Publications (81) View all
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Article: Genome-wide association analysis in sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4.
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ABSTRACT: Approximately 60-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the purpose of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases and 2,977 controls and followed up top association signals in additional 1,012 PSC cases, 4,444 UC cases and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at GPR35; P=3.0×10(-9) in the overall study population, combined odds ratio (OR; 95% confidence interval (CI)) of 1.39 (1.24-1.55)], and at 18q21 [rs1452787 at TCF4; P=2.61×10(-8) , OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. Conclusion: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, while TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. (HEPATOLOGY 2012.).Hepatology 07/2012; · 11.66 Impact Factor -
Article: Clinical features and relapse rates after surgery in type 1 autoimmune pancreatitis differ from type 2: a study of 114 surgically treated European patients.
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ABSTRACT: At the recent consensus conference on autoimmune pancreatitis (AIP) in Honolulu, we presented preliminary data from our study of surgically treated AIP patients. Our data strongly supported the separation of AIP into type 1 and type 2. Our study is based on a total of 114 surgically treated European AIP patients. Our aims were to elucidate serum IgG4 elevation, other organ involvement, relapse of disease, steroid treatment and diabetes after surgery in 114 surgically treated European AIP patients. 88 pancreaticoduodenectomies, 22 left-sided resections and 4 total pancreatectomies were examined. All cases were graded for granulocytic epithelial lesions, IgG4-positive cells, storiform fibrosis, phlebitis and eosinophilic granulocytes. Follow-up data were obtained from 102/114 patients, mean follow-up was 5.3 years. Histologically, 63 (55.3%) of the 114 patients fulfilled the criteria of type 1 AIP, while 51 (44.7%) patients fulfilled the criteria of type 2 AIP. Type 1 AIP patients were older and more often males than type 2 AIP patients. Elevation of serum IgG4, involvement of extrapancreatic organs, disease relapse, systemic steroid treatment and diabetes after surgery were noted more often in type 1 AIP, while inflammatory bowel disease (IBD) was observed mainly in type 2 AIP. Histological typing of AIP is clinically important because type 1 AIP is part of the IgG4-related disease and type 2 AIP is associated with IBD. Our data also show that relapse of disease and steroid treatment after surgery occur more frequently in type 1 than in type 2 AIP.Pancreatology 05/2012; 12(3):276-83. · 1.99 Impact Factor -
Article: Drainage patterns of right and accessory hepatic veins: anatomical-functional classification derived from 3-dimensional CT reconstructions.
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ABSTRACT: Inadequate knowledge of the right (RHV) and accessory (IHV) hepatic 'venous drainage' territories can lead to severe postoperative venous congestion after right graft live donor liver transplantation. The purpose of our study was to define the anatomical-functional RHV and IHV drainage territories. One hundred and forty consecutive live liver donor candidates were evaluated by means of 3-D CT reconstructions and 3-D virtual hepatectomies. Three RHV/IHV drainage patterns were identified and 'risky' configurations for right graft resections were defined. Livers with 'small' IHV drainage volumes (90.1±63.2mL) had dominant type IRHV/ IHV or non-dominant type III-RHV/IHV total liver (TL) complexes. All other cases had 'large' IHV volumes (294.7±115.5mL, p<0.001) with dominant type II-RHV/IHV TL complexes. Loss of IHV drainage volume (such as with no IHV reconstruction) in these cases was associated with a 'dominance transition' from right (RHV) to middle (MHV) hepatic veins, placing the grafts at 'high risk' for venous congestion. Type II-RHV/IHV complexes with large IHV drainage volumes are at 'high risk' for venous congestion in live donor liver transplantation.Hepato-gastroenterology 11/2011; 58(110-111):1664-9. · 0.66 Impact Factor -
Article: Implications for the usage of the left lateral liver graft for infants ≤10 kg, irrespective of a large-for-size situation--are monosegmental grafts redundant?
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ABSTRACT: Organ donor shortage for infant liver transplant recipients has lead to an increase in splitting and living donation. For cases in which even transplantation of the left lateral graft (Couinaud's segments II + III) results in a "large for size situation" with an estimated graft body weight ratio (GBWR) of >4%, monosegmental liver transplantation was developed. This, however, bears complications because of greater parenchymal surface and suboptimal vascular flow. We exclusively use the left lateral graft from living donors or split grafts. Temporary abdominal closure is attempted in cases of increased pressure. We report of 41 pediatric transplants in 38 children ≤10 kg. Within this group, there were 23 cases with a GBWR of ≥4, and 15 cases with a GBWR <4. There was no statistical difference in vascular or biliary complications. Despite a more frequent rate of temporary abdominal closure, we did not find a higher rate of intra-abdominal infections. Overall, patient and graft survival was excellent in both groups (one death, three re-transplants). We noticed, however, that the ventro-dorsal diameter of the graft appears to be more relevant to potential graft necrosis than the actual graft size. In conclusion, the usage of monosegmental grafts seems unnecessary if transplantation of left lateral grafts is performed by an experienced multidisciplinary team, and temporary abdominal closure is favored in cases of increased abdominal pressure.Transplant International 06/2011; 24(8):797-804. · 2.92 Impact Factor -
Article: Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9
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ABSTRACT: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1,186 PSC patients and 1,748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1,491 controls from Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls), and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes 2p16 (P-value 4.12 × 10−4), 4q27 (P-value 4.10 × 10−5), and 9q34 (P-value 8.41 × 10−4) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease (IBD), SNPs at 4q27 and 9q34 were nominally associated (P < 0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify nonrandom, evidence-based links we used GRAIL (Gene Relationships Across Implicated Loci) analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1,469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9, and REL as novel candidates. Conclusion: We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2, and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors. (HEPATOLOGY 2011;)Hepatology 05/2011; 53(6):1977 - 1985. · 11.66 Impact Factor
