (T-->C) gene polymorphism (RCIMT, 7.7 +/- 2.2 mm vs. 7.0 +/- 1.4 mm vs. 5.9 +/- 1.4 mm, P = 0.025; LCIMT, 8.5 +/- 2.5 mm vs. 7.0 +/- 1.3 mm vs. 6.1 +/- 1.2 mm, P = 0.002). Lipoprotein (a) level of TT genotype (35.5 +/- 22.5 mg/dl) was higher than CC (4.1 +/- 2.8 mg/dl) and CT (20.4 +/- 11.2 mg/dl) genotypes of TGF-beta1 codon 10 (T-->C) gene polymorphism (P = 0.037). High producers of cytokine IL-10 -1082 [GG (n = 22) vs. AA + AG (n = 50)] and low producers of TGF-beta codon 25 [GC + CC (n = 17) vs. GG (n = 55)] had lower IMT of carotid artery but the difference did not reach statistical significance (P > 0.05). The CIMT of renal transplant patients was similar in IL-10 (-819, -592) and TNF-alpha (-308, -238) genotypes. No difference was observed in 24-h ambulatory blood pressure levels, serum lipoproteins, plasma homocysteine level, erythrocyte sedimentation rate, serum CRP, serum fibrinogen level in IL-10, TNF-alpha and TGF-beta1 genotypes. Besides the well-known factors, TGF-beta1 gene polymorphisms might play a role in CVD in RTR even at early stages of asymptomatic atherosclerosis.

Effect of polymorphism of transforming growth factor beta1 gene on HBV-induced liver cirrhosis

To explore the effects of transforming growth factor beta1 (TGFbeta1) gene polymorphism on liver cirrhosis induced by HBV infection and on plasma concentration of TGFbeta1. Peripheral blood samples were collected from 134 patients with HBV-induced liver cirrhosis, which were further classified into three groups (A, B and C groups) according to Child-Pugh classification and 92 healthy blood donors. The polymorphisms at position -988, -800, -509 and codon10, codon25, and codon263 of TGFbeta1 gene were determined by PCR-ARMS- and Lightcycler respectively, combined with sequence analysis. The concentrations of TGFbeta1 and collagen type IV were measured by ELISA, and the plasma concentrations of hyaluronan and N-terminal type III procollagen peptide were measured by RIA. ARLEQUIN Ver 2.0 software was used to analyze the linkage disequilibrium between -509C > T and codon10T > C polymorphisms. No polymorphism was found at positions -800, -988, codon25 and codon263. No significant difference for -509C > T polymorphism between the diseased and control groups was found, however, the frequencies of genotype TT and allele T at codon10 in the diseased group were 0.313 and 0.537 respectively, both significantly higher than those of the control group (0.916 and 0.440 respectively, both P < 0.05). In Child-Pugh C grade group the frequency of C allele at position -509 was 0.631, significantly higher than that of T allele (0.325), but there was no significant difference for codon10T > C polymorphism. The TGFbeta1 plasma concentration did not show any difference between the genotypes -509CC and TT in the control group, however, the TGFbeta1 plasma concentration was statistically lower in the those with TT genotype than in those with CC genotype in the diseased group. Linkage disequilibrium was found between -509C > T and codon10T > C polymorphisms and the major haplotypes were C-T and T-C, of which C-T frequency was significantly higher in the patients than in the control group. The plasma concentration of TGFbeta1 was significantly higher in the populations of haplotype C-T than in those of other haplotypes. No relationship is found between -509C > T polymorphism of TGFbeta1 and liver cirrhosis in Chinese populations, but the presence of C allele at position -509 may play an important role in the progression of liver cirrhosis and may influence plasma concentration of TGFbeta1 in liver cirrhosis patients. Codon10T > C polymorphism may play a significant role in development of liver cirrhosis, but has no correlation with plasma concentration of TGFbeta1 and progression of liver cirrhosis. The -509C > T and codon10T > C polymorphisms are in tight linkage disequilibrium, and the major haplotypes are C-T and T-C. The haplotype C-T influences plasma concentration of TGFbeta1 and is closely related to liver cirrhosis.

TGFβ1 haplotypes and asthma in Indian populations

Asthma is a complex disorder of the airways of the lungs. TGF-beta1 plays a key role in airway remodeling and asthma by having both proinflammatory and anti-inflammatory activities, making TGFbeta1 an important candidate gene to study. To investigate the association of TGFbeta1 gene polymorphisms with asthma. A case-control study was designed for identifying polymorphisms and haplotypes associated with asthma and associated phenotypes. We have verified our results in 2 independent cohorts collected from northern (number of patients, 187; number of controls, 187) and western India (number of patients, 209; number of controls, 190). We measured the serum TGF-beta1 levels of selected individuals and correlated them with genotypes and haplotypes. A novel (CT)n(CA)m repeat polymorphism (BV209662) 24.9 kb upstream of TGFbeta1 was identified. A significant association was seen at the level of alleles and genotypes with asthma in the 2 cohorts studied independently (P < .05). Interestingly, a novel 3-locus haplotype, 23_G_T, was found to be significantly associated with asthma (P = .00001 in cohorts A and B) as well as with higher serum TGF-beta1 level (P = .01). On the other hand, a novel haplotype, 22_G_C, was negatively associated with asthma (P = .00001 for cohorts A and B) and with lower serum TGF-beta1 level (P = .0019). This is the first study identifying novel risk and protective haplotypes--23_G_T and 22_G_C, respectively--in the TGFbeta1 gene that are associated with asthma. We also demonstrate the functional significance of these haplotypes with serum TGF-beta1 levels. These results would be valuable in elucidating the role of TGF-beta1 in asthma pathogenesis.

Transforming growth factor-β1 gene polymorphisms are associated with progression of liver fibrosis in Caucasians with chronic hepatitis C infection

Considerable attention is focused on polymorphisms in the gene encoding transforming growth factor-beta1 (TGF-beta1), a multifunctional cytokine that is in turn a potent growth inhibitor involved in wound healing and differentiation. In humans, it promotes the pathogenesis of organ fibrosis, atherosclerosis, cancer, autoimmune and inflammatory diseases, keloid disease, and hypertrophic scarring. For this reason, much emphasis has been placed on studies elucidating the impact of TGF-beta1 and its gene variations for the susceptibility and pathogenesis of these diseases. Unfortunately, some studies have serious limitations. We have recently described a high-throughput method for investigation the Arg25Pro polymorphism of human TGF-beta1 gene and showed that the frequency of the Pro25 allele is significantly associated with hepatic fibrogenesis. In this report, we describe two novel LightCycler (LC) techniques that facilitate the examination of the two other known alterations in the coding region of TGF-beta1. We investigated whether these polymorphisms contribute to hepatitis-induced progression of fibrogenesis in Chinese and Caucasians. In the Chinese ancestry, the gene polymorphisms at codons 25 and 263 were not found and the genetic variant at codon 10 is unlikely to confer susceptibility to hepatic fibrosis. Contrarily, in Caucasians TGF-beta1 allelic variations are more frequent and the presence of prolines either in codon 25 or 10 is associated with the interindividual variability in developing more severe fibrosis during chronic hepatitis C infection. In summary, these results confirm the hypothesis that TGF-beta1 polymorphisms are associated with fibrosis progression in Caucasians chronically infected with hepatitis C.

TNF‐α and TGF‐β1 gene polymorphisms and renal allograft rejection in Koreans

This study was performed in order to evaluate the association of tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) gene polymorphisms with renal allograft rejection in Koreans. Five TNF-alpha (-1031T/C, -863C/A, -857C/T, -308G/A and -238G/A) and two TGF-beta1 (codon 10 T/C and codon 25 G/C) single-nucleotide polymorphism (SNP) sites were studied by using polymerase chain reaction (PCR) single-strand conformation polymorphism and PCR restriction fragment length polymorphism methods in 100 controls and 164 patients. The patients underwent renal transplantation, having one or more Human leukocyte antigen (HLA)-A, HLA-B and HLA-DR antigens mismatched with their donors. For the TGF-beta1 gene, we also studied the polymorphism of donors. The allele frequencies of each SNP site in controls were not different from those of patients. The frequency of TNF-alpha high-producer genotype, -308GA, and TGF-beta1 lower (intermediate)-producer genotype, codon 10 CC and codon 25 GG, were significantly higher in patients with recurrent acute rejection episodes (REs), compared to those in patients with no or one RE. The highest risk group for developing recurrent REs showed the combination of TNF-alpha high- and TGF-beta1 lower-producer genotypes. Analysis of chronic renal allograft dysfunction (CRAD) revealed that TGF-beta1 high-producer genotype of donors, codon 10 TT/TC and codon 25 GG, is associated with CRAD especially in patients with recurrent REs. The highest risk group for developing CRAD showed the combination of recipient's TNF-alpha high- and donor's TGF-beta1 high-producer genotypes. These results would be useful for predicting high-risk group for acute rejection or CRAD in renal transplantation.

Transforming growth factor-beta1 gene polymorphism modifies the histological and clinical manifestations in Japanese patients with IgA nephropathy.

Transforming growth factor (TGF)-beta1, a multifunctional cytokine, which regulates proliferation and differentiation of a variety of cell types, has the central role in the development and progression of renal injury in both animal models and human. Although it has been suggested that genetic variations in the TGF-beta1 gene are associated with the activity of the gene product, their clinical significance in glomerular disease is unknown. We investigated whether the polymorphisms of C-509T and T869C in TGF-beta1 account for interindividual variation in manifestations of IgA nephropathy (IgAN) using 626 Japanese subjects including 329 patients with histologically proven IgAN and 297 healthy controls with normal urinalysis. The frequencies of genotypes, alleles, and major haplotypes were similar between the patients and controls. The C-509T and T869C polymorphisms were in tight linkage disequilibrium, and the major haplotypes were C-C and T-T, which accounted for more than 95% of the total. In patients with -509CC and in those with the 869CC, urinary protein excretion was higher than in those with other genotypes, whereas no difference in other clinical manifestations was noted. Moreover, patients with -509CC and those with 869CC genotypes presented with a significant higher score of mesangial cell proliferation than in those with other genotypes. These results suggest that TGF-beta1 gene polymorphisms are specifically associated with heavy proteinuria and mesangial cell proliferation in Japanese patients with IgAN, although they do not confer susceptibility to this disease.

Transforming growth factor-beta1 polymorphisms in Korean patients with systemic sclerosis.

Transforming growth factor-beta1 (TGF-beta1) plays an important role in the pathogenesis of systemic sclerosis (SSc). To investigate the role of TGF-beta1 gene polymorphisms in SSc, we genotyped six biallelic polymorphic positions (position -988, -800, and -509; and codons 10, 25, and 263) in 61 Korean SSc patients and in 148 healthy controls, using polymerase chain reaction-sequence-specific primers. Genetic polymorphisms were found at position -509 and codon 10 in Koreans. The allele frequencies of C/T at position -509 were 0.59/0.41 in patients and 0.56/0.44 in controls. The allele frequencies of C/T at codon 10 were 0.40/0.60 in patients and 0.50/0.50 in controls. In conclusion, no skewed distribution of TGF-beta1 gene polymorphisms was found in Korean patients with SSc.

Significance of the tissue kallikrein promoter and transforming growth factor-β1 polymorphisms with renal progression in children with vesicoureteral reflux

Tissue kallikrein regulates blood circulation. Low urinary kallikrein excretion was associated with hypertension and renal disease in blacks. The polymorphic KLK1 promoter includes -130 GN coupled with multiple single base substitutions. The -130 G12 allele in the KLK1 promoter was associated with lower transcriptional activity and hypertensive end-stage renal disease (ESRD) in blacks. Transforming growth factor-beta1 (TGF-beta1) regulates matrix production, and induces fibrosis in a variety of tissues. High circulating TGF-beta1 levels mediating renal fibrosis and loss of function in transgenic mice. The -509 T allele in the TGF-beta1 promoter showed marginally higher transcriptional activity, and was associated with increased TGF-beta1 production in humans. The aim of this study was to investigate whether the tissue KLK1 promoter and TGF-beta1 polymorphism are involved in primary vesicoureteric reflux (VUR) with renal progression in children. Seventy-four primary VUR children were studied with regular annual follow-up for more than 18 years, all of them more than grade II (diagnosed by voiding cystourethroradiography). All of them were born before 1984. Patients were classified into two groups according to the renal function with progressive deterioration or not. Patients with baseline creatinine clearance (CCr) less than 25 mL/min were defined as having chronic renal insufficiency (CRI). The TGF-beta1 -509 T-C polymorphism was analyzed by Bsu36I restriction fragment length polymorphism (RFLP)-polymerase chain reaction (PCR). In KLK1 promoter, the -130 GN length polymorphism and multiple single base substitutions were analyzed by electrophoresis of fluoresced PCR products in sequencing gels, single strand conformation polymorphism (SSCP), allele-specific PCR, and DNA sequencing. Patients' TGF-beta1 and KLK1 promoter polymorphisms were evaluated for association with VUR susceptibility and progression in Taiwanese children. Annual echocardiography study was used to evaluate left ventricular mass index (LVMI). Four alleles were identified in the complex KLK1 promoter: A (-130 G10), B (-130 G2CG7), H (-130 G11), and K (-130 G12). The polymorphic KLK1 promoter showed no association with VUR susceptibility. However, the frequency distribution of KLK1 promoter among VUR patients with or without CRI (A, 50.0% and 67.5%; B, 17.9% and 8.3%; H, 14.3% and 18.3%; K, 17.9% and 5.8%, respectively) was statistically different (P = 0.008). Significantly higher K allele frequency was present in primary VUR with CRI children, as it was in the renal survival curve study. A significant increase of LVMI was also found in the A allele group compared with the non-A allele group of KLK1 promoter gene at the age of 18 years old with renal progression. The TGF-beta1 gene polymorphism was determined, and we found significant over-representation of the TT genotype in primary VUR patients with CRI compared with normal renal function (P= 0.0035). The K allele of KLK1 promoter and TT genotype of TGF-beta1 may be a genetic KLK1 -130 GN and -128 G-C, and the susceptibility factor contributing to progressive renal deterioration in Taiwanese primary VUR children.

Transforming growth factor-beta1 gene polymorphisms and bone turnover, bone mineral density and fracture risk in southern Chinese women.

Genetic contributions play an important role in determining bone mineral density (BMD) and bone turnover. Transforming growth factor-beta (TGF-beta) is abundant in bone and has been implicated as an important regulator of both bone formation and resorption. Several polymorphisms of the TGF-beta1 gene have recently been suggested to be associated with BMD and susceptibility to osteoporotic spine fractures. To determine the relationship between TGF-beta1 polymorphisms and BMD in southern Chinese women, three SNPs at C(-1348) -T, T29 -C, and T(861-20) -C of TGF-beta1 gene were analyzed in 237 postmenopausal southern Chinese women by RFLP and direct sequencing. BMD at the lumbar spine and hip region, biochemical markers of bone turnover, as well as serum levels of TGF-beta1 were measured. Only the T29 -C polymorphism of TGF-beta1 gene was associated with BMD and fracture risk. The prevalence of fragility fractures was significantly higher in individuals with TC genotype (P < 0.05). Serum alkaline phosphatase and osteocalcin levels as well as urinary N-telopeptide excretion were significantly higher in women with TC than with TT or CC genotypes, and the difference remained significant after adjusting for age and BMI (all P < 0.05). Women with TC genotype had lower BMD at the trochanteric (P < 0.03) and total hip region (P = 0.05). No difference was observed in the serum TGF-beta1 levels among the three genotypes. In conclusion, an association between T29 -C polymorphisms of TGF-beta1 gene and BMD, bone turnover as well as fragility fractures were demonstrated in postmenopausal southern Chinese women.

Oestrogen receptor alpha genotype, and interactions between vitamin D receptor and transforming growth factor-beta1 genotypes are associated with quantitative calcaneal ultrasound in postmenopausal women.

Quantitative ultrasound (QUS) of bone is a new radiation-free, low-cost method that measures both bone mass and quality. We investigated associations between QUS parameters and polymorphisms of vitamin D receptor (VDR), oestrogen receptor alpha (ERalpha) and transforming growth factor-beta1 (TGF-beta1) genes in postmenopausal women residing in a community. QUS and anthropometric characteristics were measured in postmenopausal women, and compared with regard to the VDR, ERalpha and TGF-beta1 genotypes. Among the 552 women who participated in the population-based Chung-Up osteoporosis prevalence study, 206 postmenopausal women, aged 60-69 years, were included. Broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured at the left calcaneus using QUS measurement of bone, and a stiffness index (SI) was calculated. We determined the BsmI and FokI polymorphisms of VDR gene and the XbaI and PvuII polymorphisms of ERalpha gene using the polymerase chain reaction-restriction fragment length polymorphism method, and Tau29 --> C polymorphism of TGF-beta1 gene using an allele-specific polymerase chain reaction assay. The XbaI polymorphism of ERalpha gene was significantly associated with SI (T-score) and BUA (P = 0.040 and P = 0.024, respectively). There were no significant differences in any QUS parameters among the genotypes of VDR and TGF-beta1. However, significant genetic interactions between the VDR and TGF-beta1 genotypes, were noted (P = 0.017 for SI and P = 0.028 for BUA between the BsmI and Tau29 --> C polymorphisms; P = 0.038 for SI and P = 0.035 for BUA between the FokI and T29 --> C polymorphisms). The combined genotypes between the BsmI and T29 --> C polymorphisms or between the FokI and T29 --> C polymorphisms, were significantly associated with the QUS parameters. This study indicates that the XbaI polymorphism of ERalpha gene may influence the Quantitative ultrasound parameters in postmenopausal women, and suggests the need for further investigations about the interactions between the VDR and TGF-beta1 genes.