Susceptibility To Acute Pancreatitis Research Articles

Meta-analysis and field synopsis of genetic variants associated with the risk and severity of acute pancreatitis.

BackgroundGenetic risk factors can provide insight into susceptibility for acute pancreatitis (AP) and disease progression towards (infected) necrotizing pancreatitis and persistent organ failure. The aim of the study was to undertake a systematic review of the genetic evidence for AP.MethodsOnline databases (MEDLINE, Embase, BIOSIS, Web of Science, Cochrane Library) were searched to 8 February 2018. Studies that reported on genetic associations with AP susceptibility, severity and/or complications were eligible for inclusion. Meta‐analyses were performed of variants that were reported by at least two data sources. Venice criteria and Bayesian false‐discovery probability were applied to assess credibility.ResultsNinety‐six studies reporting on 181 variants in 79 genes were identified. In agreement with previous meta‐analyses, credible associations were established for SPINK1 (odds ratio (OR) 2·87, 95 per cent c.i. 1·89 to 4·34), IL1B (OR 1·23, 1·06 to 1·42) and IL6 (OR 1·64, 1·15 to 2·32) and disease risk. In addition, two novel credible single‐nucleotide polymorphisms were identified in Asian populations: ALDH2 (OR 0·48, 0·36 to 0·64) and IL18 (OR 1·47, 1·18 to 1·82). Associations of variants in TNF, GSTP1 and CXCL8 genes with disease severity were identified, but were of low credibility.ConclusionGenetic risk factors in genes related to trypsin activation and innate immunity appear to be associated with susceptibility to and severity of AP.

Association between Genetic Polymorphisms of Inflammatory Response Genes and Acute Pancreatitis

ABSTRACTInflammation plays a central role in the pathophysiology of acute pancreatitis (AP). We hypothesized that changes in the function of key components of the inflammatory cascade, caused by genetic polymorphisms, could determine the development and/or severity of AP.We studied the following polymorphisms in 269 patients: IL23R rs11209026, TNF rs1800629, RIPK2 rs42490, NOD2 rs9302752, MCP1 rs1024611 and NFKB1 rs28362491.The rs11209026 A allele was related to the presence of AP (p = 0.007261; OR = 1 .523). Epistasis analysis revealed that AP susceptibility was increased by interaction between IL23R rs11209026 and TNF rs1800629 (p = 1.205 × 10−5; ORinteraction = 4.031). The rs42490-G allele was associated with an increased risk of severe pancreatitis (p = 0.01583; OR = 2.736), severe or moderately severe pancreatitis (p = 0.04206; OR = 1.609), and death (p = 0.03226; OR = 3.010).In conclusion, these results point to a plausible role for genetic polymorphisms in IL23R and RIPK2 in the development and severity of AP.

Association of IL-8-251A/T polymorphism with acute pancreatitis susceptibility: A meta-analysis

Association of <i>IL-8</i>-251A/T polymorphism with acute pancreatitis susceptibility: A meta-analysis

Correlations Between LP-PLA2 Gene Polymorphisms and Susceptibility and Severity of Acute Pancreatitis in a Chinese Population.

This case-control study explored correlations between LP-PLA2 gene polymorphisms (A379V, V279F, and R92H) and susceptibility and severity of acute pancreatitis (AP) in a Chinese population. From October 2013 to October 2015, 94 AP patients were chosen as the case group. According to the Acute Physiology and Chronic Health Evaluation (APACHE) II score standard, AP patients were divided into a mild AP (MAP) group (n = 46) and severe AP (SAP) group (n = 48). The 48 SAP patients were further divided into an SAP with multiple organ dysfunction syndrome (MODS) group (n = 42) and SAP without MODS group (n = 6). Meanwhile, 96 healthy subjects who received physical examinations at the study hospitals were selected as the control group. Serum lipoprotein-associated phospholipase A2 (LP-PLA2) levels were detected by an enzyme-linked immunosorbent assay (ELISA). The A379V (s1051931), V279F (rs16874954), and R92H (rs13989) polymorphisms of the LP-PLA2 gene were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). There were significant differences in the frequencies of the LP-PLA2 gene polymorphisms between the AP group and the control group. The distribution of V279F-AA+AC genotype and R92H-AA+AG genotype in the AP group was higher than that in the control group, whereas the SAP group and SAP with MODS group distributions were higher than those in the MAP group and SAP without MODS group (both p < 0.05). G-C-A, G-A-G, and G-C-G haploids formed by A379V, V279F, and R92H may be associated with AP susceptibility. LP-PLA2 gene polymorphisms could affect serum LP-PLA2 level, whereas the V279F-A allele gene, the R92H-A allele gene, serum LP-PLA2 level, and serum amylase may be independent risk factors for AP (all p < 0.05). These results demonstrated that the LP-PLA2 gene polymorphisms, V279F and R92H, may be associated with susceptibility to and severity of AP.

Influence of interleukin-18 gene polymorphisms on acute pancreatitis susceptibility in a Chinese population.

We investigate the relationship between IL-18 -607C/A and -137G/C genetic polymorphisms and development of acute pancreatitis in a Chinese population. A total of 153 patients were consecutively recruited from the First Affiliated Hospital of Chongqing Medical University between January 2013 and November 2014. Genotyping of IL-18 -607C/A and -137G/C variants was performed using the polymerase chain reaction-restriction fragment length polymorphism method. We observed a significant difference between acute pancreatitis patients and control subjects with respect to age (t = 2.15, P = 0.02), gender (chi-square = 3.95, P = 0.04), body mass index (t = 5.85, P < 0.001), and alcohol consumption (chi-square = 9.74, P = 0.002). Using chi-square tests, we found that the genotype distributions of IL-18 -607C/A (chi-square = 0.81, P = 0.67) and -137G/C (chi-square = 1.16, P = 0.56) polymorphisms did not differ between the acute pancreatitis and control groups. Genotype frequencies of these variants were consistent with Hardy-Weinberg equilibrium in both patient and control groups. In addition, logistic regression analysis failed to identify a significant association between these polymorphisms and acute pancreatitis risk. Our study firstly examined their association in a Chinese population, and we suggest that the IL-18 -607C/A and -137G/ C polymorphisms do not influence susceptibility to acute pancreatitis in the Chinese population studied in the present study.

Toll-like receptor 4 polymorphisms to determine acute pancreatitis susceptibility and severity: a meta-analysis.

To investigate the correlation of toll-like receptor 4 (TLR4) gene Asp299Gly and Thr399Ile polymorphisms and acute pancreatitis (AP) risk and severity. To get a more precise estimation of the relationship, a comprehensive search was performed to examine all the eligible studies of TLR4 Asp299Gly and Thr399Ile polymorphisms and AP risk. The odds ratios with 95% confidence intervals were used to assess the strength of the association. Publication bias was analyzed by Begg's funnel plots. In total, six studies with 1255 cases and 998 controls were included in this meta-analysis. Totally, no significant associations were found between TLR4 Asp299Gly or Thr399Ile polymorphisms and AP risk using five models with high homogeneity (P > 0.05). Furthermore, stratification analysis by ethnicity or assay also found no significant association in these two polymorphisms (P > 0.05), and TLR4 Asp299Gly was not associated with AP severity (P > 0.05). In addition, no publication bias was found in these studies (P > 0.05). Our current meta-analysis suggests that TLR4 Asp299Gly and Thr399Ile polymorphisms may not be risk factors to AP susceptibility.

Epidermal Growth Factor Serum Levels and the 61 G/A Polymorphism in Patients with Acute Pancreatitis

Epidermal growth factor (EGF) binds to pancreatic acinar cells and facilitates recovery from acute pancreatitis (AP). In animal models, EGF protects against pancreatic injury and prevents septic complications. The role of EGF in human AP is unknown. The aim of this study was to assess EGF serum levels in AP patients and whether the EGF +61 G/A single nucleotide polymorphism (SNP) affects susceptibility and/or severity of AP. Hospitalized AP patients were prospectively enrolled. Demographics, clinical features, DNA and early serum samples were collected when available. Patients were classified into mild (79%) and severe AP (21%) based on organ failure for >or=48 h. Early serum samples were quantitatively assayed for EGF levels. The EGF +61 G/A SNP was evaluated by restriction fragment length polymorphism analysis. There were 179 patients ascertained with AP. EGF levels were measured in a subgroup of 60 patients with early serum samples (17 severe) and in serum from 58 healthy controls. Serum EGF levels within 48 h from the onset of pain were significantly lower in AP patients (mean 13.5 pg/ml) compared to controls (25.2 pg/ml; P=0.015). Furthermore, EGF levels were significantly lower in severe patients when compared to mild (7.8 vs. 14.3 pg/ml; P=0.026). DNA from all 179 patients and 189 healthy controls was sequenced. The EGF +61 G/A SNP did not affect susceptibility to or severity of AP. EGF serum levels are decreased early in the course of AP and are further suppressed in severe AP. The EGF +61 G/A polymorphism has no effect on AP.

Polymorphisms in Tumour Necrosis Factor Alpha (TNFα) Gene in Patients with Acute Pancreatitis

Proinflammatory cytokines, such as tumour necrosis factor α (TNFα), play fundamental roles in the pathogenesis of acute pancreatitis (AP). The aim of this study was to determine if polymorphisms in the TNFα gene are associated with AP. Two polymorphisms located in the promoter region (positions −308 and −238) in TNFα gene were determined using polymerase chain reaction- (PCR-) restriction fragment length polymorphism (RFLP) methods in 103 patients with AP and 92 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression analysis adjusted for age, sex, BMI and smoking. The frequencies of TNFα polymorphisms were both similar in patients with mild or severe pancreatitis, so were in pancreatitis patients and in controls. We suggest that both SNPs of TNFα are not genetic risk factor for AP susceptibility (OR = 1.63; 95% CI: 1.13−4.01 for TNFα −308 and OR = 0.86; 95% CI: 0.75−1.77 for TNFα −238).

Adiponectin Polymorphisms and Serum Adiponectin Levels in Severe Acute Pancreatitis

Purpose: Acute pancreatitis (AP) is an acute inflammatory event that originates within the pancreas. Most patients develop mild AP (MAP); however, in some patients, there is an exaggerated systemic inflammatory response that results in severe AP (SAP). Obesity is a known risk factor for developing SAP. Adipokines released from adipose tissue play a role in the inflammatory response to injury. We hypothesize that adipokines such as adiponectin mediate the effect of obesity in AP. Methods: AP patients and controls were enrolled. SAP was defined as the presence of remote organ failure. The single nucleotide polymorphisms (SNPs) of interest in adiponectin (+45 T/G and +276 G/T) were evaluated by polymerase chain reaction (PCR) amplification and DNA sequencing. Serum samples were quantitatively assayed for adiponectin levels. Results: There were 133 patients with AP (108 with MAP and 25 with SAP) and 133 healthy controls. No associations between the two adiponectin SNPs and AP susceptibility or severity were found. There were 60 patients (27 with MAP and 33 with SAP) for whom serum adiponectin levels were available. Serum adiponectin levels from days 1–3 were significantly lower in SAP patients (N = 10; median: 3.74; range: 0.83–8.92 mg/ml) than in MAP patients (N = 26; median: 6.58; range: 1.31–15.37 mg/ml) (P= 0.02). There were no statistically significant differences in serum adiponectin levels among patients with different genotypes at the +45 and +276 loci. However, when the analysis was restricted to lean patients only, serum adiponectin levels were lower in patients with the +45 T/G genotype (N = 2; median: 3.18; range: 1.18–5.18 mg/ml) than the +45 T/T genotype (N = 20; median: 8.07; range: 3.02–18.20) (P= 0.05); there were no patients with the G/G genotype in this subgroup. Multivariate logistic regression controlling for BMI, +45 locus genotype, and sex showed that serum adiponectin level from days 1–3 was a significant predictor of SAP (P= 0.03; OR:0.36, 95% CI: 0.14–0.90). A receiver operating characteristics (ROC) curve using serum adiponectin levels from days 1–3 as the predictor for severity had an area under the curve (AUC) of 0.75. Conclusion: Adiponectin polymorphisms did not alter the risk of developing AP or SAP. Serum adiponectin levels were lower in patients with SAP and can be helpful in predicting the severity of AP.Figure

Functional Polymorphisms of the GSTT-1 Gene Do Not Predict the Severity of Acute Pancreatitis in the United States

Background/Aim: Acute pancreatitis (AP) is an inflammatory response to pancreatic injury that is clinically classified as mild AP or severe AP, depending on specific criteria. Rahman and colleagues [Gastroenterology 2004;126:1312–1322] reported that genetic variation in the glutathione S-transferase theta-1 gene (GSTT-1) is associated with susceptibility and severity of AP in England. Our aim was to determine whether the same GSTT-1 polymorphism affects the severity of AP in a population from Pittsburgh, Pa., USA. Methods: Ninety-one consecutive patients with AP (19 severe) were prospectively evaluated. The GSTT-1 haplotypes were determined by PCR amplification in all patients and 268 controls. The resulting genotypes were classified as functional (GSTT-1*A/*A or *A/null) and nonfunctional (GSTT-1 null/null) phenotypes. Results: The relative frequencies of functional GSTT-1 phenotypes were similar in subjects with severe AP (15 of 19, 78.9%) and mild AP (61 of 72, 84.7%; p = 0.54) and in the controls (228 of 268, 85.1%; p = 0.66). Furthermore, the GSTT-1 functional and nonfunctional phenotypes were not associated with serum C-reactive protein levels (11.9 vs. 7.3 mg/dl; p = 0.19), interleukin-6 levels (74 vs. 60 pg/ml; p = 0.9), APACHE II scores (7 vs. 9; p = 0.26), or 48-hour Ranson scores (1 vs. 1; p = 0.63). Conclusion: Functional GSTT-1 phenotypes do not correlate with susceptibility to AP or severity of AP in our patient population.

Pancreatic Secretory Trypsin Inhibitor (SPINK1) Gene Mutations in Patients With Acute Pancreatitis

Mutations in the secretory trypsin inhibitor (SPINK1) gene have been found to be associated with hereditary and chronic pancreatitis. There are no previous reports on SPINK1 mutations in patients with acute pancreatitis (AP). The study population consists of 371 patients with AP, of which 207 patients had mild and 164 had a severe form of the disease. The etiologies of AP were identified. Four hundred fifty-nine blood donors served as controls. SPINK1 N34S and P55S mutations were detected by minisequencing and confirmed by direct sequencing. The N34S mutation was found in 29 (7.8%) of the patients and in 12 (2.6%) of the controls (P < 0.0001, Fisher exact test). There was no difference in the frequency of the P55SS mutation between the groups. A majority of the patients (n = 229; 61.7%) had alcohol-induced AP. The frequency of the N34S mutation was higher in the subgroups of severe AP (15/164; 9.1%) and alcohol-induced AP (21/229; 9.2%), but the differences were not statistically significant. No differences in age at admission and number of attacks of AP were observed between the groups. SPINK1 N34S mutation enhances the susceptibility of AP.