TGF-β1 Genotypes Research Articles

TGF-β1 genotype and phenotype in breast cancer and their associations with IGFs and patient survival

Transforming growth factor-β (TGF-β)-mediated signals play complicated roles in the development and progression of breast tumour. The purposes of this study were to analyse the genotype of TGF-β1 at T29C and TGF-β1 phenotype in breast tumours, and to evaluate their associations with IGFs and clinical characteristics of breast cancer. Fresh tumour samples were collected from 348 breast cancer patients. TGF-β1 genotype and phenotype were analysed with TaqMan® and ELISA, respectively. Members of the IGF family in tumour tissue were measured with ELISA. Cox proportional hazards regression analysis was performed to assess the association of TGF-β1 and disease outcomes. Patients with the T/T (29%) genotype at T29C had the highest TGF-β1, 707.9 pg mg−1, followed by the T/C (49%), 657.8 pg mg−1, and C/C (22%) genotypes, 640.8 pg mg−1, (P=0.210, T/T vs C/C and C/T). TGF-β1 concentrations were positively correlated with levels of oestrogen receptor, IGF-I, IGF-II and IGFBP-3. Survival analysis showed TGF-β1 associated with disease progression, but the association differed by disease stage. For early-stage disease, patients with the T/T genotype or high TGF-β1 had shorter overall survival compared to those without T/T or with low TGF-β1; the hazard ratios (HR) were 3.54 (95% CI: 1.21–10.40) for genotype and 2.54 (95% CI: 1.10–5.89) for phenotype after adjusting for age, grade, histotype and receptor status. For late-stage disease, however, the association was different. The T/T genotype was associated with lower risk of disease recurrence (HR=0.13, 95% CI: 0.02–1.00), whereas no association was found between TGF-β1 phenotype and survival outcomes. The study suggests a complex role of TGF-β1 in breast cancer progression, which supports the finding of in vitro studies that TGF-β1 has conflicting effects on tumour growth and metastasis.

TGF-β1 genotypes in cirrhosis: Relationship with the occurrence of liver cancer

This study aimed to verify whether specific single nucleotide polymorphisms (SNPs) of the transforming growth factor-β1 (TGF-β1) may predispose to end-stage liver disease and/or hepatocellular carcinoma (HCC). One hundred eighty-eight consecutive patients transplanted for liver cirrhosis (HBV N = 21, HCV N = 68, alcoholic N = 55 and others N = 23) and a control group of 140 healthy blood donors were investigated. Four SNPs were studied by restriction fragment length assays: −800G > A, −509C > T, Leu10Pro and Arg25Pro. Patients were found to possess the −509T/∗ (TT 53/188, CT 85/188, CC 50/188 vs TT 22/140, CT 61/140, CC 57/140; p < 0.002) and Arg25Pro C/∗ genotypes (CC 1/188, CG 31/188, GG 156/188 vs CC 0/140, CG 13/140, GG 127/140; p < 0.05) more frequently than controls. Patients with cirrhosis complicated by HCC possessed more frequently the Leu10Pro T/∗ genotype than patients without HCC (TT 20/54, CT 26/54, CC 8/54 vs TT 31/134, CT 69/134, CC 34/134; p < 0.05). The analysis of molecular variance detected significant genotypic differentiations between controls and cirrhotics but not between cirrhotics with or without HCC. In conclusion, TGF-β1 SNPs probably facilitate the development of liver cirrhosis, while they seem to have a limited role in predicting the occurrence of HCC.

Relationship Between TGF-β1 Genotypes and the Development of Otitis Media (OM) During Respiratory Syncytial Virus (RSV) in Young Children

Relationship Between TGF-β1 Genotypes and the Development of Otitis Media (OM) During Respiratory Syncytial Virus (RSV) in Young Children

TGF-β1 Gene Polymorphisms and Peritoneal Equilibration Test Results in CAPD Patients

Transforming growth factor-β1 (TGF-β1) stimulates the expression of collagen mRNA in cultured human peritoneal mesangial cells, which may predispose them to developing peritoneal fibrosis. Polymorphisms in the signal sequence genetically may be responsible for increased TGF-β1 production (i.e., a substitution at amino acid position 10 and 25, +869 Leu10–Pro and +915 Arg25–Pro, respectively). The aim of this study was to find out whether there is any relation between peritoneal equilibration test (PET) results and TGF-β1 gene polymorphism. Thirty-two CAPD patients and 72 healthy subjects were included into the study. Each CAPD patient had undergone two PET with a two-year interval. The patients were classified according to the results of a baseline PET as high (high-high average) and low (low-low average) transporters. In high transporters group (n = 20), the genotype frequencies were found as 45% Leu/Leu, 55% Leu/Pro for codon 10; and 85% Arg/Arg, 15% Arg/Pro for codon 25. In low transporters group (n = 12), the genotype frequencies were detected as 66.7% Leu/Leu and 33.3% Leu/Pro for codon 10; and 83.3% Arg/Arg, 16.7% Arg/Pro for codon 25. The distribution of the TGF-β1 genotypes in our control population was compatible with a Hardy-Weinberg equilibrium. We found no relation between TGF-β1 genotypes and peritoneal transport group (χ2 test, p > 0.5). There was no relation between TGF-β1 genotype and longitudinal change in peritoneal transport. This study is the first study analyzing the possible link between TGF-βl gene polymorphisms and the characteristics of peritoneal transport and longitudinal change of peritoneal transport characteristics in CAPD patients. Further work is needed to clarify the functional importance of these two polymorphisms in TGF-β1 production and in the development of peritoneal fibrosis.

Association between Genetic Variation in Transforming Growth Factors β1 and β3 and Renal Dysfunction in Non-Diabetic Chinese

Genetic variants of transforming growth factor (TGF) β1 have been reported to be associated with diabetic nephropathy. Few studies investigated polymorphisms in the TGF-β1 and TGF-β3 genes in relation to renal dysfunction in non-diabetic subjects. In all, 601 non-diabetic Chinese were genotyped for the TGF-β1 T869C and TGF-β3 IVS3-98G>A polymorphisms by PCR-restriction fragment length polymorphism and real-time allele-specific PCR, respectively. Renal dysfunction was defined as a predicted glomerular filtration rate (GFR) of 60mL/min/1.73m2 or less. 24-hour urinary albumin excretion was measured by an immunonephelometric assay in 352 hypertensive subjects. Our study sample included 184 (30.6%) women, 396 (65.9%) hypertensive patients (65.9%), and 94 (15.6%) patients with renal dysfunction. In men but not women, the TGF-β1 TC genotype was significantly (p = 0.0005) overrepresented in patients with renal dysfunction (52.2% vs 36.8% in subjects with normal renal function). Accordingly, in men, with adjustment for age, body mass index, and systolic and diastolic blood pressure, serum creatinine concentration was significantly (p ≤ 0.03) higher in the TC heterozygotes than TT and CC homozygotes. Furthermore, in 231 male hypertensive patients, with similar adjustments applied, 24-hour urinary albumin excretion was significantly (p = 0.02) higher in the IVS3-98 AA homozygotes than G allele carriers. In further multivariate regression analysis, only in men, TGF-β1 and TGF-β3 genotypes as independent predictors had statistically significant effect on serum creatinine (p = 0.007) and urinary albumin excretion (p = 0.022), respectively. Our study demonstrated the associations of genetic variants in the TGF-β genes with renal dysfunction and albuminuria in non-diabetic Han Chinese men but not women.

TGF-β1 Variants in Chronic Beryllium Disease and Sarcoidosis

Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-beta1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-beta1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-beta1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-beta1 variants or haplotypes. The -509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the -509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the -509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the -509C and codon 10T, implicated in lower levels of TGF-beta1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-beta1, although future studies will be needed to correlate TGF-beta1 protein levels with known TGF-beta1 genotypes and assess whether there is a shared mechanisms for TGF-beta1 in these two granulomatous diseases.

TGFB1 Single Nucleotide Polymorphisms Are Associated With Adverse Quality of Life in Prostate Cancer Patients Treated With Radiotherapy

To investigate whether the presence of single nucleotide polymorphisms (SNPs) located within TGFB1 might be predictive for the development of adverse quality-of-life outcomes in prostate cancer patients treated with radiotherapy. A total of 141 prostate cancer patients treated with radiotherapy were screened for SNPs in TGFB1 using DNA sequencing. Three quality-of-life outcomes were investigated: (1) prospective decline in erectile function, (2) urinary quality of life, and (3) rectal bleeding. Median follow-up was 51.3 months (range, 12-138 months; SD, 24.4 months). Those patients who possessed either the T/T genotype at position -509, the C/C genotype at position 869 (pro/pro, codon 10) or the G/C genotype at position 915 (arg/pro, codon 25) were significantly associated with the development of a decline in erectile function compared with those who did not have these genotypes: 56% (9 of 16) vs. 24% (11 of 45) (p = 0.02). In addition, patients with the -509 T/T genotype had a significantly increased risk of developing late rectal bleeding compared with those who had either the C/T or C/C genotype at this position: 55% (6 of 11) vs. 26% (34 of 130) (p = 0.05). Possession of certain TGFB1 genotypes is associated with the development of both erectile dysfunction and late rectal bleeding in patients treated with radiotherapy for prostate cancer. Therefore, identification of patients harboring these genotypes may represent a means to predict which men are most likely to suffer from poor quality-of-life outcomes after radiotherapy for prostate cancer.

TGF-β1 gene polymorphisms in periodontal diseases

Background: Genetic polymorphisms in the TGF-β1 gene were shown to interfere with the transcriptional activity of the TGF-β1 gene, and this influences the production, secretion or activity of the TGF-β1 growth factor. Transforming growth factor-β1 (TGF-β1) gene polymorphism is associated with risk of inflammatory diseases. Objectives: The aim of this study was to evaluate TGF-β1 gene polymorphisms in a Turkish population with different periodontal diseases and to investigate the association between TGF-β1 genotype and clinical periodontal parameters. Methods: A total of 134 subjects were included in this study. Genomic DNA was isolated from 51 patients with chronic periodontitis (CP), 43 with generalized aggressive periodontitis (G-AgP) and 40 healthy controls. Three TGF-β1 gene polymorphisms were identified by PCR-RFLP and MS-PCR at positions + 915G/C, Thr263Ile and 713/8delC. Probing pocket depth (PPD), clinical attachment loss (CAL), plaque accumulation (plaque %) and bleeding of probing were obtained. Chi-square, Mann–Whitney U test and logistic regression analysis were used. Results: There was a slightly significant difference in + 915C positive genotype distributions between CP and control groups (OR: 2.46, CI: 1.010–6.005, p = 0.047). No significant differences were present between G-AgP and controls in + 915C positive genotype. Thr263Ile and − 713/8delC genotype distributions were not different between study groups. There were significant differences in PPD and CAL scores between + 915C positive and negative CP patients. Conclusion: These findings suggest that the TGF-β1 (+ 915C) polymorphic allele might be associated with chronic periodontitis in the Turkish population.

Association Between TGF-B1 Genotype and the Development of Otitis Media (OM) in Young Children during Respiratory Virus Season

Association Between TGF-B1 Genotype and the Development of Otitis Media (OM) in Young Children during Respiratory Virus Season

TGF-β1 codon 25 gene polymorphism is associated with cirrhosis in patients with hereditary hemochromatosis

Hereditary hemochromatosis (HHC) is an autosomal recessive disorder of iron metabolism with variable penetrance. Only a minority of C282Y homozygotes develop clinical overt disease and cirrhosis. The phenotypic heterogeneity of HHC may be due to host genetic factors influencing fibrogenesis such as cytokine gene polymorphisms. In this respect, we investigated the impact of functional genetic polymorphisms of TGF-β1 (codon 10 Leu/Pro, codon 25 Arg/Pro), TNF-α (−308 G/A, −238 G/A) and angiotensinogen (−6 G/A) on the development of cirrhosis in HHC. One hundred and forty-nine (111 male, mean age: 51.0 ± 12.9) C282Y homozygotes who underwent liver biopsy were studied. Genotyping was performed by RFLP analysis. TGF-β1 codon 25 genotypes Arg/Pro and Pro/Pro were more common in patients with cirrhosis than in those without (23.6% vs. 7.4%, p = 0.005). In contrast, the distribution of TGF-β1 codon 10, TNF-α and angiotensinogen genotypes was not different. Logistic regression analysis identified male sex, age, serum ferritin and TGF-β1 codon 25 Arg/Pro and Pro/Pro as independent predictors for the presence of cirrhosis. The adjusted odds ratio for TGF-β1 codon 25 Arg/Pro and Pro/Pro was 2.8 (95% CI 1.4–5.7, p = 0.004). In conclusion, C282Y homozygotes carrying TGF-β1 genotypes Arg/Pro and Pro/Pro are more likely to develop cirrhosis than those with genotype Arg/Arg.

Combined Genetic Assessment of Transforming Growth Factor-β Signaling Pathway Variants May Predict Breast Cancer Risk

There is growing evidence that common variants of the transforming growth factor-beta (TGF-beta) signaling pathway may modify breast cancer risk. In vitro studies have shown that some variants increase TGF-beta signaling, whereas others have an opposite effect. We tested the hypothesis that a combined genetic assessment of two well-characterized variants may predict breast cancer risk. Consecutive patients (n = 660) with breast cancer from the Memorial Sloan-Kettering Cancer Center (New York, NY) and healthy females (n = 880) from New York City were genotyped for the hypomorphic TGFBR1*6A allele and for the TGFB1 T29C variant that results in increased TGF-beta circulating levels. Cases and controls were of similar ethnicity and geographic location. Thirty percent of cases were identified as high or low TGF-beta signalers based on TGFB1 and TGFBR1 genotypes. There was a significantly higher proportion of high signalers (TGFBR1/TGFBR1 and TGFB1*CC) among controls (21.6%) than cases (15.7%; P = 0.003). The odds ratio [OR; 95% confidence interval (95% CI)] for individuals with the lowest expected TGF-beta signaling level (TGFB1*TT or TGFB1*TC and TGFBR1*6A) was 1.69 (1.08-2.66) when compared with individuals with the highest expected TGF-signaling levels. Breast cancer risk incurred by low signalers was most pronounced among women after age 50 years (OR, 2.05; 95% CI, 1.01-4.16). TGFBR1*6A was associated with a significantly increased risk for breast cancer (OR, 1.46; 95% CI, 1.04-2.06), but the TGFB1*CC genotype was not associated with any appreciable risk (OR, 0.89; 95% CI, 0.63-1.21). TGFBR1*6A effect was most pronounced among women diagnosed after age 50 years (OR, 2.20; 95% CI, 1.25-3.87). This is the first study assessing the TGF-beta signaling pathway through two common and functionally relevant TGFBR1 and TGFB1 variants. This approach may predict breast cancer risk in a large subset of the population.

Transforming Growth Factor-β1 Gene Polymorphism in Renal Transplant Recipients

Background. Cytokine transforming growth factor (TGF) is involved in regulation of tissue repair after injury. More recently, TGF–β1 codon 10 gene polymorphism has been shown to be associated with circulating TGF-β levels. We tested whether TGF-β1 genotype polymorphism was predictive of renal allograft function decline. Patients and Methods. The study population consisted of 129 consecutive cadaveric or living related renal transplant recipients at our center between 1985 and 2001. The recipient TGF-β1 genotype polymorphism was determined from peripheral blood leucocytes DNA. The primary endpoint was rate of glomerular filtration rate decline between the first year and the third year of transplant. Results. Baseline glomerular filtration rate as estimated by MDRD study equation at 1 year measured 50 ± 17 mL/min/1.73 m2. At the end of the 3-year follow-up period, 52 patients (40%) experienced biopsy-confirmed acute rejections. Frequency and severity of allograft rejection did not differ with TGF-β genotypes. However, the decline in glomerular filtration rate was significantly greater in Leu/Leu (TT) than Leu/Pro (CT) recipients, 6.3 ± 16.9 mL/min/1.73 m2 versus 0.1±10.2 mL/min/1.73 m2, p = 0.04. Conclusion. Our results demonstrate that recipient TGF-β1 codon 10 Leu/Leu homozygosity is a potential risk factor of kidney allograft function decline.

Transforming growth factor beta-1 and gene polymorphisms in oriental ankylosing spondylitis.

To study serum levels of transforming growth factor beta-1 (TGFbeta1) and the expression of TGFbeta1 in in vitro peripheral blood mononuclear cell (PBMC) cultures in oriental ankylosing spondylitis (AS) patients, and to determine their association with codon 10 and 25 TGFB1 gene polymorphisms. Serum levels of TGFbeta1 were measured by enzyme-linked immunosorbent assay (ELISA). The ability of PBMCs to synthesize TGFbeta1 and other cytokines was assessed by in vitro cultures stimulated with mitogen. Genomic DNA was extracted from PBMCs of AS patients (n=72) or unrelated healthy controls (n=96). The codon 10 and 25 polymorphisms in the TGFB1 gene were analysed using standard polymerase chain reaction-based methods. AS patients had significantly higher serum TGFbeta1 levels than controls (P<0.001). There was no difference in the distribution of codon 10 and 25 TGFB1 genotypes between AS patients and controls. Incubation of AS and control PBMC with phytohaemagglutinin (PHA) led to upregulation of TGFbeta1, interleukin-10, tumour necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) assessed by ELISA. Importantly, PHA-induced TGFbeta1 production was significantly enhanced in AS patients compared with normal controls whereas the production of the pro-inflammatory cytokines TNFalpha and IFNgamma was reduced. Our results show that AS patients express significantly higher levels of serum TGFbeta1 independent of the codon 10 and 25 genotype. Activation of AS PBMCs led to enhanced TGFbeta1 production accompanied by reduction of TNFalpha and IFNgamma while the converse was observed in normal controls.

Relevance of IL10, TGFβ1, TNFα, and IL4Rα Gene Polymorphisms in Kidney Transplantation: A Collaborative Transplant Study Report

Single nucleotide polymorphisms (SNPs) of cytokine genes have been shown to influence cytokine plasma levels. Cytokines are important mediators during organ graft rejection. It was reported that certain cytokine genotypes are associated with improved kidney graft survival.In the present study, SNPs within the IL10 promoter gene, the first exon of the TGFβ1 gene, the TNFα promoter gene, and the IL4Rα gene were analyzed in 2298 first and 1901 repeat cadaver kidney recipients. We found no significant effect on the survival rate of first grafts. Among retransplants, we observed that recipients who were homozygous for the high TNFα producer genotype −308 A had a significantly lower graft survival rate than patients who were carriers of the low producer genotype −308 G (at 3 years: 63.0% vs. 79.5%; pcorrected= 0.0116). The results of this large-scale study suggest that IL10, TGFβ1, TNFα, and IL4Rα cytokine genotypes do not affect the survival of primary kidney grafts. The outcome of retransplants appears to be affected by TNFα genotypes only.

A novel polymorphism of the gene encoding furin, a TGF-β1 activator, and the influence on cardiac allograft vasculopathy formation

Background: Coronary vasculopathy (CV) is an important determinant of survival following cardiac transplantation. We have previously shown that G915C polymorphism of the Transforming Growth Factor-β1 (TGF-β1) gene strongly influences CV development. Furin is a proprotein convertase enzyme important in TGF-β1 activation. We investigated for polymorphism within the promoter region of the gene for furin ( fur). Allelic variation of the fur gene, in conjunction with TGF-β1 polymorphism, was subsequently related to the development of CV. Methods and Results: The fur gene promoter region (position −1199 to +39) was analysed by SSCP and sequencing. A C/T single nucleotide substitution polymorphism at position −231* was identified. Using PCR the fur and TGFB1 genotypes were identified in 115 cardiac transplant recipients. CV was diagnosed at routine surveillance post-transplant coronary angiography. Fur polymorphism had no influence on vasculopathy development; median time to diagnosis, *C/C homozygotes, 2.27 years (2.10–4.32), *C/T heterozygotes 2.97 years (2.09–4.24), *T/T homozygotes 2.65 years (2.33–4.08), ( P=0.95). Allelic variation did not influence Kaplan Meier actuarial analysis of disease onset ( P=0.54). Ninety-three percent of recipients were high TGF-β1 producers. We used fur polymorphism to substratify patients with the +915*G/G TGFB1 (high producing) allele. Fur polymorphism did not influence CV development within this TGF-β1 high producer cohort, when analysed by time to first diagnosis and Kaplan Meier testing. Conclusions: We have described a novel polymorphism at position −231* in the gene encoding furin. The fur −231* single nucleotide polymorphism in isolation, or in conjunction with TGFB1 polymorphism, is not useful as a genetic risk marker for cardiac transplant associated coronary vasculopathy.

Association between TNF-α and TGF-β genotypes in infants and parental history of allergic rhinitis and asthma

The development and expression of allergic rhinitis and asthma may be influenced by the elaboration of specific cytokines. Cytokine genotypes moderate illness severity in a variety of inflammatory disorders. Cytokine genotyping was performed on 124 infants (85% white, 57% male) to determine whether specific cytokine genotypes are associated with a parental history of allergic rhinitis and/or asthma. DNA was extracted from buccal brushings and assayed for tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin (IL)-6, IL-10, and transforming growth factor (TGF)-β1 genotypes using polymerase chain reaction–sequence specific primer technology. Outcomes consisted of parental history of allergy and asthma, and results were evaluated by logistic regression. TNF-α and TGF-β genotypes were related to maternal and/or paternal history of allergic rhinitis and asthma, respectively. The frequencies of the genotype associated with high production of TNF-α were 41% versus 18% in infants with and without a parental history of allergic rhinitis, respectively ( p < 0.01). The frequencies of the genotype associated with low production of TGF-β1 were 14% versus 1% in infants with and without a parental history of asthma, respectively ( p < 0.01). There were no associations between IFN-γ, IL-6, and IL-10 genotypes and any of the outcome parameters. These results suggest a role for TNF-α and TGF-β1 genotypes in the pathogenesis of allergic rhinitis and asthma, respectively. If confirmed by future studies, cytokine genotyping may be a useful tool for identifying at-risk infants who may benefit from the selective use of preventative and/or early intervention treatments for these disorders.

Association between TNF and TGF gene polymorphisms in infants and family history of allergic rhinitis and asthma

Rationale The development and expression of allergic rhinitis and asthma may be influenced by the elaboration of specific cytokines. Cytokine gene polymorphisms moderate illness severity in a variety of inflammatory disorders. Methods Cytokine genotyping was performed on 124 infants (85% Caucasian; 57% male) to determine whether specific cytokine gene polymorphisms are associated with a parental history of allergic rhinitis and/or asthma. DNA was extracted from buccal brushings and assayed for TNF-α, IFN-γ, IL-6, IL-10 and TGF-β1 genotypes using polymerase chain reaction-sequence specific primer technology. Outcomes consisted of parental history of allergy and asthma, and results were evaluated by logistic regression. Results TNF-α and TGF-β genotypes were related to maternal and/or paternal history of allergic rhinitis and asthma, respectively. The frequencies of the genotype associated with high production of TNF-α were 41% versus 18% in infants with and without a parental history of allergic rhinitis, respectively (p<0.01). The frequencies of the genotype associated with low production of TGF-β1 were 14% versus 1% in infants with and without a parental history of asthma, respectively (p<0.01). There were no associations between IFN-γ, IL-6 and IL-10 genotypes and any of the outcome parameters. Conclusions These results suggest a role for TNF-α and TGF-β1 genotypes in the pathogenesis of allergic rhinitis and asthma, respectively. If confirmed by future studies, cytokine genotyping may be a useful tool for identifying “at risk” infants who may benefit from the selective use of preventative and/or early intervention treatments for these disorders.

Association Analysis of the Plasminogen Activator Inhibitor-1 4G/5G Polymorphism in Hispanics and African Americans: The IRAS Family Study

Objective: Plasminogen activator inhibitor type-1 (PAI-1) plays a central role in fibrolysis and has recently been hypothesized to influence components of the insulin resistance syndrome. We consider whether the 4G/5G polymorphism influences components of insulin resistance and obesity solely through PAI-1 protein levels or also though a secondary pathway. In addition, we explore whether transforming growth factor (TGF-β1), a key regulator of PAI-1 expression, modifies the influence of the PAI-1 4G/5G polymorphism on these traits. Methods and Results: The Insulin Resistance and Atherosclerosis (IRAS) Family Study genotyped 287 African American (18 pedigrees) and 811 Hispanic American (45 pedigrees) individuals for the 4G/5G PAI-1 and two TGF-β1 polymorphisms (R25P, C-509T). Individuals were recruited from three clinical centers located in San Antonio (urban Hispanic), San Luis Valley (rural Hispanic) and Los Angeles (African American). The presence of the 4G PAI-1 allele was positively associated with PAI-1 protein level (combined sample p < 0.0001). Hispanic Americans average 65% higher PAI-1 protein levels than African Americans (p < 0.0001). Consistently across ethnic groups, increased PAI-1 protein levels were associated with increased insulin resistance and overall and central obesity (p value < 0.0001, combined sample). Adjusting for PAI-1 protein levels, there was evidence of an association of PAI-1 genotype (4G) with insulin sensitivity (p < 0.002) and subcutaneous fat (p < 0.01). These associations were not influenced by TGF-β1 genotypes. Conclusions: PAI-1 protein is a strong correlate of insulin resistance (IR) and obesity in Hispanics and African Americans. However, PAI-1 4G/5G polymorphism appears to influence insulin resistance and obesity beyond its direct influence on serum PAI-1 protein levels.

The transforming growth factor-β1 gene polymorphism (G915C) is not associated with systemic lupus erythematosus

Lymphocyte production of transforming growth factor (TGF)-beta1 is decreased in systemic lupus erythematosus (SLE). The lack of this immunoregulatory cytokine may contribute to the characteristic T cell disregulation and aberrant B cell stimulation in SLE patients. The less common C allele of the TGFB1 polymorphism (G915C) is associated with a lower TGF-beta1 production capacity. We performed a population-based case-control study to analyse the impact of this polymorphism on disease susceptibility, on clinical SLE manifestations and autoantibody production. A total of 203 German Caucasian SLE patients (fulfilling the 1982 ACR disease duration 11.5 +/- 7.0 years) and 158 ethnically, age- and sex-matched healthy controls were genotyped with a mutagenically separated polymerase chain reaction. There were no significant differences in the genotype distribution and allele frequencies between patients (915 C = 0.08) and healthy controls (915 C = 0.10). Comparing subgroups of patients, we found no association of major disease manifestations or specific autoantibodies with TGFB1 genotypes or alleles. The TGFB1 polymorphism (G915C) neither significantly contributes to the disease susceptibility, nor predisposes to clinical and immunological manifestations typical of SLE. Further studies are needed to corroborate the pathogenic role of TGF-beta1 in SLE patients and to identify the precise genetic elements controlling its production.

Cytokine gene polymorphisms moderate illness severity in infants with respiratory syncytial virus infection

Illness severity and frequency of complications in infants with respiratory syncytial virus (RSV) infection may be influenced by the local elaboration of cytokines. Cytokine gene polymorphisms moderate severity of illness in various inflammatory and infectious diseases. We performed cytokine genotyping on 77 infants hospitalized with confirmed RSV infection to determine whether specific cytokine gene polymorphisms are associated with illness severity or complications. DNA was extracted from buccal brushings and assayed for tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-6 and IL-10, and transforming growth factor (TGF)-β1 genotypes using polymerase chain reaction–sequence-specific primer technology. Clinical outcomes consisted of severity scores of lower respiratory illness, blood oxygen saturation, lengths of oxygen supplementation, and intensive care unit (ICU) and hospital stays, and the presence or absence of pneumonia and otitis media. IFN-γ genotype was related to severity of lower respiratory illness, duration of ICU stay, and frequency of otitis media. Additionally, IL-6 genotype was related to the length of oxygen (O 2) supplementation and hospital stay, IL-10 genotype to the frequency of pneumonia, and TGF-β1 genotype to O 2 saturations at presentation. There were no associations between TNF-α genotype and any of the outcome parameters. These results demonstrate that certain cytokine gene polymorphisms contribute to illness severity and complications during RSV infection in infants. If future prospective studies confirm these observations, cytokine genotyping may be a useful tool for identifying “at risk” infants who may benefit from the selective use of preventive or early intervention treatments for RSV.