Fucosyltransferase 2 (FUT2) non-secretor status and blood group B are associated with elevated serum lipase activity in asymptomatic subjects, and an increased risk for chronic pancreatitis: a genetic association study

Weiss, Frank Ulrich; Schurmann, Claudia; Guenther, Annett; Ernst, Florian; Teumer, Alexander; Mayerle, Julia; Simon, Péter; Völzke, Henry; Radke, Dörte; Greinacher, Andreas; Kuehn, Jens-Peter; Zenker, Martin; Völker, Uwe; Homuth, Georg; Lerch, Markus M.

doi:10.1136/gutjnl-2014-306930

Cited by 86 publications

(66 citation statements)

References 46 publications

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“…1 For rs632111, the same (non-significant) direction of effect was observed, while for rs8176693, the effect direction was reverse. Interaction and subgroup analysis revealed significant interaction effects of rs632111 with alcohol consumption ( p value 0.04, OR 0.82, 95% CI 0.68 to 0.99) and for rs8176693 for the subgroup of alcohol-dependent individuals ( p value 0.04, OR 0.78, 95% CI 0.62 to 0.98); however, these associations would not withstand correction for multiple testing.…”

mentioning

confidence: 83%

Genetic variants of lipase activity in chronic pancreatitis: Table 1

Kirsten

Scholz

Kovacs

et al. 2015

Gut

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We read with great interest the article by Weiss et al 1 reporting genetic associations of rs632111 (fucosyltransferase 2; FUT2), rs8176693 (ABO) and rs889512 (chymotrypsinogen B2; CTRB2) with lipase levels. Weiss et al also claimed that the variants at the FUT2 and ABO loci were associated with chronic pancreatitis (CP). No association with CP was observed for the CTRB2 locus. Elevated lipase levels are a diagnostic criterion for acute pancreatitis and might mirror subclinical pancreatic injury in patients without severe complaints. Hence, variants associated with elevated serum lipase levels might also be associated with CP risk. In a recent genome-wide association study, genetic variants of CP risk were identified in PRSS1 and CLDN2-MORC4. 2A large European replication study refined these associations to alcohol-related CP. 3 However, no associations were revealed at FUT2 and ABO in the former genome-wide association study. 2Given the relatively moderate association of genetic variants with CP in the paper by Weiss et al, we analysed the above-mentioned FUT2 and ABO single nucleotide polymorphism (SNPs) regarding association with CP in a German cohort of 1458 cases (non-alcohol-related CP n=584; alcohol-related CP n=874) and 5133 controls derived from the KORA study and patients with alcohol dependence (GESGA (-) consortium) according to DSM-IV criteria to replicate the finding. Controls included 1488 individuals with alcohol consumption of >60 g/day and 1915 individuals with alcohol consumption of <20 g/day.All individuals were genotyped using Illumina SNP-chip technology. Briefly, data was filtered using Plink 1.9 at an individual-and SNP-wise call-rate >0.99 for relatedness ( pi-hat <0.185), minor allele frequency >0.01 and HardyWeinberg disequilibrium with p value >10 −6 . Imputation at 1000 Genomes reference panel ( phase 1, release 3, software SHAPEIT V.2+IMPUTE2.3.0) was performed with 279 188 high-quality SNPs available in all cohorts. Analyses were conducted with R applying logistic regression with the first three principal components of the SNP data included as covariates to account for possible population stratification. We analysed additive, recessive and dominant models of inheritance and subgroup and interaction analysis regarding alcohol consumption status.Our analyses revealed no significance for rs632111 and rs8176693 in statistical models reported previously (table 1).1 For rs632111, the same (non-significant) direction of effect was observed, while for rs8176693, the effect direction was reverse. Interaction and subgroup analysis revealed significant interaction effects of rs632111 with alcohol consumption ( p value 0.04, OR 0.82, 95% CI 0.68 to 0.99) and for rs8176693 for the subgroup of alcohol-dependent individuals ( p value 0.04, OR 0.78, 95% CI 0.62 to 0.98); however, these associations would not withstand correction for multiple testing.Next, we screened whether there were stronger associations in the vicinity of the reported SNPs. Here, the two regions did not reveal any convincin...

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confidence: 83%

Genetic variants of lipase activity in chronic pancreatitis: Table 1

Kirsten

Scholz

Kovacs

et al. 2015

Gut

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“…They represent mere risk factors without Mendelian inheritance and a significant percentage of the healthy population will carry these single nucleotide polymorphisms without ever developing pancreatitis. Among patients, the proportion of carriers is simply higher 20 . These genetic changes affect the genes for carboxypeptidase A1 ( CPA1 , the risk ratio [RR] for which increases 30-fold but prevalence is rare), the pancreatic secretory trypsin inhibitor SPINK1 (20-fold and common), carboxyl-ester lipase ( CEL , 6-fold and rare), chymotrypsinogen C ( CTRC , 5-fold and common), the cystic fibrosis transmembrane conductance regulator ( CFTR , 2–3-fold and common), the blood type ABO locus (2,7-fold for blood type B versus O and common) and the calcium sensing receptor ( CASR , 1.9-fold and common).…”

Section: Pathophysiology Of Chronic Pancreatitismentioning

confidence: 99%

Chronic Pancreatitis in the 21st Century - Research Challenges and Opportunities

et al. 2016

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A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to focus on research gaps and opportunities in chronic pancreatitis (CP) and its sequelae. This conference marked the 20th year anniversary of the discovery of the cationic trypsinogen (PRSS1) gene mutation for hereditary pancreatitis. The event was held on July 27, 2016, and structured into 4 sessions: (1) pathophysiology; (2) exocrine complications; (3) endocrine complications; and (4) pain. The current state of knowledge was reviewed; many knowledge gaps and research needs were identified that require further investigation. Common themes included the need to design better tools to diagnose CP and its sequelae early and reliably, identify predisposing risk factors for disease progression, develop standardized protocols to distinguish type 3c diabetes mellitus from other types of diabetes and design effective therapeutic strategies through novel cell culture technologies, animal models mimicking human disease, and pain management tools. Gene therapy and cystic fibrosis conductance regulator (CFTR) potentiators as possible treatments for CP were discussed. Importantly, the need for chronic pancreatitis endpoints and intermediate targets for future drug trials was emphasized.

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“…Preliminary reports which await further validation include CTSB [60], MYO9B [61], and UBR1 [62], or the association of an increased pancreatitis risk with ABO blood group and the so-called “secretor status,” which is determined by a mutation of the fucosyltransferase gene FUT2 [29, 63]. Additional genetic variants are being evaluated and will likely be added to this list in the future.…”

Section: Recurrent Acute and Chronic Pancreatitis: Distinction And Etmentioning

confidence: 99%

“…Commonly prescribed drugs which are known to be associated with acute pancreatitis are angiotensin-converting enzyme (localized angioedema), statins (direct and accumulation toxicity), oral contraceptives or hormone replacement therapy, especially estrogen (hypertriglyceridemia, local arteriolar thrombosis), diuretics, antiviral therapy (HIV), valproic acid, and antidiabetic agents such as GLP-1 mimetic [25-28]. Interestingly, while it was shown that being the carrier of ABO blood type B increases the risk of developing chronic pancreatitis [29], a recent study has found that the same association exists for drug-induced (i.e., azathioprine-induced) acute pancreatitis in patients with inflammatory bowel disease [30]. …”

Section: Acute Pancreatitis: Definition and Etiologymentioning

confidence: 99%

Etiology and Risk Factors of Acute and Chronic Pancreatitis

Weiss

Laemmerhirt

Lerch³

2019

Visc Med

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Based on the recognition of common etiological and genetic risk factors, acute and chronic pancreatitis are increasingly regarded as a continuum of the same disease, with a significant overlap of clinical manifestations and phenotypes but distinct morphological and imaging appearances. Recent population-based and cohort studies have found that tobacco smoke conveys a greater risk than immoderate alcohol consumption for the development of chronic pancreatitis, and hypertriglyceridemia has been identified as a risk factor for acute pancreatitis – even when plasma levels are only mildly elevated. Hereditary pancreatitis, in its autosomal dominant form, is associated with mutations in the cationic trypsinogen gene (PRSS1), whereas a number of germline variations in other genes have been found to represent risk factors for chronic as well as acute pancreatitis. For now, most of these involve the pancreatic digestive protease/antiprotease system. Oftentimes, affected patients are burdened with multiple or accumulating risk factors, and genetic traits when combined with environmental toxins compound the chance of developing the disease. Determining the underlying etiology of pancreatitis is worth the effort since formerly intractable varieties such as autoimmune pancreatitis are now becoming increasingly treatable, and subtype-specific therapeutic modalities may become available.

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Fucosyltransferase 2 (FUT2) non-secretor status and blood group B are associated with elevated serum lipase activity in asymptomatic subjects, and an increased risk for chronic pancreatitis: a genetic association study

Cited by 86 publications

References 46 publications

Genetic variants of lipase activity in chronic pancreatitis: Table 1

Genetic variants of lipase activity in chronic pancreatitis: Table 1

Chronic Pancreatitis in the 21st Century - Research Challenges and Opportunities

Etiology and Risk Factors of Acute and Chronic Pancreatitis

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