A polymorphism of NADPH oxidase p22 phox is associated with reduced susceptibility to acute rejection in renal allograft recipients.

BACKGROUND: Reactive oxygen species (ROS) such as superoxide (O(2)(-)) play important roles in inflammatory processes. By altering the redox environment, ROS modulate the activation of transcription factors and cytokine genes involved in acute cellular rejection. The NAD(P)H oxidase is a multi-subunit enzyme present in leucocytes and endothelial cells, and is a key source of O(2)(-). 3 single nucleotide polymorphisms (SNPs) of the p22 phox subunit were investigated in a large cohort of renal allograft recipients. METHODS: The C242T, A640G and A-930G SNPs were studied in 244 Caucasian patients with end stage renal failure (ESRF) (148 renal allograft recipients and 96 dialysis patients) using standard PCR. Acute rejection was diagnosed by renal biopsy in 66 allograft recipients (44.6%). Normal controls were DNA samples extracted from 131 umbilical cord bloods following uncomplicated obstetric delivery. RESULTS: A highly significant increase in the frequency of the T242 allele in patients with ESRF compared to controls (31.3% vs 16.7%, p<0.0001) and in allograft recipients without acute rejection compared to those with rejection (37.8% vs 27.3%, p<0.0001) was demonstrated. CONCLUSION: These results show that the T242 allele may predispose to the development of ESRF, but paradoxically reduce susceptibility to acute rejection through reduced NAD(P)H oxidase activity.

Genetic association analyses of non-synonymous single nucleotide polymorphisms in diabetic nephropathy.

AIMS/HYPOTHESIS: Diabetic nephropathy, characterised by persistent proteinuria, hypertension and progressive kidney failure, affects a subset of susceptible individuals with diabetes. It is also a leading cause of end-stage renal disease (ESRD). Non-synonymous (ns) single nucleotide polymorphisms (SNPs) have been reported to contribute to genetic susceptibility in both monogenic disorders and common complex diseases. The objective of this study was to investigate whether nsSNPs are involved in susceptibility to diabetic nephropathy using a case-control design. METHODS: White type 1 diabetic patients with (cases) and without (controls) nephropathy from eight centres in the UK and Ireland were genotyped for a selected subset of nsSNPs using Illumina's GoldenGate BeadArray assay. A chi (2) test for trend, stratified by centre, was used to assess differences in genotype distribution between cases and controls. Genomic control was used to adjust for possible inflation of test statistics, and the False Discovery Rate method was used to account for multiple testing. RESULTS: We assessed 1,111 nsSNPs for association with diabetic nephropathy in 1,711 individuals with type 1 diabetes (894 cases, 817 controls). A number of SNPs demonstrated a significant difference in genotype distribution between groups before but not after correction for multiple testing. Furthermore, neither subgroup analysis (diabetic nephropathy with ESRD or diabetic nephropathy without ESRD) nor stratification by duration of diabetes revealed any significant differences between groups. CONCLUSIONS/INTERPRETATION: The nsSNPs investigated in this study do not appear to contribute significantly to the development of diabetic nephropathy in patients with type 1 diabetes.

Interleukin 12B gene polymorphism and apparent resistance to hepatitis C virus infection.

Cellular immunity with interferon gamma production could have a role in protection from hepatitis C virus (HCV). Interleukin (IL)-12 is a key cytokine in promoting such anti-viral T helper 1 (Th1) responses. We hypothesized that a genetic background able to promote cellular responses may be associated with apparent protection from infection and have investigated the distribution of the functional 1188A/C polymorphism of IL-12B in HCV exposed but uninfected cases. The frequency of the high IL-12-producing C allele was determined by restriction enzyme genotyping in 76 exposed-uninfected individuals and 105 healthy controls. Overall, the C allele was found in 27.6% of exposed-uninfected cases compared with 16.7% of healthy controls [chi(2) = 6.3, P = 0.02, odds ratio (OR) = 1.9, 95% confidence interval (CI) = 1.1-3.2]. CC genotype was found in 10.5% of exposed-uninfected cases compared with 0.9% controls (chi(2) = 9.3, P = 0.01, OR = 12, 95% CI = 1.5-100). Individuals at high risk of HCV infection yet who remain uninfected may be resistant in some way to infection. In our cohort of exposed-uninfected cases a genetic background of enhanced IL-12 production was associated with apparent resistance to HCV infection. This lends support to a central role for cellular immune responses in protecting from infection.

A novel polymorphism in the 5' flanking region of the glucose transporter (GLUT1) gene is strongly associated with diabetic nephropathy in patients with Type 1 diabetes mellitus.

Glucose transporter 1 (GLUT1) activity has been implicated in renal hypertrophy and extracellular matrix formation in mesangial cells. Recent studies have suggested that polymorphisms in the GLUT1 gene are associated with susceptibility to diabetic nephropathy (DN) in patients with diabetes mellitus. In this study, a novel polymorphism (A-2841T) in the 5' flanking region of GLUT1 was examined in 288 patients with Type 1 diabetes mellitus (T1DM) and 101 normal controls. The polymorphisms were amplified and the fragment digested with the enzyme HpyCH4V. There was a highly significant increase in the frequency of the TT-2841 genotype in patients with nephropathy (n=131) compared with those with either no microvascular complications after a 20-year duration of diabetes (uncomplicated; n=72; 54.5% vs. 2.7%, chi=79.4, P<.000001). There was no difference between the uncomplicated group and those who only had retinopathy (n=50; 2.7% vs. 4.0%, respectively). The frequency in recently diagnosed patients was 17.1% and only 2.0% in normal controls. In contrast, the AA genotype was found in 13.6% of the nephropaths, 76.3% of uncomplicated, 48.0% of retinopaths, and 65% of normal controls. These results confirm previous reports of an association between the GLUT1 gene and susceptibility to DN but not retinopathy. The localisation of this polymorphism suggests that it may be involved in the expression of the gene.

Polymorphisms of the aldose reductase gene and susceptibility to diabetic microvascular complications.

Diabetes is a major cause of mortality and morbidity due to the long term microvascular complications of this disease. There is now convincing evidence to show that genetic factors together with elevated blood glucose play an important role in the susceptibility to diabetic nephropathy as well as retinopathy. The polyol pathway is thought to play an important role in the pathogenesis of diabetic microvascular complications. Aldose reductase is the first and rate-limiting enzyme of the polyol pathway. Polymorphisms in the promoter region as well as elsewhere in the gene have been associated with susceptibility to nephropathy, retinopathy as well as diabetic neuropathy. These associations have been replicated in patients with either type 1 or type 2 diabetes mellitus as well as across ethnic groups. These polymorphisms in the promoter region are also associated with expression of the gene. Although clinical trials using inhibitors of aldose reductase to treat diabetic microvascular complications have largely been unsuccessful, the identification of the susceptibility genes may help in the design of future drug regimens.

Space-time clustering of childhood Type 1 diabetes in Devon and Cornwall, England.

AIMS: Several studies on space-time clustering have been reported in childhood diabetes, but the findings are conflicting. The present study was undertaken to examine whether such clustering could be detected at either birth or the time of diagnosis in the far South-west of England. METHODS: A cohort of 518 children aged 0-15 years and diagnosed with Type 1 diabetes from 1975 to 1996 contained in the population-based Cornwall and Plymouth Children's Diabetes Register (CPCDR) were included in the analyses. The case ascertainment for this register is estimated to be 94.4% complete. Mantel's modification of Knox's method was employed. A method based on K-function was also used, for the first time, to investigate the space-time clustering of diabetes. RESULTS: Significant space-time clustering at diagnosis was found by the Knox's test in the following combinations of critical cut-off thresholds: 25, 35 and 50 km and 90, 270 and 360 days (all P < 0.05), with the highest significance found at 35 km and 360 days (P = 0.0011). K-function analysis also confirmed the overall clustering (P = 0.013). CONCLUSIONS: There is strong evidence of space-time clustering in the onset of childhood Type 1 diabetes in Devon and Cornwall, England. These results lend some support to the hypothesis that viral infections and some unknown localized environmental factors play a role in the development of childhood Type 1 diabetes.

Expression of hypoxia-inducible factor 1alpha in tumours of patients with glioblastoma.

Angiogenesis is a prominent feature of glioblastomas but the mechanisms involved in the control of this process are poorly understood. We have investigated the potential role of a recently described transcription factor, hypoxia-inducible factor 1 (HIF-1), which initiates the transcription of a number of hypoxia-inducible genes, including those encoding vascular endothelial growth factor and its receptors. HIF-1 protein expression was assessed by immunocytochemistry, using a monoclonal antibody to the alpha subunit (HIF-1alpha). HIF-1 mRNA expression was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) and the ribonuclease protection assay (RPA). Strong nuclear expression of HIF-1alpha protein was seen in the majority of glioblastomas and anaplastic astrocytomas, particularly surrounding areas of necrosis in glioblastomas. In the majority of these tumours upregulation of HIF-1alpha mRNA was also demonstrated, with a significant increase in glioblastomas compared to lower grade tumours. No correlation was found between the presence of HIF-1alpha protein and immunohistochemical expression of p53 protein. These findings are in keeping with an important role of HIF-1alpha in the vascularization of glioblastomas and suggest that upregulation is at least partly at a transcriptional level.

NFkappaB polymorphisms and susceptibility to type 1 diabetes.

Nuclear factor kappa B (NFkappaB) is an important transcription factor that is involved in the response to oxidative stress and inflammation. Recent studies suggest that it may be involved in the development of diabetic microvascular complications. A highly polymorphic (CA) dinucleotide repeat microsatellite has been identified in the regulatory region of the NFkappaB gene. The aim of this study was to investigate whether this polymorphic region was associated with susceptibility to type 1 diabetes, or its late complications. Genomic DNA was extracted from the peripheral blood of 217 patients with type 1 diabetes mellitus (T1DM) and 111 normal healthy controls. In our population 18 alleles (A1-A18) were identified. There was a highly significant decrease in the frequency of allele 146 bp (A14) in type 1 diabetes (0.03) compared with the normal controls (0.28) (chi(2) = 79.8, Pc = 0.00001). In contrast, the frequency of the allele 138 bp (A10) was significantly increased in patients with type 1 diabetes (0.17) compared with the normal controls (0.02) (chi(2) = 32.8, P < 0.00000). These results demonstrate that the NFkappaB gene may play a role in the susceptibility to type 1 diabetes: individuals with the A10 allele may be more likely to develop diabetes compared with the A14 allele.

Drinking water composition and childhood-onset Type 1 diabetes mellitus in Devon and Cornwall, England.

AIMS: Previous studies have reported inconsistent results on the association between some compositions (e.g. nitrate) in domestic water and the risk of childhood-onset Type 1 diabetes mellitus. This study aimed to examine the relationship between nitrate, zinc and magnesium in drinking water and the risk of childhood-onset Type 1 diabetes mellitus. METHODS: The study covers the Cornwall and the former Plymouth Health Authority Regions in the far south-west of England. Five hundred and seventeen children, aged 0-15 years, diagnosed with Type 1 diabetes mellitus between 1975 and 1996, were identified for inclusion in the study. Domestic water data (nitrate, Zn, Mg, Cu, Al, Ca, Fe and Mn) between 1993 and 1997 were provided by South-west Water Plc, UK, for each of the 40 Water Supply Zones in which the subjects had been resident at the time of diagnosis. The standardized incidence ratio (SIR) of the disease was calculated for each Water Supply Zone using the UK 1991 census population data. The relationship between the SIR of the disease and the water quality indicators in thirds (three strata of low, medium and high concentrations) was examined by chi2 test for trend and Poisson regression analysis. RESULTS: The initial analyses by chi2 test for trend on the relation of SIRs and drinking water compositions suggested that copper, magnesium and nitrate might have some protective effects, but Poisson regression analyses showed that only zinc and magnesium were significant factors. The data suggest that the incidence rate of childhood diabetes is significantly lower when the concentrations of zinc and magnesium in the domestic drinking water are in the range 22.27-27.00 microg/l (incidence rate ratio (IRR), 0.76; 95% CI, 0.59-0.97) and greater than 2.61 mg/l (IRR, 0.72; 95% CI, 0.58-0.91), respectively. CONCLUSIONS: Our findings suggest evidence of a possible association between zinc and magnesium in the domestic drinking water and childhood diabetes in the far south-west of England. However, these possible protective effects of zinc and magnesium in domestic drinking water warrant further confirmation.

Mutations of the cationic trypsinogen gene in hereditary and non-hereditary pancreatitis.

BACKGROUND/AIMS: Mutations in the cationic trypsinogen gene have been detected in patients with hereditary pancreatitis (HP). This study investigates the prevalence of the R122H, N29I, A16V and -28delTCC mutations in the common, non-hereditary forms of chronic pancreatitis and in a HP family. METHODS: DNA was prepared from blood samples of 53 patients with chronic pancreatitis (36 alcoholic, 14 idiopathic and 3 hereditary), 20 alcoholic controls and 20 healthy, ethnically matched controls. The R122H and A16V mutations were identified by the polymerase chain reaction (PCR) and restriction enzyme digestion. A nested-PCR was used to identify the N29I mutation. The -28delTCC deletion and the C133807T polymorphism were sought by direct sequencing. RESULTS: The R122H mutation was detected in 1 patient with alcoholic chronic pancreatitis and all 3 affected members of a HP family. The N29I, A16V and -28delTCC mutations were not detected in any of the study subjects. At the C133807T polymorphism, the C allele and C/C genotype were significantly increased in alcoholic chronic pancreatitis (p = 0.001 and p = 0.0004, respectively) while the T allele and CT genotype were significantly reduced (p = 0.001 and p = 0.004, respectively) compared to healthy controls. CONCLUSIONS: Mutations of the cationic trypsinogen gene are rarely found in chronic pancreatitis patients of typical aetiology. Screening for these mutations should be considered in those with a family history consistent with hereditary pancreatitis but may also be appropriate in a well-defined subgroup of patients with non-hereditary chronic pancreatitis, i.e. those who have developed the disease before the age of 30.

Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy.

BACKGROUND: Despite good metabolic control, many patients with type 1 diabetes still develop nephropathy, implicating a role for genetic factors. Recent studies examining the regulatory region of the aldose reductase (ALR2) gene, the rate-limiting enzyme of the polyol pathway, support its role as a candidate gene for nephropathy. Here we report the quantitation of ALR2, together with sorbitol dehydrogenase mRNA in the peripheral blood mononuclear cells (PBMCs) of type 1 diabetic patients with (N = 29) and without nephropathy (N = 11) following stimulation with high levels of D-glucose. METHODS: PBMCs from patients and normal controls were cultured for five days with phytohemagglutinin in either normoglycemia (11 mmol/L D-glucose) or supplemented with 10 mmol/L D-glucose (moderate hyperglyemia) or 20 mmol/L D-glucose (hyperglycemia). The RNA was extracted and analyzed by ribonuclease protection assay. RESULTS: ALR2 mRNA levels were significantly elevated with increasing D-glucose concentration (normal to hyperglycemic) in those patients with nephropathy (P < 0.0001). In marked contrast, in those without nephropathy and in the normal healthy controls, there was no change in mRNA expression. Furthermore, those patients with nephropathy and the Z-2/X susceptibility genotype had the greatest increase in ALR2 mRNA compared with those with low-risk genotypes (P < 0.007). CONCLUSION: These results show that patients with nephropathy exhibit marked disturbances in the expression of the enzyme components of the polyol pathway. Ultimately this leads to tissue damage and ischemia.

Study of polymorphisms in the CYP2E1 gene in patients with alcoholic pancreatitis.

Cytochrome P450IIEI (CYP2E1) is an ethanol-inducible enzyme. Recently, several novel polymorphisms in the CYP2E1 gene have been identified. A polymorphism at position -35 [G(-35)T] appears to be of functional significance in transcription assays. The aim of this study was to investigate if this and other polymorphisms, at position -1019 [C(-1019)T], 4808 [G(4808)A], and 7668 [T(7668)A] of the CYP2E1 gene are associated with alcoholic pancreatitis. DNA was extracted from peripheral blood of 38 patients with alcoholic chronic pancreatitis (CP), 19 patients with alcoholic acute pancreatitis (AP), 46 alcoholic controls (AC), and 155 normal controls (NC). The polymorphisms were examined by digestion with the corresponding restriction endonucleases following PCR amplification. The results have shown that the frequencies of the rare alleles of these polymorphisms were not significantly different between the CP, AP, and AC groups and NC. Therefore, our study results suggest to us that the polymorphisms investigated in the CYP2E1 gene are unlikely to be involved in the susceptibility and pathogenesis of alcoholic pancreatitis.

A study of cytokine gene polymorphisms and protein secretion in renal transplantation.

Although there is evidence that cytokine gene polymorphisms are associated with varying quantities of cytokine protein production, the exact role of these polymorphisms in allograft rejection remains unclear. In a previous study, we demonstrated a significant association between high IL-10 secretion in mixed lymphocyte culture (MLC), together with HLA mismatching for at least 4-6 antigens, with the occurrence of acute rejection following renal transplantation. We, therefore, wished to ascertain whether cytokine gene polymorphisms are associated with varying levels of protein secretion and/or allograft rejection in the same group of patients. Cytokine protein secretion in MLC for IL-4, IL-6, IL-10 and IFN-gamma was measured by ELISA in 49 patient-donor pairs. Protein secretion for the above cytokines was also measured in phytohaemagglutinin (PHA) stimulated cultures in 30 normal controls. In both patient and control groups, single nucleotide polymorphism analysis for IL-4 G(-590)T, IL-6 G(-174)C, IL-10 G(-1082)A, IL-10 C(-819)T, IL-10 C(-592)A, TNF-alpha G(-308)A and microsatellite analysis for IFNG (CA repeat) was performed. No correlation was found between cytokine gene polymorphisms and cytokine protein secretion in either mitogen stimulated cultures (control group) or MLC (patient group). In addition, no correlation was demonstrated between cytokine gene polymorphisms and renal allograft rejection.

Polymorphisms of the glucose transporter (GLUT1) gene are associated with diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a major cause of morbidity and mortality in patients with type 1 diabetes mellitus. Recent studies suggest that genetic factors, including polymorphisms in the flanking region of the aldose reductase gene (5'ALR2), play an important role in the pathogenesis of nephropathy. Glucose transporter (GLUT1) activity has been implicated in renal hypertrophy and extracellular matrix formation in mesangial cells. The aim was to investigate the frequency of a polymorphism within the GLUT1 gene in 186 Caucasoid patients with type 1 diabetes and 104 normal controls. METHODS: Amplimers flanking the Xba-I polymorphic site in the second intron were employed to amplify DNA from subjects. The amplified DNA was restricted with endonuclease Xba-I, separated by gel electrophoresis, and visualized. In the absence of an Xba-I site, a fragment of 1.1 kilobase was seen, whereas fragments of 0.9 and 0.2 were generated if the Xba-I site was present. RESULTS: There was a highly significant increase in the frequency of the 1.1 allele in those patients with nephropathy (N = 70) compared with those with no proteinuria or retinopathy after 20 years of diabetes (uncomplicated N = 44, 61.4 vs. 40.9%, respectively, P < 0.001). The 1.1/1.1 genotype was also significantly increased in the nephropathy group compared with the uncomplicated group of patients (37.1 vs. 13.6%, respectively, P < 0.01). The frequency of the 1.1/1.1 genotype was similar in 30 patients with retinopathy but not nephropathy when compared with the uncomplicated group of patients (13.6 vs. 16.7%). Furthermore, only 8 out of 49 patients with DN had the Z+2 5'ALR2 DN "protective" allele and the 0.9 GLUT1 allele in contrast to 21 out of 39 uncomplicated patients (P < 0.0002). CONCLUSION: These results suggest that the GLUT1 gene together with the aldose reductase gene are associated with susceptibility to DN in patients with type 1 diabetes.

A polymorphism in the promoter region of the gene for interleukin-6 is associated with susceptibility to type 1 diabetes mellitus.

Type 1 diabetes mellitus is an autoimmune disease characterized by the destruction of the insulin-producing islet beta cells. It is likely that several genetic and environmental factors contribute to this process. There is increasing evidence showing that polymorphisms in cytokine genes may play an important role in modifying the immune response. Interleukin-6 (IL-6) is a cytokine that has been implicated in a number of immune-mediated diseases. Further, there is a polymorphism at position -174 (G(-174)C) of the promoter region of the IL-6 gene that may alter the expression of the gene. In this study, the G(-174)C polymorphism was investigated in 257 Caucasoid patients with type 1 diabetes, 53 two-parent-proband trios, and 120 normal, healthy controls. DNA was amplified using amplimers that flank the G(-174)C site, and the products were digested with the restriction endonuclease NlaIII to detect the G or the C allele. The homozygous G,G(-174) genotype was increased in the patients compared with the normal controls (50.6% vs. 33.3%, p < 0.002), with a decrease in the C,C genotype in the patients compared with the controls (12.5% vs. 24.2%, respectively, p < 0.004). In the 53 trios studied, the G allele was transmitted in 29 of 53 informative meioses. There was no association with age at onset of diabetes or the presence of diabetic complications. In conclusion, these results suggest that the IL-6 gene may contribute to the genetic susceptibility to type 1 diabetes.

Cytokine secretion in mixed lymphocyte culture: a prognostic indicator of renal allograft rejection in addition to HLA mismatching.

We have previously demonstrated significant inter-individual variations in cytokine protein secretion between normal individuals and patients prior to renal transplantation. In this study, pre-transplant patient vs. donor mixed lymphocyte cultures (MLC) were set up between 57 renal allograft patient/donor pairs, and secretion of cytokine protein (IL-2, IL-4, IL-6, IL-10 and IFN-gamma) into the culture supernatant measured by ELISA. Significant inter-individual variations in protein secretion in MLC were observed for all cytokines studied. Univariate analysis demonstrated that high levels of IFN-gamma and IL-10 in MLC and spontaneous IL-4, together with female donor sex and a high degree of HLA mismatching (especially HLA-DR) were significantly associated with rejection. However, multivariate analysis revealed the greatest risk of rejection (RR = 25.5, P = 0.003) was associated with a combination of high IL-10 secretion in MLC and mismatching for at least four HLA antigens (HLA-A, -B and -DR). It remains to be determined whether cytokine secretion in MLC is linked to cytokine gene polymorphisms. In future, assays for measuring either cytokine secretion or genetic polymorphisms may prove to be useful in aiding donor selection and tailoring immunosuppressive therapy.

Chemokines MCP-1 and RANTES in isolated rat pancreatic acinar cells treated with CCK and ethanol in vitro.

The role of cholecystokinin (CCK) and ethanol on the expression and secretion of monocyte chemoattractant protein-1 (MCP-1) and regulated on activation, normal T-cell expressed and secreted (RANTES) chemokines from isolated rat pancreatic acinar cells was investigated. CCK at concentrations of 1 nM and 100 nM and ethanol at concentrations of 75, 200, 400, and 600 mM were used to stimulate isolated acini. The levels of MCP-1 and RANTES in the incubation medium were determined by enzyme-linked immunoabsorbent assay (ELISA). In the control groups, MCP-1 and RANTES were secreted into the incubation medium, and both increased with time. MCP-1 increased from baseline 17.6 pg/ml to 74.1 pg/ml, whereas RANTES increased from 255.5 to 318.3 pg/ml at 390 min. CCK at 100 nM caused a sustained increase in MCP-1 levels to 89.6 pg/ml at 390 min in the incubation medium, whereas the levels of RANTES gradually decreased after 180 min and reached its lowest level at 390 min. Ethanol at a concentration of 600 mM increased the levels of RANTES in the incubation medium, but inhibited the levels of MCP-1 at all concentrations (75, 200, 400, and 600 mM). In summary, rat pancreatic acinar cells secrete MCP-1 and RANTES, and the stimulation of these chemokines by CCK and ethanol suggests that they may be involved in the pathogenesis of acute pancreatitis.

Investigation of the interleukin 1 gene cluster and its association with acute pancreatitis.

The interleukin 1 (IL-1) gene cluster has been implicated in acute pancreatitis. Penta-allelic and bi-allelic polymorphisms exist in the IL-1RN and IL-1B genes, respectively. The aim of the study was to investigate these polymorphisms in acute pancreatitis. Genotype and allele frequencies were determined in patients (n = 116) and healthy controls (n = 170) using the polymerase chain reaction. PCR products from the IL-1B study were further digested with Taq I restriction endonuclease. Patients were categorised according to aetiology, severity, and organ-failure scores. Allele 1 of the IL-1RN polymorphism was significantly increased in patients compared with controls (72.0 vs. 63.0%; p = 0.029, Pc = 0.029), in severe cases compared with controls (81.9 vs. 63.0%; p = 0.002, Pc = 0.004), in idiopathics compared with controls (82.4 vs. 63.0%; p = 0.002, Pc = 0.006), and in severe cases compared with mild cases (81.9 vs. 67.5%; p = 0.023, Pc = 0.046). Allele 2 was significantly decreased in severe cases compared with controls (18.1 vs. 33.0%; p = 0.013, Pc = 0.026), in idiopathics compared with controls (17.6 vs. 33%; p = 0.013, Pc = 0.039), and in severe cases compared with mild cases (18.1 vs. 32.5%; p = 0.023, Pc = 0.046). No significant differences were found for the Taq I allele or genotype frequencies between controls and patients/subgroups of patients. IL-1RN appears to determine severity of acute pancreatitis and susceptibility to idiopathic acute pancreatitis. No association was found between IL-1B and the disease.