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J Wang,
J W Yang,
A Zeevi,
S A Webber,
D M Girnita,
R Selby,
J Fu,
T Shah, V Pravica,
I V Hutchinson,
G J Burckart
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ABSTRACT: Inosine 5'-monophosphate dehydrogenase 1 (IMPDH1) catalyzes the rate-limiting step of the de novo pathway for purine synthesis and is a major target of the immunosuppressive drug mycophenolic acid (MPA). Few variants of the IMPDH1 gene have been reported. The objective of this study was to identify and characterize IMPDH1 variants to determine whether genetic variation contributes to differences in MPA response and toxicity in transplant patients. Seventeen genetic variants were identified in the IMPDH1 gene with allele frequencies ranging from 0.2 to 42.7%. In this study, 191 kidney transplant patients who received mycophenolate mofetil were genotyped for IMPDH1. Two single-nucleotide polymorphisms, rs2278293 and rs2278294, were significantly associated with the incidence of biopsy-proven acute rejection in the first year post-transplantation. Future studies of the multifactorial nature of acute rejection must consider IMPDH1 polymorphisms in MPA-treated patients.
Clinical Pharmacology & Therapeutics 06/2008; 83(5):711-7. · 6.04 Impact Factor
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ABSTRACT: Aspergillus fumigatus is ubiquitous and yet causes invasive, chronic and allergic disease of the lung. Chronic cavitary pulmonary aspergillosis (CCPA) is a slowly destructive form of pulmonary aspergillosis, without immunocompromise. We hypothesized that CCPA cytokine gene polymorphisms would differ from patients with allergic bronchopulmonary aspergillosis (ABPA) and uninfected controls. We have profiled functional cytokine gene polymorphisms for interleukin (IL)-10, IL-15, transforming growth factors (TGF)-beta1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma in patients with CCPA (n = 24) who were compared with other forms of aspergillosis (mostly ABPA) (n = 15) and with ethnically matched controls (n = 65-330). Results are described with reference to the high-producing genotype in each case. Susceptibility to aspergillosis (all patients compared with normal controls) was associated with higher frequency of the IL-15 +13689*A allele (OR = 2.37, P = 0.0028) and A/A genotype (chi(2) = 10.31, P < 0.001), with a lower frequency of the TNF-alpha-308*A/A genotype (chi(2) = 11.05, P < 0.01). Within the aspergillosis patients, CCPA is associated with lower frequency of the IL-10 -1082*G allele (OR = 0.38, P = 0.0006) and G/G genotype (chi(2) = 22.45, P < 0.001) and with a lower frequency of the TGF-beta1 +869 *T allele (OR +0.42, P < 0.0029) and T/T genotype (chi(2) = 17.82, P < 0.001) compared with non-CCPA patients and normal controls. Patients infected with Aspergillus appear to be higher producers of IL-15, a Th2-promoting cytokine, and lower producers of TNF-alpha, a cytokine central in protective responses. CCPA occurs in patients who are genetically lower producers of both IL-10 and TGF-beta1. As these cytokines are regulatory and anti-inflammatory, CCPA may be a consequence of poor inflammatory response control in the lung.
International Journal of Immunogenetics 09/2006; 33(4):297-302. · 1.29 Impact Factor
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O Tapirdamaz, V Pravica,
H J Metselaar,
B Hansen,
L Moons,
J B J van Meurs,
I V Hutchinson,
J Shaw,
K Agarwal,
D H Adams,
C P Day,
J Kwekkeboom
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ABSTRACT: The cytotoxic T lymphocyte antigen 4 (CTLA-4) gene encodes for a membrane bound (mCTLA-4) and a soluble (sCTLA-4) isoform, which are both involved in regulation of T cell function. The CTLA-4 +49A/G single nucleotide polymorphism (SNP) influences expression of mCTLA-4; +6230G/A SNP affects the production of sCTLA-4.
To examine whether these functional SNPs influence the rate of rejection after liver transplantation.
Liver graft recipients (n = 483) were genotyped for both SNPs, and haplotypes were reconstructed. Association with rejection was tested by the log rank test using the Kaplan-Meier method with time to the first acute rejection episode as outcome. Multiple analysis of SNPs together with demographic factors was performed by Cox regression.
Three haplotypes were observed in the cohort: +49A/+6230A, +49A/+6230G, and +49G/+6230G. The +49A/+6230G haplotype was significantly and dose dependently associated with acute rejection (p = 0.01). Of the demographic factors tested, only underlying liver disease was significantly associated with rejection. Adjusted for underlying liver disease, each additional +49A/+6230G haplotype allele resulted in a significantly higher risk of acute rejection (risk ratio 1.34 (95% confidence interval 1.04-1.72); p = 0.02). Patients who lacked this haplotype had the lowest, carriers an intermediate, and homozygotes the highest risk of acute rejection.
The CTLA-4 +49A/+6230G haplotype, which encodes for normal mCTLA-4 expression but reduced sCTLA-4 production, is a co-dominant risk allele for acute rejection after clinical liver transplantation. This implies that even under immunosuppression, CTLA-4 is critically involved in the regulation of the human immune response to allogeneic grafts.
Gut 07/2006; 55(6):863-8. · 10.11 Impact Factor
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ABSTRACT: We describe a novel T to C transition at position -198 from the transcription start of the human nerve growth-factor (NGF) gene. In British Caucasoid healthy control group that we have genotyped, T and C allele frequencies are 0.633 and 0.367, respectively. This polymorphism affects vitamin D receptor (VDR) binding to its motif in the NGF promoter.
International Journal of Immunogenetics 01/2006; 32(6):379-82. · 1.29 Impact Factor
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ABSTRACT: Interleukin (IL)-10 is an anti-inflammatory cytokine. The protective role of this cytokine against different diseases has been demonstrated in several studies. However, no such study has been carried out on gingivitis. The objective of this study was to determine whether differences exist between Caucasian children with and without gingivitis in the distribution of IL-10 alleles at position -1082.
A total of 260 Caucasian children (86 controls, 174 patients), aged 8 to 12 years, from the University Dental Hospital of Manchester, U.K., were examined. Plaque (PI), calculus (CI), gingival (GI), and bleeding on probing (BOP) indices were used to assess gingival health. DNA was obtained from buccal epithelial cells. Amplification refractory mutation system polymerase chain reaction (ARMS-PCR) was used for genotyping IL-10 polymorphism. Chi square tests were carried out to test the association between allele and genotype frequencies and the severity of gingivitis. Multiple logistic regression was used to determine the role of IL-10 gene polymorphism at position -1082 while adjusting for potential confounders such as plaque, age, and gender.
Gingivitis was present in 67% of the children examined. Frequencies of alleles -1082*A and -1082*G were 45% and 55%, respectively. An increased risk of having gingivitis was found in allele A positive children (G/A, A/A); 75% versus 25% in allele A negative children (G/G); (P = 0.01). The -1082*A allele was significantly more common in children with gingivitis; 49% versus 37% in controls (P = 0.01). Multivariate logistic regression analysis showed that allele A remained a risk factor for gingivitis in children (P = 0.03) regardless of plaque or age. Also, allele A positive children were at increased odds of having gingivitis of 1.8 (95% confidence interval [CI]: 1.05 to 3.06) compared to allele A negative children after adjusting for plaque, age, and gender.
These data suggest that the -1082*A allele could be a risk factor for gingivitis.
Journal of Periodontology 10/2005; 76(9):1455-62. · 2.60 Impact Factor
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ABSTRACT: Coronary vasculopathy (CV) is an important determinant of survival following cardiac transplantation. We have previously shown that G915C polymorphism of the Transforming Growth Factor-beta1 (TGF-beta1) gene strongly influences CV development. Furin is a proprotein convertase enzyme important in TGF-beta1 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-beta1 polymorphism, was subsequently related to the development of CV.
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-beta1 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-beta1 high producer cohort, when analysed by time to first diagnosis and Kaplan Meier testing.
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.
Transplant Immunology 12/2004; 13(3):185-90. · 1.46 Impact Factor
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ABSTRACT: The immune system has been implicated in the pathogenesis of certain clinical manifestations of parvovirus B19 infection, including rash and arthralgia. Cytokines feature in the pathogenesis of parvovirus B19 infection, so inherited variability in cytokine responses to B19 infection might have a bearing on the symptomatology of parvovirus B19 infection.
To investigate the possible role of cytokine gene polymorphisms in the clinical manifestations of parvovirus B19 infection.
Thirty six patients with a variety of symptoms at acute infection and follow up (mean, 22.0 months) and controls (99-330, depending on the locus) were examined for the following cytokine polymorphisms: tumour necrosis factor alpha (TNF alpha), -308; interferon gamma (IFN-gamma), +874; interleukin 6 (IL-6), -174; IL-10, -592, -819, and -1082; and transforming growth factor beta1 (TGF beta 1), +869 (codon 10) and +915 (codon 25).
The TNF alpha -308*A allele occurred in 13.9% of the parvovirus group compared with 27.0% of the control group (odds ratio (OR), 0.44; p = 0.02). The TGF beta 1 CG/CG haplotype was more frequent in the parvovirus group than in the controls (16.7% v 5%; OR, 4.8; p = 0.02). Within the B19 infected group, the TGF beta 1 +869 T allele was associated with skin rash at acute infection (p = 0.005), whereas at follow up the IFN-gamma +874 T allele was associated with the development of anti-B19 non-structural protein 1 antibodies (p = 0.04).
The results of the present study suggest that inherited variability in cytokine responses may affect the likelihood of developing symptoms during parvovirus infection.
Journal of Clinical Pathology 11/2003; 56(10):725-7. · 2.31 Impact Factor
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ABSTRACT: Inflammation may play a role in the pathogenesis of irritable bowel syndrome in some individuals, such as in those who develop symptoms following a dysenteric illness. Persisting inflammation, resulting from an imbalance of cytokines regulating the inflammatory response, is one possible mechanism. As the elaboration of cytokines is under genetic control, this study was designed to establish whether there might be a genetic predisposition to an altered pattern of anti-inflammatory cytokine production in patients with irritable bowel syndrome.
A total of 230 unselected patients with irritable bowel syndrome and 450 healthy, ethnically matched controls were studied.
DNA was extracted from peripheral blood leucocytes of subjects. Allele and genotype frequencies were determined for the anti-inflammatory cytokine interleukin 10 at the site (-1082) concerned with production in lymphocytes. Transforming growth factor beta(1) (codons 10 and 25) genotypes were also examined in a smaller group of subjects.
Patients with irritable bowel syndrome had significantly reduced frequencies of the high producer genotype for interleukin 10 than controls (21% v 32%; p=0.003). There was no apparent relationship with any particular bowel habit subtype. Genotypes for transforming growth factor beta(1) were not altered.
These preliminary results suggest that at least some patients with irritable bowel syndrome may be genetically predisposed to produce lower amounts of the anti-inflammatory cytokine interleukin 10. This lends some support to the hypothesis that there may be an inflammatory or genetic component in some cases of this condition and that further studies in specific irritable bowel syndrome subgroups are justified.
Gut 02/2003; 52(1):91-3. · 10.11 Impact Factor
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ABSTRACT: African-American race is associated with an increased risk of allograft loss, suggesting that African-American patients may form an immunologically higher risk group. Previously, we demonstrated that immune cell costimulatory molecule expression is significantly higher in African-Americans than in Caucasians. Polymorphic variations in the genes for cytokines have been associated with a number of immunological conditions, and with transplant rejection. This study was performed to determine the distribution, in African-American and Caucasian renal transplant recipients, of single nucleotide polymorphisms (SNPs) in the following cytokine genes: tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin (IL)-6, IL-10, and transforming growth factor-beta (TGF-beta). Cytokine production from blood cells was determined, and cell-surface B7 (CD80, CD86) expression was measured. There was a significant link between IL-10 genotype and acute rejection episodes, but only in African-American patients (p < 0.01). Also, African-American patients had a significantly higher probability of having the IL-6 G-allele (p < 0.0001), which is associated with a high production of IL-6 protein. Incubation of blood cells with IL-6 resulted in increased expression of surface CD80 and CD86, while IL-10 decreased CD80 expression. This study demonstrated a clear correlation of the IL-6 G-allele with increased cellular CD80 expression and the IL-10 G-allele with decreased CD80 expression. These data raise the possibility that specific genotypes are associated with local cytokine regulation of cell-surface costimulatory molecule expression. African-American patients may have a genetically determined, quantitatively different immune response than Caucasian patients, contributing to adverse transplant outcomes.
Pediatric Transplantation 02/2002; 6(1):69-77. · 1.48 Impact Factor
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ABSTRACT: The purpose of our prospective, case-controlled study was to investigate the hypothesis that women who are genetically programmed to produce high or medium levels of IL-10 were more likely to develop cancer of the uterine cervix than individuals genetically predisposed to low IL-10 production. The population was recruited from patients attending gynecological clinics at 2 hospitals in Harare, Zimbabwe. Laboratory tests were performed in the Departments of Immunology, Chemical Pathology and Medical Microbiology, Medical School, University of Zimbabwe, and simultaneously at the Department of Biological Sciences, University of Manchester, United Kingdom. Included in our study were 77 women with histologically proven cancer of the uterine cervix and 69 age- and parity-matched healthy women. All of the patients and healthy controls were from the Shona ethnic group that inhabits northern Zimbabwe. DNA was purified from cervical cytobrush samples obtained from women with cervical cancer. Control DNA was extracted from urine or peripheral blood samples from the healthy women. The Qiagen DNA extraction kit was used. Detection of allele A and/or G at -1082 in the promoter region of the IL-10 gene was carried out using the ARMS-PCR technique. Polymorphism in the amplified products was detected by gel electrophoresis in the presence of ethidium bromide and were bands visualized under UV light. The data comprise 77 women who developed invasive cervical cancer and 69 healthy women matched for age and parity. Patients with cancer were significantly (p = 0.001) more likely to be predisposed to produce higher (A/G) levels of IL-10. The genotype encoding for high (G/G) production of IL-10 was only observed in one cancer patient. The prevalence of low producers of IL-10 in the cancer group was significantly lower than in the healthy women. There were no high producers amongst the healthy women. These data suggest that the genetically acquired ability to produce higher levels of IL-10 may be a significant factor in the development of cervical cancer.
International Journal of Cancer 01/2002; 94(6):792-4. · 5.44 Impact Factor
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M C Warlé,
A Farhan,
H J Metselaar,
W C Hop,
A J van der Plas,
M Kap,
S de Rave,
J Kwekkeboom,
P E Zondervan,
J N IJzermans,
H W Tilanus, V Pravica,
I V Hutchinson,
G J Bouma
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ABSTRACT: Individuals may differ in their capacity to produce cytokines. Since cytokines play a key role in allograft rejection, we investigated whether inter-individual differences in cytokine production by in vitro stimulated PBMC are related to the occurrence of acute liver transplant rejection. Our study group comprised 49 liver transplant recipients and 30 healthy individuals. Rejection, which occurred within one month after liver transplantation, was defined in 22 patients ("rejectors") as biopsy-proven rejection, treated with high dose prednisolone. Patients who never experienced rejection episodes were termed as "nonrejectors" (n=27). PBMC of healthy individuals and of liver transplant recipients, collected late after transplantation (mean 3.5 years), were cultured in the presence and absence of Concanavalin A. The production of TNF-alpha, IFN-gamma, IL-10, and IL-13 was measured in supernatant after 1, 2, 3, 4, and 7 days of cell culture. In cell culture, stimulated PBMC of rejectors were found to produce significantly higher levels of TNF-alpha, while there was a trend towards higher production of IFN-gamma and IL-10 as compared to nonrejectors. After grouping patients into high or low cytokine producers based upon reference levels of the healthy individuals using multivariate analysis it was found that occurrence of acute liver transplant rejection correlated to high production of TNF-alpha and low production of IL-13. After stimulated cell culture PBMC of liver transplant recipients show a differential production of TNF-alpha and IL-13 which is correlated with the occurrence of acute liver transplant rejection.
Human Immunology 12/2001; 62(11):1258-65. · 2.84 Impact Factor
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ABSTRACT: We have identified a new single nucleotide polymorphism within the promoter region of the human allograft inflammatory factor (AIF-1) gene. The polymorphism, defined by Genbank accession number AF097515, was characterized as a C/T single base pair substitution at position -932. The T allele is associated with both HLA-DR2 and HLA-B7. Also, this allele creates the consensus binding site for the E-box that has high affinity for the basic helix-loop-helix (bHLH) family of transcription factors.
European Journal of Immunogenetics 09/2001; 28(4):449-50.
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ABSTRACT: Atopic dermatitis (AD) is associated with hyperresponsiveness of lymphocytes to allergens. In acute AD only T(H)2-type lymphocytes are activated, whereas in more chronic forms of AD, the activity of both T(H)1- and T(H)2-type lymphocytes increases. IL-10 and transforming growth factor beta(1) (TGF-beta(1)) are immunosuppressive cytokines that inhibit the activity of both T(H) cell types in human subjects.
The aim of this study was to determine whether children with moderately severe chronic AD had IL10 or TGFB1 genotypes known to be associated with low cytokine production.
Using amplification refractory mutation screening PCR, we examined TGFB1 and IL10 gene polymorphisms, which are known to affect cytokine production, in 68 children with moderately severe AD and in 50 nonatopic children.
The odds ratio of children with AD having a low TGFB1 producer genotype was 4.8 (95% CI, 2.4--9.7) compared with the control subjects (P <.0001). There were no differences in the frequency of IL10 gene polymorphisms between groups.
TGFB1 genotype may partly explain the strong genetic predisposition to AD.
Journal of Allergy and Clinical Immunology 08/2001; 108(2):281-4. · 11.00 Impact Factor
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ABSTRACT: Approximately one in 300 women experience recurrent pregnancy loss (RPL), the aetiology of which is unknown in at least 40% of cases. Previously, some studies have shown increased production of pro-inflammatory cytokines (tumour necrosis factor-alpha and interferon-gamma) and reduced production of anti-inflammatory cytokines (interleukin-10) by circulating blood lymphocytes isolated from these patients when compared with controls. The reasons for this are unclear. The production of these cytokines are partly under genetic control. This study investigated whether polymorphisms in these three cytokine genes known to be associated with either high or low production, are associated with idiopathic RPL. No association was found. It may be that genetic factors are not a major determinant of cytokine production during pregnancy, or alternatively it may be that the observed differences in cytokine production by peripheral lymphocytes do not accurately indicate what is occurring at the local maternofoetal interface during successful and abortive pregnancies.
Journal of Reproductive Immunology 08/2001; 51(1):21-7. · 2.97 Impact Factor
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ABSTRACT: Cytokine production is under genetic control, and certain allelic variants of cytokine genes are associated with higher or lower cytokine production in vitro and in vivo. Psoriasis is associated with an overexpression in the involved skin of T-helper cell type 1 (Th1) cytokines, e.g. interferon (IFN) -gamma and tumour necrosis factor (TNF) alpha and relative underexpression of Th2 cytokines, e.g. interleukin (IL) -4 and IL-10. Objective We investigated the hypothesis that allelic variants of genes for a high production of Th1 cytokines or TNF-alpha, or conversely low production of Th2 cytokines might represent a risk factor for developing psoriasis.
Genotyping for IFN-gamma, IL-10, IL-4 and TNF-alpha was undertaken for 84 patients with psoriasis and compared with control data on file.
Genotype frequencies showed no differences between patients and controls for IFN-gamma, TNF-alpha or IL-4. For IL-10, patients with late onset psoriasis (over 40 years) were more likely to be heterozygous at position - 1082 (P = 0.02), corresponding to intermediate production of IL-10 in vitro and in vivo.
Psoriasis is not determined by a genotype consistent with high production of Th1 cytokines or low production of Th2 cytokines. Thus, the Th1 cytokine profile found in psoriatic plaques is most likely a consequence of local factors.
British Journal of Dermatology 05/2001; 144(4):849-53. · 3.67 Impact Factor
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ABSTRACT: Our group has previously described five different size alleles of an interferon (IFN)-gamma microsatellite. Analyzing this polymorphism, this study correlated high IFN-gamma production with a 12 CA repeat allele (allele 2). Further, our group has described interleukin (IL)-10 polymorphism defining in vitro high and low IL-10 producer status.
Samples from 88 of 115 consecutive cadaveric renal transplants were used to define polymorphism of both IFN-gamma and IL-10. Patients were separated into high and low genotypes based on the previously reported association between certain genotypes and in vitro production. Graft survival, acute rejection, and serum creatinine at 5 years were analyzed for comparison between groups.
The genotype associated with high IFN-gamma production was found in 70 patients. The incidence of acute rejection was 54.3% in the high IFN-gamma genotype group, compared with 44.4% in the low IFN-gamma group. Requirement for antithymocyte globulin therapy was greater in the high IFN-gamma group (odds ratio [OR]=2.5). Among HLA-DR-mismatched patients, IFN-gamma genotype was more strongly associated with rejection (OR=2.86). In the cyclosporine monotherapy subgroup, patients with high IFN-gamma genotype had a 61% incidence of rejection compared with only 20% in the low IFN-gamma genotype patients (OR=3.06). Graft survival was similar between the two groups. When the analysis was controlled for the presence of delayed graft function, 40.5% of the high IFN-gamma genotype patients had serum creatinine levels above 200 micromol/L compared with only 14.3% of the low IFN-gamma genotype recipients at 5 years after transplantation (P=0.05). The high IL-10 genotype was shown to be associated with better graft function at 5 years (75 vs. 50%, P=0.09).
In this study we have shown that high producer genotype for IFN-gamma may have an influence on acute rejection of kidney transplants, particularly in patients on cyclosporine monotherapy. It is also associated with worse long-term graft function. On the contrary high IL-10 production may have a long-term protective effect.
Transplantation 04/2001; 71(5):674-7. · 4.00 Impact Factor
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ABSTRACT: Background Cytokine production is under genetic control, and certain allelic variants of cytokine genes are associated with higher or lower cytokine production in vitro and in vivo. Psoriasis is associated with an overexpression in the involved skin of T-helper cell type 1 (Th1) cytokines, e.g. interferon (IFN) -γ and tumour necrosis factor (TNF) α and relative underexpression of Th2 cytokines, e.g. interleukin (IL) -4 and IL-10.Objective We investigated the hypothesis that allelic variants of genes for a high production of Th1 cytokines or TNF-α, or conversely low production of Th2 cytokines might represent a risk factor for developing psoriasis.Methods Genotyping for IFN-γ, IL-10, IL-4 and TNF-α was undertaken for 84 patients with psoriasis and compared with control data on file.Results Genotype frequencies showed no differences between patients and controls for IFN-γ, TNF-α or IL-4. For IL-10, patients with late onset psoriasis (over 40 years) were more likely to be heterozygous at position − 1082 (P = 0·02), corresponding to intermediate production of IL-10 in vitro and in vivo.Conclusions Psoriasis is not determined by a genotype consistent with high production of Th1 cytokines or low production of Th2 cytokines. Thus, the Th1 cytokine profile found in psoriatic plaques is most likely a consequence of local factors.
British Journal of Dermatology 03/2001; 144(4):849 - 853. · 3.67 Impact Factor
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European Journal of Immunogenetics 03/2001; 28(1):95-6.
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ABSTRACT: To determine any relationship between polymorphisms in the genes encoding tumour necrosis factor alpha (TNFalpha), interleukin-10 (IL-10) and transforming growth factor beta1 (TGFbeta1) and end-stage liver disease.
Whole-blood samples were taken from patients attending the Scottish Liver Transplant Unit with end-stage liver disease (primary biliary cirrhosis, n = 61; alcoholic liver disease, n = 25; primary sclerosing cholangitis, n = 17; viral disease, n = 8; type 1 auto-immune hepatitis, n = 8; acute liver failure, n = 20). DNA was extracted and the polymorphisms at positions TNF -308, IL-10 -1082 and TGFbeta1 +869 and +915 were determined using sequence-specific oligonucleotide probes. Samples were also analysed from normal healthy controls.
There was a significant difference between patients with primary sclerosing cholangitis and healthy controls, with 65% of patients (11/17) possessing at least one TNF2 allele (A at position -308) compared with 38% of controls (P = 0.02). Four of the eight patients with auto-immune hepatitis were homozygous for TNF2 while the other four were heterozygous (P = 0.001). No significant difference between controls and patients was seen in polymorphisms for IL-10 or TGFbeta1. No association between genotype and Child's class was found in primary biliary cirrhosis.
Patients with primary sclerosing cholangitis and auto-immune hepatitis are more likely to possess TNF2 than normal controls. This allele has been associated with an increased production of TNFalpha in vitro and may indicate a predisposition to these inflammatory conditions.
European Journal of Gastroenterology & Hepatology 01/2001; 12(12):1329-33. · 1.76 Impact Factor
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ABSTRACT: We have described previously a variable length CA repeat sequence in the first intron of the human IFN-gamma gene and showed that allele #2 is associated with high in vitro IFN-gamma production. In a consecutive study, allele #2 was found to be associated with allograft fibrosis in lung transplant patients, confirming its role as a marker of high IFN-gamma production, both in vivo and in vitro. In this study we have sequenced 50 PCR products that had been typed previously by PAGE for the identification of CA microsatellite alleles. We report on a novel single nucleotide polymorphism, T to A, at the 5' end of the CA repeat region in the first intron of the human IFN-gamma gene (+874*T/A). There is an absolute correlation between the presence of T allele and the presence of the high-producing microsatellite allele #2. This T to A polymorphism coincides with a putative NF-kappa B binding site which might have functional consequences for the transcription of the human IFN-gamma gene. Therefore, the T to A polymorphism could directly influence the level of IFN-gamma production associated with the CA microsatellite marker.
Human Immunology 10/2000; 61(9):863-6. · 2.84 Impact Factor
