Chronic pancreatitis with polycystic kidney disease: A rare coincidence?

IntroductionIn children, chronic pancreatitis (CP) is usually associated with anatomical anomalies of the pancreas and biliary tract or is genetically determined. Autosomal dominant polycystic kidney disease (ADPKD) may present with extrarenal cyst formation, sometimes involving the pancreas. Large enough, these cysts may cause pancreatitis in ADPKD patients.Case presentationHerein, we present a case of a 12-year-old Caucasian girl with recurrent pancreatitis with no identifiable traumatic, metabolic, infectious, drug, or immunologic causes. Structural anomalies of the pancreas, including cysts, were ruled out by imaging. However, bilateral cystic kidneys were found as an incidental finding. Her family history was negative for pancreatitis, but positive for polycystic kidney disease. Molecular analysis of ADPKD-causing mutations revealed a novel c.9659C>A (p.Ser3220*) mutation in the PKD1 gene confirming the clinical suspicion of ADPKD. Although CP may rarely occur as an extrarenal manifestation of ADPKD with pancreatic cysts, it is unusual in their absence. Thus, molecular analysis of pancreatitis susceptibility genes was performed and a homozygous pathologic c.180C>T (p.G60=) variant of the CTRC gene, known to increase the risk of CP, was confirmed.ConclusionThis is the first reported case of a pediatric patient with coincidence of genetically determined CP and ADPKD. Occurrence of pancreatitis in children with ADPKD without pancreatic cysts warrants further investigation of CP causing mutations.     

Loss-of-function variant in chymotrypsin like elastase 3B (CELA3B) is associated with non-alcoholic chronic pancreatitis

BackgroundGenetic alterations in digestive enzymes have been associated with chronic pancreatitis (CP). Recently, chymotrypsin like elastase 3B (CELA3B) emerged as a novel risk gene. Thus, we evaluated CELA3B in two European cohorts with CP.MethodsWe analyzed all 8 CELA3B exons in 550 German non-alcoholic CP (NACP) patients and in 241 German controls by targeted DNA sequencing. In addition, we analyzed exons 6 and 7 by Sanger sequencing and the c.129+1G>A variant by melting curve analysis in 1078 further German controls. As replication cohort, we investigated up to 243 non-German European NACP patients and up to 1665 controls originating from Poland, Hungary, and Sweden. We assessed the cellular secretion and the elastase activity of recombinant CELA3B variants.ResultsIn the German discovery cohort, we detected a splice-site variant in intron 2, c.129+1G>A, in 9/550 (1.64%) CP patients and in 5/1319 (0.38%) controls (P=0.007, OR=4.4, 95% CI=1.5–13.0). In the European replication cohort, this variant was also enriched in patients (9/178 [5.06%]) versus controls (13/1247 [1.04%]) (P=0.001, OR=5.1, 95% CI=2.1–12.0). We did not find the two previously reported codon 90 variants, p.R90C and p.R90L.ConclusionsOur data indicate that CELA3B is a susceptibility gene for CP. In contrast to previous reports suggesting that increased CELA3B activity is associated with CP risk, the splice-site variant identified here is predicted to cause diminished CELA3B expression. How reduced CELA3B function predisposes to pancreatitis remains to be elucidated.     

Meta-analysis of the impact of the SPINK1 c.194 + 2T > C variant in chronic pancreatitis

Background and aimsThe SPINK1 c.194 + 2T > C variant has been increasingly recognized as an important risk factor for chronic pancreatitis (CP). However, there is no clear agreement on its contribution to different ethnicities and CP etiologies. To address this issue, a meta-analysis of literature was performed.MethodsStudies addressing the presence of the SPINK1 c.194 + 2T > C variant in CP patients and controls were retrieved from the PubMed, EMBASE and Cochrane databases. Initial analysis included all CP patients, followed by subgroup analyses for East Asian and non-East Asian patients, and for idiopathic CP (ICP) and non-ICP.ResultsA total of 13 studies were retrieved for analysis, comprising 2097 cases and 4019 controls. There were 126 cases (10.01%) carrying the SPINK1 c.194 + 2T > C variant in cases, while only two controls were carriers (0.05%). Overall, the variant was significantly associated with an increased risk of CP (OR = 25.73). In the subgroup, the variant was significantly associated with increased risk of CP in East Asians (OR = 73.16), and in non-East Asians (OR = 10.21). Further, the contribution of the variant in ICP (OR = 35.31) was found to be higher than in non-ICP (25.75).ConclusionsThe SPINK1 c.194 + 2T > C variant is a strong risk factor for CP, especially in East Asian patients with ICP.     

Complete Analysis of the Human Mesotrypsinogen Gene (PRSS3) in Patients with Chronic Pancreatitis

Background/Aims: A sustained imbalance of pancreatic proteases and their inhibitors seems to be important for the development of chronic pancreatitis (CP). Mesotrypsin (PRSS3) can degrade intrapancreatic trypsin inhibitors that protect against CP. Genetic variants that cause higher mesotrypsin activity might increase the risk for CP. Methods: We analyzed all 5 exons and the adjacent non-coding sequences of PRSS3 by direct sequencing of 313 CP patients and 327 controls. Additionally, exon 4 was investigated in 855 patients and 1,294 controls and a c.454+191G>A variant in 855 patients and 1,467 controls. The c.499A>G (p.T167A) variant was analyzed functionally using transiently transfected HEK293T cells. Results: In the exonic regions, the previously described common c.94_96delGAG (p.E32del) variant and a novel p.T167A non-synonymous alteration were identified. Extended analysis of the p.T167A variant revealed no association toCP and in functional assays p.T167A showed normal secretion and activity. Variants of the intronic regions, including the extensively analyzed c.454+191G>A alteration, were not associated with the disease. Haplotype reconstruction using variants with a minor allele frequency of >1% revealed no CP-associated haplotype. Conclusions:     

Associations between interleukin-10 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis and meta-regression

This study aimed to explore whether interleukin-10 polymorphisms are associated with susceptibility to rheumatoid arthritis (RA). Studies that have analyzed the associations of the interleukin-10-1082G>A, -592C>A, and -819C>T polymorphisms with RA were searched for in PubMed and EMBASE. Sensitivity and cumulative analyses were conducted to measure the robustness of our findings. Egger’s linear regression and Begg’s funnel plots were performed to analyze publication bias. The source of heterogeneity was analyzed by subgroup analysis and meta-regression. This meta-analysis involved 2661 RA patients and 3249 controls in 16 studies. There were significant associations with RA in the AG vs AA model (OR?=?0.79, 95% CI?=?0.67–0.93, P?<?0.01) and the AG + GG vs AA model (OR?=?0.80, 95% CI?=?0.69–0.93, P?<?0.01) for the interleukin-10-1082G>A polymorphism, in the TC vs TT model (OR?=?0.61, 95% CI?=?0.44–0.84, P?<?0.01) and the CC vs TT model (OR?=?0.64, 95% CI?=?0.46–0.89, P?<?0.01) for the interleukin-10-819C>T polymorphism, and in the AC vs AA model (OR?=?0.73, 95% CI?=?0.56–0.96, P?=?0.03) and the AC + CC vs AA model (OR?=?0.68, 95% CI?=?0.47–0.98, P?=?0.04) for the interleukin-10-592C>A polymorphism. Meta-regression revealed that the genotyping method was a major cause of heterogeneity in the AC vs AA model and the AC + CC vs AA model for the interleukin-10-592C>A polymorphism. This meta-analysis showed the interleukin-10-1082G>A, -592C>A, and -819C>T polymorphisms are correlated with the susceptibility to RA. Meta-regression indicated that the genotyping method is a major driver of heterogeneity in the relationship between the interleukin-10-592C>A polymorphism and RA.     

Genetics of pancreatitis: a guide for clinicians

It is now generally believed that pancreatitis results from pancreatic autodigestion. An inappropriate conversion of pancreatic zymogens to active enzymes within the pancreatic parenchyma is thought to initiate the inflammatory process. A key role has been attributed to the activation of trypsinogen to trypsin, converting all proteolytic proenzymes to their active form. Several gain-of-function mutations in the cationic trypsinogen gene (PRSS1) have been identified in patients with chronic pancreatitis (CP). These mutations lead to enhanced intrapancreatic trypsinogen activation. In contrast, a variant in the anionic trypsinogen (PRSS2) gene, p.G191R, has been described that mitigates intrapancreatic trypsin activity and thereby plays a protective role. Beside trypsinogen mutations, loss-of-function variants in SPINK1, encoding a pancreatic trypsin inhibitor, are strongly associated with idiopathic CP. Approximately 15-40% of patients with so-called idiopathic CP carry p.N34S on one allele or on both alleles. Chymotrypsin C (CTRC) degrades all human trypsin isoforms with high specificity. Two CTRC alterations, p.R254W and p.K247_R254del, are significantly associated with idiopathic as well as alcohol-related CP. Functional analysis of the variants revealed impaired activity and/or reduced secretion. Thus, loss-of-function mutations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. Albeit the association between CFTR, the gene mutated in cystic fibrosis, and idiopathic CP is now well established, the pathogenic mechanisms are poorly understood. Nearly 25-30% of patients carry at least one CFTR mutation, but few patients only were compound-heterozygous. Several patients, however, are trans-heterozygous for a CFTR alteration and a PRSS1, SPINK1, or CTRC variant, respectively.     

Common calcium-sensing receptor (CASR) gene variants do not modify risk for chronic pancreatitis in a Hungarian cohort

The calcium-sensing receptor (CASR) is expressed in the pancreas where it might regulate calcium concentrations in pancreatic secretions. Two independent studies reported conflicting results claiming that commonly occurring missense variants of the CASR gene are risk factors for chronic pancreatitis (CP). Here, we attempted to replicate the association between CASR variants and CP. We analyzed 337 patients and 840 controls from the Hungarian National Pancreas Registry either by direct sequencing of exon 7 and the flanking noncoding regions or by TaqMan SNP genotyping assays. We identified two common missense variants, c.2956G>T (p.A986S), and c.2968A>G (p.R990G), three low-frequency variants, c.3031C>G (p.Q1011E), c.2610G>A (p.E870=) and c.160T>A, and 8 rare variants including the novel variant c.1895G>A (p.G632D). When allelic or genotype distributions were considered, none of the CASR variants associated with CP. Subgroup analysis of nonalcoholic versus alcoholic patients revealed no disease association either. Our results demonstrate that common CASR variants do not modify the risk for CP and should not be considered as genetic risk factors in the clinical setting.     

Meta-analysis of the impact of SPINK1 p.N34S gene variation in Caucasic patients with chronic pancreatitis. An update

BackgroundSPINK1 p.N34S gene variation is one of the endogenous factors which seem to be associated with chronic pancreatitis (CP). However, in literature there is no clear agreement regarding its contribution in different ethnicity and CP etiologies.AimTo investigate the role of SPINK1 p.N34S gene variation in CP patients with European origin by means of meta-analysis.MethodsLiterature search was conducted and case–control studies evaluating Caucasian population, published between May 2007 and May 2015, were included. We also included Caucasian selected studies analyzed in previous meta-analysis. We carried out meta-analysis including all selected studies. After that, we performed two additional meta-analyses considering the incidence of SPINK1 p.N34S gene variation in alcoholic or in idiopathic CP patients vs control group.ResultsTwenty-five studies were included and the total number of subjects was 8800 (2981 cases and 5819 controls). The presence of p.N34S variation increased nine times the overall CP risk in population of European origin [OR 9.695 (CI 95% 7.931–11.851)]. Also, the contribution of SPINK1 in idiopathic pancreatitis [OR 13.640 (CI 95% 8.858–21.002)] was found to be higher than in alcoholic CP [5.283 (CI 95% 3.449–8.092)].ConclusionThe association between SPINK1 p.N34S gene variation and CP is confirmed. Also, we confirmed that the idiopathic etiology needs a better definition by means of genetic analysis.     

Thrombomodulin gene c.1418C&gt;T polymorphism and risk of recurrent venous thromboembolism

Thrombomodulin gene (THBD) is a critical cofactor in protein C anticoagulant system. THBD c.1418C>T polymorphism is reported to be associated with higher risk of primary venous thromboembolism (VTE) but its role in VTE recurrence is unknown. The aim of this study was to investigate the role of THBD polymorphism in VTE recurrence. THBD c.1418C>T polymorphism was genotyped by using Taqman polymerase chain reaction in a prospective population based study of 1465 consecutive objectively verified VTE patients. Uni- and multivariate Cox regression were performed for the risk assessment of VTE recurrence. Patients who had VTE before inclusion or had recurrence or died during anticoagulant treatment were excluded. Among the remaining (N = 1046) patients, 126 (12.05 %) had VTE recurrence during the follow up period (from 1998 to 2008). THBD polymorphism was not significantly associated with risk of VTE recurrence in the univariate [Hazard ratio (HR) 1.11, 95 % confidence interval (CI) 0.78–1.59, p = 0.55] as well as the multivariate analysis adjusted for age, sex and thrombophilia (HR 1.11, 95 % CI 0.78–1.59, p = 0.54). Similarly, in unprovoked first VTE (n = 614), no association was observed between THBD polymorphism and risk of VTE recurrence (HR 1.22 and 95 % CI 0.78–1.89, p = 0.38). In this prospective study, our results do not suggest a predictive role for THBD c.1418C>T polymorphism in VTE recurrence.     

Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms

BackgroundPrevious genome-wide association studies (GWAS) identified genome-wide significant risk loci in chronic pancreatitis and investigated underlying disease causing mechanisms by simple overlaps with expression quantitative trait loci (eQTLs), a procedure which may often result in false positive conclusions.MethodsWe conducted a GWAS in 584 non-alcoholic chronic pancreatitis (NACP) patients and 6040 healthy controls. Next, we applied Bayesian colocalization analysis of identified genome-wide significant risk loci from both, our recently published alcoholic chronic pancreatitis (ACP) and the novel NACP dataset, with pancreas eQTLs from the GTEx V8 European cohort to prioritize candidate causal genes and extracted credible sets of shared causal variants.ResultsVariants at the CTRC (p = 1.22 × 10^?21) and SPINK1 (p = 6.59 × 10^?47) risk loci reached genome-wide significance in NACP. CTRC risk variants colocalized with CTRC eQTLs in ACP (PP4 = 0.99, PP4/PP3 = 95.51) and NACP (PP4 = 0.99, PP4/PP3 = 95.46). For both diseases, the 95% credible set of shared causal variants consisted of rs497078 and rs545634. CLDN2-MORC4 risk variants colocalized with CLDN2 eQTLs in ACP (PP4 = 0.98, PP4/PP3 = 42.20) and NACP (PP4 = 0.67, PP4/PP3 = 7.18), probably driven by the shared causal variant rs12688220.ConclusionsA shared causal CTRC risk variant might unfold its pathogenic effect in ACP and NACP by reducing CTRC expression, while the CLDN2-MORC4 shared causal variant rs12688220 may modify ACP and NACP risk by increasing CLDN2 expression.     

A rare PRSS1 p.S127C mutation is associated with chronic pancreatitis and causes misfolding-induced ER-stress

Background/Objectives: Sequence variants in several genes have been identified as being associated with an increased inherited risk to develop chronic pancreatitis (CP). In a genetic survey of a CP patient we identified in the PRSS1gene a new c.380C > G sequence variation, giving rise to a non-synonymous p.S127C mutation. Functional studies were performed to analyze the associated pathophysiology of the variant.MethodsFollowing generation of an expression vector for the new PRSS1 variant we compared its expression, secretion and catalytic activity with already known PRSS1 risk variants in HEK 293T cells. The intracellular protein accumulation and induction of endoplasmic reticulum (ER)-stress was analyzed.ResultsPrediction tool analysis indicated a probably deleterious effect of the p.S127C variant on protein function which was confirmed by detection of a secretion defect in HEK293T cells leading to intracellular protein accumulation. While protein misfolding was associated with reduced trypsin activity, the increased expression of BIP and presence of spliced XBP1 indicated that the p.S127C variant induces ER stress and activates the UPR signaling pathway.ConclusionsThe disease mechanism of the PRSS1 p.S127C variant involves defective protein secretion and the induction of ER-stress due to accumulation of presumably misfolded trypsinogen within the ER. The new variant should be considered disease-causing with an incomplete penetrance. Our results confirm that in addition to dysregulated trypsin-activity or reduced fluid secretion, ER-stress induction is an important trigger for acinar cell damage and the development of recurrent or chronic pancreatic inflammation.     

Association of Novel Chymotrypsin C Gene Variations and Haplotypes in Patients with Chronic Pancreatitis in Chinese in Taiwan

Background/Aims: Variations and haplotypes of thechymotrypsin C (CTRC) gene in Chinese patients with chronic pancreatitis (CP) and control subjects with genotype-phenotype correlation were investigated. Methods: One hundred and twenty-six patients with CP were analyzed. The entire sequence of coding regions of exons 2, 3 and 7 and their neighboring intronic regions in introns 1,2 and 6 of the CTRC gene were analyzed using PCR sequence-specific primers and direct sequencing. The exonic region of exon 7 and the neighboring intronic region of intron 6 were also analyzed in 90 geographically matched healthy control subjects, Results: In total, 4 novel variations were identified in exons 2,3 and 7 in 3 CP patients. A total of 2.3% (3/126) of our CP patients carried variations of the CTRC gene. We also first identified six new intronic variations in intron 6 which had not been reported before. The GAGGGG, GAGGAG and GAGTAG haplotypes assembled by six locus intronic variations c.640-41/C.640-40/C.640-39/C.640-37/C.640-36/C.640-35 in intron 6 were associated with a significantly higher susceptibility risk of CP (OR 66.75, 37.00, and 9.37, respectively). Conclusion: Novel CTRC gene variations and haplotypes are associated with CP in a Chinese population.     

IRS1 gene variants,dysglycaemic metabolic changes and type-2 diabetes risk

Background and aimsA recent genome-wide association study identified rs2943641C > T, 500 kb from the insulin receptor substrate-1 gene (IRS1), as a type-2 diabetes (T2D) susceptibility locus. We aimed to replicate this association by meta-analysis and examine whether common variants within IRS1, present on the HumanCVD BeadChip, were associated with T2D risk.Methods and resultsWe genotyped rs2943641 in 2389 prevalent or incident T2D patients and 6494 controls from two prospective and three case studies based in UK and in the European Atherosclerosis Research Study-II (EARSII; n = 714). Thirty-three IRS1 variants had been genotyped in the prospective Whitehall-II study (n = 4752) using the HumanCVD BeadChip. In a fixed-effects meta-analysis of the UK study cohorts rs2943641T allele was associated with 6% lower risk of T2D (p = 0.18), with T-allele carriers having an odds ratio (OR) of 0.89 (95% confidence interval [CI]: 0.80–1.00, p = 0.056) compared to CC subjects. The T-allele was also associated with lower fasting insulin and homeostasis model assessment index of insulin resistance in Whitehall-II and with lower post-load insulin after an oral glucose tolerance test in EARSII (all p < 0.05). None of the IRS1 variants on the chip showed linkage disequilibrium with rs2943641. In silico analysis with follow-up genotyping (total n = 9313) identified that the rare allele of the IRS1 promoter variant rs6725556A > G showed association with reduced T2D risk (OR per G-allele: 0.82, 95%CI: 0.69–0.96, p = 0.015).ConclusionsWe confirm the association of rs2943641T with T2D protection. There is a possible independent effect on risk of a putative IRS1 promoter variant.     

Genetic deficiency of chemokine receptor CCR5 is a strong risk factor for symptomatic West Nile virus infection: a meta-analysis of 4 cohorts in the US epidemic

West Nile virus (WNV) causes disease in approximately 20% of infected humans. We previously reported that homozygosity for CCR5Delta32, a nonfunctional variant of chemokine receptor CCR5, is markedly increased among symptomatic WNV-seropositive patients from Arizona and Colorado. To confirm this, we analyzed cohorts from California and Illinois. An increase in CCR5-deficient subjects was found in both (for California, odds ratio [OR], 4.2 [95% confidence interval {CI}, 1.5-11.9] [P= .004]; for Illinois, OR, 3.1 [95% CI, 0.9-11.2] [P= .06]). A meta-analysis of all 4 cohorts showed an OR of 4.2 (95% CI, 2.1-8.3 [P= .0001]). Thus, CCR5 deficiency is a strong and consistent risk factor for symptomatic WNV infection in the United States.     

Association of Cardiovascular Disease With Coronavirus Disease 2019 (COVID-19) Severity: A Meta-Analysis

Observational studies have reported an association between underlying cardiovascular diseases (CVD) and worse prognosis in COVID-19 patients, but this still remains unclear. We conducted a meta-analysis of recent studies that reported the association of CVD with worse prognosis and increased mortality in COVID-19 patients. Literature search through PubMed, the Cochrane Library, and Embase was completed by 2 reviewers from November 1, 2019 to April 20, 2020. Inclusion criteria were observational case-control or cohort studies on COVID-19 patients with a history of CVD included, which reported outcomes of COVID-19 infection severity, clearly outlined the definition of “severe disease” and with sample size >10. Data were abstracted independently by 2 authors. Studies were divided into 2 separate cohorts for analysis: severity (severe vs nonsevere) and mortality (nonsurvivors vs survivors). Data was pooled into a meta-analysis to estimate pooled odds ratio (OR) with 95% confidence interval (95% CI) for each outcome. A total of 18 studies (n = 4858 patients) were included. Sixteen studies were from China, while 2 were from the United States. Pre-existing CVD was associated with a significantly increased risk of a severe form of COVID-19 (OR = 3.14; 95% CI 2.32-4.24; I² = 0%; Q = 8.68, P= 0.73) and overall risk of COVID-19 all-cause mortality (OR = 11.08; 95% CI: 2.59-47.32; I² = 55%; P = 0.11). However, this study did not find a significant association between previous history of CVD and mortality in severe COVID-19 disease (OR = 1.72; 95% CI: 0.97-3.06, I² = 0%, P = 0.46). Pre-existing CVD is associated with worse outcomes among patients with COVID-19. Clinicians and policymakers need to take account of these findings in implementing risk stratification models.     

Association between shift work and risk of metabolic syndrome: A systematic review and meta-analysis

AimsA comprehensive assessment of the association of shift work with risk of metabolic syndrome (MetS) through a systematic review and meta-analysis has not been reported. We aimed to evaluate the relationship from observational studies.Data synthesisWe searched PubMed, Embase, and Web of Science databases from inception to December 16, 2020. Articles were chosen according to established inclusion criteria. Studies with data on men and women and different types of shift work were treated as independent studies. Relative risks (RRs) and 95% confidence intervals (CIs) were pooled by using random-effects models with heterogeneity (I²) > 50%; otherwise, a fixed-effects model was used. A total of 7192 articles was searched from PubMed, Embase and Web of science. Finally, we included 23 articles (38 studies) in this meta-analysis. The pooled RRs and 95% CI of MetS risk with shift work, 1-shift work, 2-shift work, and 3-shift work versus non-shift work were 1.30 (95% CI 1.19–1.41), 0.95 (95% CI 0.82–1.11), 1.19 (95% CI 0.91–1.56) and 1.17 (95% CI 1.00–1.37), respectively. The results from subgroup analyses stratified by sex, age, and region supported our overall findings that shift work is a risk factor for MetS.ConclusionsThis meta-analysis suggests that shift work increases risk of MetS. Higher risk of MetS was found in the shift workers who were 2-shift or 3-shift or women or Asian workers.     

Prediction models for heart failure in the community: A systematic review and meta-analysis

Aims

Multivariable prediction models can be used to estimate risk of incident heart failure (HF) in the general population. A systematic review and meta-analysis was performed to determine the performance of models.

Methods and results

From inception to 3 November 2022 MEDLINE and EMBASE databases were searched for studies of multivariable models derived, validated and/or augmented for HF prediction in community-based cohorts. Discrimination measures for models with c-statistic data from ≥3 cohorts were pooled by Bayesian meta-analysis, with heterogeneity assessed through a 95% prediction interval (PI). Risk of bias was assessed using PROBAST. We included 36 studies with 59 prediction models. In meta-analysis, the Atherosclerosis Risk in Communities (ARIC) risk score (summary c-statistic 0.802, 95% confidence interval [CI] 0.707–0.883), GRaph-based Attention Model (GRAM; 0.791, 95% CI 0.677–0.885), Pooled Cohort equations to Prevent Heart Failure (PCP-HF) white men model (0.820, 95% CI 0.792–0.843), PCP-HF white women model (0.852, 95% CI 0.804–0.895), and REverse Time AttentIoN model (RETAIN; 0.839, 95% CI 0.748–0.916) had a statistically significant 95% PI and excellent discrimination performance. The ARIC risk score and PCP-HF models had significant summary discrimination among cohorts with a uniform prediction window. 77% of model results were at high risk of bias, certainty of evidence was low, and no model had a clinical impact study.

Conclusions

Prediction models for estimating risk of incident HF in the community demonstrate excellent discrimination performance. Their usefulness remains uncertain due to high risk of bias, low certainty of evidence, and absence of clinical effectiveness research.     

Mouse model of PRSS1 p.R122H-related hereditary pancreatitis highlights context-dependent effect of autolysis-site mutation

Mutation p.R122H in human cationic trypsinogen (PRSS1) is the most frequently identified cause of hereditary pancreatitis. The mutation blocks protective degradation of trypsinogen by chymotrypsin C (CTRC), which involves an obligatory trypsin-mediated cleavage at Arg122. Previously, we found that C57BL/6N mice are naturally deficient in CTRC, and trypsinogen degradation is catalyzed by chymotrypsin B1 (CTRB1). Here, we used biochemical experiments to demonstrate that the cognate p.R123H mutation in mouse cationic trypsinogen (isoform T7) only partially prevented CTRB1-mediated degradation. We generated a novel C57BL/6N mouse strain harboring the p.R123H mutation in the native T7 trypsinogen locus. T7R123H mice developed no spontaneous pancreatitis, and severity parameters of cerulein-induced pancreatitis trended only slightly higher than those of C57BL/6N mice. However, when treated with cerulein for 2 days, more edema and higher trypsin activity was seen in the pancreas of T7R123H mice compared to C57BL/6N controls. Furthermore, about 40% of T7R123H mice progressed to atrophic pancreatitis in 3 days, whereas C57BL/6N animals showed full histological recovery. Taken together, the observations indicate that mutation p.R123H inefficiently blocks chymotrypsin-mediated degradation of mouse cationic trypsinogen, and modestly increases cerulein-induced intrapancreatic trypsin activity and pancreatitis severity. The findings support the notion that the pathogenic effect of the PRSS1 p.R122H mutation in hereditary pancreatitis is dependent on its ability to defuse chymotrypsin-dependent defenses.     

Association of endothelial lipase Thr111Ile polymorphism with proliferative retinopathy in type 2 diabetes patients

AimOur previous study demonstrated that the endothelial lipase (EL) C.584C>T polymorphism (rs2000813, p.Thr111Ile) was significantly associated with diabetic retinopathy (DR). The present work was conducted to see if this specific variant of the EL gene was more specifically linked to the severity of DR.MethodsThis retrospective cohort study was based on a review of the institutional charts of 287 type 2 diabetes patients (mean age = 59.7 years; mean BMI = 29.0 kg/m²; mean HbA_1c = 8.4%) genotyped for the EL C.584C>T polymorphism (rs2000813, p.Thr111Ile). The stage of DR was also determined for each genotype (CC, CT, TT).ResultsOn univariate analysis, the minor allele homozygote TT variant was significantly associated with severe DR (OR: 4.3; 95% CI: 1.4, 13.1) compared with the major CC homozygote. No significant result was found for the CT heterozygote. Multivariate analysis revealed an increased risk for TT homozygotes to present with severe non-proliferative DR (OR: 8.09; 95% CI: 1.23, 53.1) or proliferative DR. Other associations were not significant.ConclusionMinor allele homozygosity for this EL variant (c.584C>T) could be a significant risk factor for developing severe, sight-threatening disease due to proliferative DR. Further prospective studies of this EL polymorphism in a larger population sample are needed to confirm these results.     

CD14 and IL6 polymorphisms are associated with a pro-atherogenic profile in young adults with acute myocardial infarction

This study investigated the relationship of polymorphisms in genes encoding CD14, IL-6 and TLR4 with metabolic, inflammatory and endothelial markers in young adults with acute myocardial infarction (AMI). Glucose, lipids, nitrate and inflammatory markers, flow mediated vasodilatation (FMV) and flow mediated by nitrate (FMN) were evaluated in 102 AMI and 108 non-AMI (control group) young individuals (<45 years). CD14 ?260C>T (rs2569190), IL6 ?174G>C (rs1800795) and TLR4 c.896A>G (rs4986790) and TLR4 c.1196C>T (rs4986791) polymorphisms were analyzed by PCR–RFLP. Minor allele frequencies of CD14, IL6 and TLR4 polymorphisms were similar between AMI and control groups (p > 0.05). In AMI group, individuals carrying IL6 ?174CC genotype had higher serum triglycerides, VLDL cholesterol and glucose compared to the IL6 ?174GG/GC genotype carriers (p < 0.05). Multiple logistic analysis showed that IL6 ?174CC genotype carriers had increased risk for hyperglycemia (>5.77 mmol/l) [OR: 6.75, 95 % CI: 1.80–24.40, p = 0.004] and hypertriglyceridemia (>2.68 mmol/l) [OR: 3.00, 95 % CI: 1.00–9.00, p = 0.043]. Moreover, CD14 ?260TT genotype was associated with reduced serum HDL cholesterol [OR: 3.10, 95 % CI: 1.00–9.01, p = 0.044] and apolipoprotein AI [OR: 3.20, 95 % CI: 1.00–9.70, p = 0.038] in AMI group. Relationship between CD14 and IL6 variants and altered inflammatory and endothelial (nitrate, FMV and FMN) markers was not found in both AMI and control groups. The IL6 ?174G>C and CD14 ?260C>T polymorphisms are likely to be associated with a pro-atherogenic profile but not with increased inflammatory markers and endothelial dysfunction in young AMI patients.