Pharmacogenomics and lung transplantation: clinical implications.
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ATP Binding Cassette Transporter, Subfamily B↗
Biomedical subjects
I V Hutchinson
Publications and source records attributed to I V Hutchinson.
Cytokine profiling of pulmonary aspergillosis.
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.
Adult↗
Polymorphisms in the T cell regulatory gene cytotoxic T lymphocyte antigen 4 influence the rate of acute rejection after liver transplantation.
BACKGROUND: 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. AIM: To examine whether these functional SNPs influence the rate of rejection after liver transplantation. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Acute Disease↗
Angiotensin converting enzyme insertion/deletion polymorphism does not influence postcardiac transplantation hypertension onset or progression.
BACKGROUND: The angiotensin converting enzyme insertion deletion polymorphism (ACE I/D) has been associated with much cardiovascular pathology, including posttransplantation hypertension. Hypertension is a significant cause of morbidity and mortality after cardiac transplantation. We investigated the influence of the ACE I/D polymorphism on posttransplantation hypertension. METHODS: A total of 211 heart transplant recipients and 154 corresponding donors were genotyped for the ACE I/D polymorphism by polymerase chain reaction. ACE enzymatic activity was measured by spectrophotometric kinetic analysis. Sitting systolic and diastolic blood pressures were recorded at 3 consecutive visits, and the mean was calculated. Clinical data, including demographics and medication, were collected for all recipients. Results were analyzed by the chi-square test and analysis of variance, taking a p value of <0.05 to be significant. RESULTS: A total of 41.7% of the subjects were hypertensive (diastolic blood pressure >90 mm Hg) at the time of the study, with 79.6% taking at least one antihypertensive agent. We found no difference between the number of antihypertensive agents, cyclosporin dose and level, renal function, or systolic blood pressure for the different recipient or donor genotypes. We also found no significant correlation between ACE enzymatic activity and systolic or diastolic blood pressure. CONCLUSIONS: Our study of 211 recipients and 154 corresponding donors is the largest investigation of this polymorphism in a cardiac transplantation population. We found no apparent relationship between the ACE genotype (of either donor or recipient) and systemic hypertension (absolute measurements and the number or dose of antihypertensive agents used).
Alleles↗
Donor CCR5 Delta32 polymorphism and outcome following cardiac transplantation.
BACKGROUND: Chemokines regulate the recruitment and trafficking of leukocytes during an immune response. Animal models have shown correlations between chemokine production and leukocyte infiltration during allograft rejection. Also, antagonism of chemokine receptors in transplant models has produced prolonged graft survival. Individuals homozygous for a 32 base pair deletion in the CC chemokine receptor 5 (CCR5) gene have an inactive receptor. Renal transplant recipients homozygous for the deletion have been shown to survive significantly longer than those heterozygous or homozygous for the wild type allele. CCR5 ligands are upregulated during allograft rejection aiding infiltration of leukocytes. We investigated the influence of CCR5Delta32 polymorphism on outcome following human cardiac transplantation. METHODS: Recipients and corresponding donors were genotyped for CCR5Delta32 polymorphism using polymerase chain reactions. RESULTS: We found no correlation between recipient genotype and outcome following transplantation. However, there was a significant correlation between donor genotype and mortality in patients transplanted for a nonischemic condition (DD = n/a, ID = 4%, II = 25%, P = .0014). CONCLUSIONS: The induction of CCR5 expression in endomyocardial biopsy tissue is known to correlate with leukocyte graft infiltration. We suggest that donor CCR5 may be more important for leukocyte trafficking during rejection than recipient CCR5 expression. The CCR5 gene is highly conserved, and due to the small population available for this study, more work is required from other centers.
Base Sequence↗
CD4-veCD8-ve CD30+ve T cells are detectable in human lung transplant patients and their proportion of the lymphocyte population after in vitro stimulation with donor spleen cells correlates with preservation of lung physiology.
INTRODUCTION: Survival following lung transplantation is less than 50% at 5 years, mainly due to immune-mediated chronic rejection. Recently a novel subset of T cells, CD4-veCD8-ve CD30+ve, so-called double negative (DN) CD30+ve T cells, has been described and shown to be responsible for tolerance in an animal model of skin transplantation. METHODS: We investigated 18 lung transplant recipients for the presence of DN CD30+ve T cells in resting peripheral blood and also following in vitro stimulation of recipient peripheral blood mononuclear cells (PBMCs) with donor spleen cells. RESULTS: Small percentages (0.2% to 6%) of DN T cells are detectable in resting PBMCs of human transplant patients (n = 18), but these did not correlate with allograft function, acute rejection episodes, HLA mismatch, or CMV status. On repeated stimulation of recipient PBMCs (two exposures) in vitro by donor spleen cells (2:1 ratio stimulators to responders) the percentage of DN CD30+ve T cells within the lymphocyte pool correlated with preservation of allograft lung function (both for FEV(1), P = .009, and FEF(25-75), P = .036) and was inversely correlated with grade of chronic rejection. On repeated exposure of recipient PBMCs to donor spleen cells with a 1:1 ratio the percentage of DN CD30+ve T cells correlated with the number of acute rejection episodes of grade 2 or greater. The total number of HLA mismatches correlated with the percentage DN CD30+ve T cells present after primary stimulation of recipient PBMCs with donor spleen cells (1:1 ratio). The number of mismatches at the B locus inversely correlated with the percentage of DN CD30+ve T cells after primary stimulation of recipient PBMCs with donor spleen cells (1:1 ratio; P = .031, n = 18). CONCLUSION: Percentages of DN CD30+ve T cells present following repeated stimulation of recipient PBMCs by donor spleen cells correlated with preservation of graft function following lung transplantation.
Antigens, CD↗
The effects of ACE inhibition on serum angiotensin II concentration following cardiac transplantation.
AIMS: ANGII mediates vascular neointimal formation through smooth muscle cell stimulation and enhanced production of growth factors leading to increased arterial medial layer thickness, which is a characteristic of transplant arteriosclerosis. ACE inhibition is known to be of benefit to patients with cardiovascular risk factors. We aimed to determine the effect of ACE inhibitor therapy on ACE enzymatic activity and serum ANGII levels following cardiac transplantation. METHODS: A total of 43 serum samples from eight transplant recipients were used for analysis. Samples were taken monthly from the date of transplant for the initial 6 months. ANGII was measured using sandwich ELISA. ACE enzymatic activity was measured using spectrophotometric kinetic analysis. RESULTS: There was a significant reduction in ACE enzymatic activity among individuals treated with ACE inhibitor therapy (18.0 +/- 16.6 vs 31.8 +/- 23.4, P = .008). We found significantly higher ANGII serum levels in patients receiving ACE inhibitor therapy compared to those not (2.4 +/- 2.1 vs 8.0 +/- 7.4, P = .002). There was also a significant positive correlation between ACE enzymatic activity and ANGII serum level (coefficient 0.332, P = .03). CONCLUSIONS: Our results suggest an effective ACE independent pathway for ANGII conversion. Chymase can convert ANGI with higher affinity than ACE. Also, chymase is stored in mast cells, which infiltrate the myocardium following transplantation. This data indicate that pharmacological chymase inhibition may be a possible therapeutic strategy following transplantation.
Adult↗
The distribution of cardiac macrophages in myocardial ischaemia and cardiomyopathy.
AIMS: Recent evidence has implicated the macrophage as an effector cell in the inflammatory processes in transplant rejection, as well as cardiac disease, including coronary atherosclerosis. Although the latter is a vascular disease, the entire myocardium is affected. We have previously demonstrated the presence and distribution of macrophages in the 'normal' human heart. In this paper the distribution of myocardial macrophages, in the various chambers of the failing human heart, from cases of coronary atheroma and cardiomyopathy undergoing heart transplantation is documented. METHODS AND RESULTS: Tissue blocks were removed at specific sites taken from six cases with ischaemic heart disease (IHD) (four males, two females, age range 54-62 years), and four cases with idiopathic dilated cardiomyopathy (IDCM) (three males, one female, age range 18-49 years). These were compared with hearts from five cases of sudden death, unrelated to heart disease. Sections were stained with a CD68 pan macrophage marker. Positive cells were enumerated in 20 random fields. Results were analysed using a generalized linear modelling method using a Poisson distribution. Macrophages were identified within the interstitium and often close to blood vessels in all hearts. Macrophages from IHD hearts demonstrated the most intense staining and were often larger and more elongated than those found in 'normal' control hearts. Macrophages were also often degranulated and staining was diffuse in the interstitium. Overall, there were significantly more macrophages in most areas from IHD hearts than from IDCM hearts or control hearts (P < 0.001). CONCLUSIONS: Significantly more macrophages were found in all four chambers in diseased hearts compared with controls. Macrophage numbers were higher in the atria than in ventricles in the diseased myocardium. This study suggests selective recruitment of macrophages into the atria in the disease states studied.
Adolescent↗
Novel polymorphism in the promoter region of the human nerve growth-factor gene.
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.
Alleles↗
The relationship between interleukin-10 gene polymorphism at position -1082 and susceptibility to gingivitis in children.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: These data suggest that the -1082*A allele could be a risk factor for gingivitis.
Alleles↗
A novel polymorphism of the gene encoding furin, a TGF-beta1 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-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. 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-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. 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.
Adult↗
Donor and recipient-transforming growth factor-beta 1 polymorphism and cardiac transplant-related coronary artery disease.
BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) has been implicated in the pathogenesis of coronary vasculopathy following cardiac transplantation. The TGFB1 gene contains polymorphisms at positions +915* (Arg25Pro) and +869* (Leu10Pro) which may influence TGF-beta1 expression. We investigated the relationship between the development of coronary vasculopathy and the prevalence of these alleles in a cardiac transplant population. METHODS: Vasculopathy was diagnosed at routine surveillance post-transplant coronary angiography. Using sequence-specific polymerase chain reaction we identified the TGFB1 +915* and +869* genotypes in 147 cardiac transplant recipients and 134 cardiac donors. RESULTS: TGFB1 +915*C allele carriers (low producers) made up 10.5% of the recipient population but were significantly less likely to develop coronary vasculopathy (P=0.03). Median time to diagnosis was 6.0 years (3.9-8.72) in +915*C allele carriers compared to 2.75 years (2.10-4.22) in *G/G homozygotes (p=0.002). Pre- and 1 year post-transplant clinical variables were equivalent between the two groups. Multivariate analysis identified the recipient +915*G/G genotype (hazard ratio 2.96 (95% CI, 1.09-9.98); p=0.039), donor age (hazard ratio 1.05 (95% CI, 1.02-1.09); p=0.008) and number of acute rejection episodes of ISHLT grade 3 or greater in the first year (hazard ratio 1.12 (95% CI, 1.01-1.23); p=0.03) as significant predictors of vasculopathy. The recipient TGFB1 +869*, and both alleles in the donor, had no influence on vasculopathy development. CONCLUSIONS: Recipient TGFB1 +915* genotype influences the development of cardiac transplant-related coronary vasculopathy. This gives an important insight to the pathophysiology of the disease. On the contrary, donor TGFB1 +915* and TGFB1 +869* polymorphisms do not appear to be important and cannot be used as genetic risk factors.
Coronary Angiography↗
Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component?
BACKGROUND AND AIMS: 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. SUBJECTS: A total of 230 unselected patients with irritable bowel syndrome and 450 healthy, ethnically matched controls were studied. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Alleles↗
Cytokine gene polymorphisms associated with symptomatic parvovirus B19 infection.
BACKGROUND: 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. AIMS: To investigate the possible role of cytokine gene polymorphisms in the clinical manifestations of parvovirus B19 infection. METHODS: 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). RESULTS: 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). CONCLUSIONS: The results of the present study suggest that inherited variability in cytokine responses may affect the likelihood of developing symptoms during parvovirus infection.
Adolescent↗
Effect of rapamycin and prednisolone in differentiated THP-1 and U937 cells.
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Actins↗
Association of cytokine single nucleotide polymorphisms with B7 costimulatory molecules in kidney allograft recipients.
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.
Adult↗
Tumour necrosis factor alpha gene polymorphism: a predisposing factor to non-ischaemic myocardial dysfunction?
BACKGROUND: Tumour necrosis factor alpha (TNF alpha) is implicated in the pathophysiology of heart failure. Plasma TNF alpha is raised in patients with myocardial dysfunction in proportion to the symptoms. OBJECTIVE: To determine whether this genetic variant is over represented in heart transplant recipients. PATIENTS: 175 heart transplant recipients and a control group of 212 healthy volunteers were studied. The reason for transplantation was severe symptomatic myocardial dysfunction in all cases. METHODS: The TNF alpha genotype was determined by polymerase chain reaction and gel electrophoresis. The populations were compared for their fit to Hardy-Weinberg equilibrium by calculating the expected frequencies of each genotype and comparing them to the observed values. A chi(2) test was used to determine the significance of the difference between the observed and expected values. RESULTS: No differences were found in the frequency of the TNF2 allele between all heart transplant recipients taken together (54/175, 31%) and healthy volunteers (58/212, 27%). A higher proportion of TNF2 allele carriers was present in cardiac recipients with a pretransplant diagnosis of viral mediated or idiopathic heart failure than in those with ischaemic myocardial dysfunction (26/69 (37.7%) v 28/106 (26.4%), p = 0.03). PATIENTS with a non-ischaemic aetiology had a higher prevalence of TNF2 than healthy volunteers (26/69 (37.7%) v 58/212 (27%), p = 0.05). CONCLUSIONS: The TNF2 allele is overrepresented in patients with end stage non-ischaemic myocardial dysfunction. This may represent a genetic predisposition in a small subset of patients who could respond favourably to anti-TNF alpha treatment.
Biomarkers↗
Cancer of the uterine cervix may be significantly associated with a gene polymorphism coding for increased IL-10 production.
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.
Adult↗