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Background: Few studies have investigated the blood proteome of inflammatory bowel disease (IBD). We characterized the serum abundance of proteins encoded at 163 known IBD risk loci and tested these proteins for their biomarker discovery potential. Methods: Based on the Human Protein Atlas (HPA) antibody availability, 218 proteins from genes mapping at 163 IBD risk loci were selected. Targeted serum protein profiles from 49 Crohn’s disease (CD) patients, 51 ulcerative colitis (UC) patients, and 50 sex- and age-matched healthy individuals were obtained using multiplexed antibody suspension bead array assays. Differences in relative serum abundance levels between disease groups and controls were examined. Replication was attempted for CD-UC comparisons (including disease subtypes) by including 64 additional patients (33 CD and 31 UC). Antibodies targeting a potentially novel risk protein were validated by paired antibodies, Western blot, immuno-capture mass spectrometry, and epitope mapping. Results: By univariate analysis, 13 proteins mostly related to neutrophil, T-cell, and B-cell activation and function were differentially expressed in IBD patients vs healthy controls, 3 in CD patients vs healthy controls and 2 in UC patients vs healthy controls (q < 0.01). Multivariate analyses further differentiated disease groups from healthy controls and CD subtypes from UC (P < 0.05). Extended characterization of an antibody targeting a novel, discriminative serum marker, the laccase (multicopper oxidoreductase) domain containing 1 (LACC1) protein, provided evidence for antibody on-target specificity. Conclusions: Using affinity proteomics, we identified a set of IBD-associated serum proteins encoded at IBD risk loci. These candidate proteins hold the potential to be exploited as diagnostic biomarkers of IBD. Jochen M. Schwenk, Mauro D’Amato and Jonas Halfvarson contributed equally.

Mesangial matrix expansion is an important process in the initiation of chronic kidney disease, yet the genetic factors driving its development are unknown. Our previous studies have implicated Far2 as a candidate gene associated with differences in mesangial matrix expansion between mouse inbred strains. Consistent with the hypothesis that increased expression of Far2 leads to mesangial matrix expansion through increased production of platelet-activating factor precursors, we show that FAR2 is capable of mediating de novo platelet-activating factor synthesis in vitro and driven by the transcription factor NKX3.2. We demonstrate that knockdown of Far2 in mice delays the progression of mesangial matrix expansion with at least six months (equivalent to ~15 yr in human). Furthermore, we show that increased FAR2 expression in human patients is associated with diabetic nephropathy, lupus nephritis, and IgA nephropathy. Taken together, these results highlight FAR2’s role in the development of mesangial matrix expansion and chronic kidney disease.

Contains fulltext : 108497.pdf (Publisher’s version ) (Closed access) In kidney transplantation, complement activation was found to be induced by donor brain death, renal ischemia-reperfusion injury and allograft rejection. There are three known pathways of complement activation: the classical, lectin and the alternative pathway. The lectin complement pathway can be activated upon pattern recognition by mannan binding lectin (MBL) or ficolins (FCN). Single nucleotide polymorphisms (SNPs) in the genes encoding the lectin pathway proteins determine their functional activity and serum levels. The aim of this study was to investigate the role of the lectin gene profile of the donor and recipient on post-transplant outcome. A total of 12 functional SNPs in the MBL2, FCN2 and MBL-associated serine proteases 2 (MASP2) genes of 1271 donor-recipient pairs were determined. Lectin genotypic variants were analyzed for association with primary non-function (PNF), delayed graft function (DGF), biopsy proven acute rejection, death-censored graft survival and patient survival. Multivariate analyses found no association of donor and recipient MBL2 and MASP2 genotype with allograft outcome. Analysis of separate functional SNPs and haplotypes in the FCN2 gene of the donor and recipient did not reveal an association with transplant outcome. Also, the joint effect of the MBL2 and FCN2 genotype was not associated with allograft outcome.This study shows that the genetic profile of the lectin pathway of complement activation of the donor and recipient is not associated with allograft outcome after kidney transplantation. 01 februari 2012

Background: Urinary uromodulin (UMOD) predicts renal prognosis in native kidneys, but data are conflicting. We investigated its prognostic impact for graft failure (GF) in renal transplant recipients (RTR; n = 600). Methods: UMOD concentration was measured cross-sectionally in RTR at 6.0 years [2.6–11.4] post-transplant, in matched patients with native chronic kidney disease (CKD) and healthy subjects. In 59 cases, RTR allograft biopsies were reviewed. Results: During a follow-up of 5.3 years [4.5–5.7], GF had occurred in 7% of RTR. Median UMOD excretion (mg/24 h) was 20.4 in RTR, 11.6 in CKD and 5.7 in controls (p < 0.001). There was a curvilinear association between UMOD excretion and baseline renal function (p < 0.003) and death-censored GF, with 5.5, 11.5 and 4.0% of the cases in subsequent UMOD excretion tertiles, respectively (p = 0.002). On multivariate Cox regression analysis, hazard ratios for GF for the 1st and 3rd tertiles were 0.37 (p = 0.01) and 0.21 (p = 0.001), respectively. Interstitial fibrosis and tubular atrophy were more severe in the middle tertile (p = 0.007). Conclusions: Urinary UMOD is elevated in RTR and associated with graft function, morphology and outcome in a bimodal fashion. Dissection of the disparate mechanisms of GF prediction by urinary UMOD might provide new clues for its alleged pathogenetic significance in progressive renal function loss.

none 44 si IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. open Ek, Weronica E; Reznichenko, Anna; Ripke, Stephan; Niesler, Beate; Zucchelli, Marco; Rivera, Natalia V; Schmidt, Peter T; Pedersen, Nancy L; Magnusson, Patrik; Talley, Nicholas J; Holliday, Elizabeth G; Houghton, Lesley; Gazouli, Maria; Karamanolis, George; Rappold, Gudrun; Burwinkel, Barbara; Surowy, Harald; Rafter, Joseph; Assadi, Ghazaleh; Li, Ling; Papadaki, Evangelia; Gambaccini, Dario; Marchi, Santino; Colucci, Rocchina; Blandizzi, Corrado; Barbaro, Raffaella; Karling, Pontus; Walter, Susanna; Ohlsson, Bodil; Tornblom, Hans; Bresso, Francesca; Andreasson, Anna; Dlugosz, Aldona; Simren, Magnus; Agreus, Lars; Lindberg, Greger; Boeckxstaens, Guy; Bellini, Massimo; Stanghellini, Vincenzo; Barbara, Giovanni; Daly, Mark J; Camilleri, Michael; Wouters, Mira M; D'Amato, Mauro Ek, Weronica E; Reznichenko, Anna; Ripke, Stephan; Niesler, Beate; Zucchelli, Marco; Rivera, Natalia V; Schmidt, Peter T; Pedersen, Nancy L; Magnusson, Patrik; Talley, Nicholas J; Holliday, Elizabeth G; Houghton, Lesley; Gazouli, Maria; Karamanolis, George; Rappold, Gudrun; Burwinkel, Barbara; Surowy, Harald; Rafter, Joseph; Assadi, Ghazaleh; Li, Ling; Papadaki, Evangelia; Gambaccini, Dario; Marchi, Santino; Colucci, Rocchina; Blandizzi, Corrado; Barbaro, Raffaella; Karling, Pontus; Walter, Susanna; Ohlsson, Bodil; Tornblom, Hans; Bresso, Francesca; Andreasson, Anna; Dlugosz, Aldona; Simren, Magnus; Agreus, Lars; Lindberg, Greger; Boeckxstaens, Guy; Bellini, Massimo; Stanghellini, Vincenzo; Barbara, Giovanni; Daly, Mark J; Camilleri, Michael; Wouters, Mira M; D'Amato, Mauro

Reznichenko A, Sinkeler SJ, Snieder H, van den Born J, de Borst MH, Damman J, van Dijk MC, van Goor H, Hepkema BG, Hillebrands JL, Leuvenink HG, Niesing J, Bakker SJ, Seelen M, Navis G. SLC22A2 is associated with tubular creatinine secretion and bias of estimated GFR in renal transplantation. Physiol Genomics 45: 201-209, 2013. First published January 22, 2013; doi:10.1152/physiolgenomics.00087.2012.-Genomewide association studies reported SLC22A2 variants to be associated with serum creatinine. As SLC22A2 encodes the organic cation transporter 2 (OCT2), the association might be due to an effect on tubular creatinine handling. To test this hypothesis we studied the association of SLC22A2 polymorphisms with phenotypes of net tubular creatinine secretion: fractional creatinine excretion (FEcreat) and bias of estimated glomerular filtration rate (eGFR). We also studied the association with end-stage renal disease (ESRD) and graft failure (GF) in renal transplant recipients. SLC22A2 single nucleotide polymorphisms (SNPs), rs3127573 and rs316009, were genotyped in 1,142 ESRD patients receiving renal transplantation and 1,186 kidney donors as controls. GFR was measured with I-125-iothalamate clearance. Creatinine clearance was also assessed. FEcreat was calculated from the simultaneous clearances of creatinine and I-125-iothalamate. Donor rs316009 was associated with FEcreat (beta -0.053, P = 0.024) and with estimated [modification of diet in renal disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)] but not measured GFR. In line with this, donor rs316009 was associated with bias of the MDRD and CKD-EPI but not the Cockroft-Gault equation. Both SNPs were associated with ESRD: odds ratios [95% CI] 1.39 [1.16-1.67], P = 0.00065, and 1.23 [1.02-1.48], P = 0.042, for rs3127573 and rs316009, respectively. Neither SNP was associated with GF. Thus, SLC22A2 is associated with phenotypes of net tubular creatinine secretion and ESRD.

Background In recent genetic association studies, common variants including rs12917707 in the UMOD locus have shown strong evidence of association with eGFR, prevalent and incident chronic kidney disease and uromodulin urinary concentration in general population cohorts. The association of rs12917707 with end-stage renal disease (ESRD) in a recent case-control study was only nominally significant. Methods To investigate whether rs12917707 associates with ESRD, graft failure (GF) and urinary uromodulin levels in an independent cohort, we genotyped 1142 ESRD patients receiving a renal transplantation and 1184 kidney donors as controls. After transplantation, 1066 renal transplant recipients were followed up for GF. Urinary uromodulin concentration was measured at median [IQR] 4.2 [2.2-6.1] yrs after kidney transplantation. Results The rs12917707 minor allele showed association with lower risk of ESRD (OR 0.89 [0.76-1.03], p = 0.04) consistent in effect size and direction with the previous report (Böger et al, PLoS Genet 2011). Meta-analysis of these findings showed significant association of rs12917707 with ESRD (OR 0.91 [0.85-98], p = 0.008). In contrast, rs12917707 was not associated with incidence of GF. Urinary uromodulin concentration was lower in recipients-carriers of the donor rs12917707 minor allele as compared to non-carriers, again consistent with previous observations in general population cohorts. Conclusions Our study thus corroborates earlier evidence and independently confirms the association between UMOD and ESRD.

Contains fulltext : 110462.pdf (Publisher’s version ) (Open Access) Chronic kidney disease (CKD) is a complex disorder. As genome-wide association studies identified cubilin gene CUBN as a locus for albuminuria, and urinary protein loss is a risk factor for progressive CKD, we tested the hypothesis that common genetic variants in CUBN are associated with end-stage renal disease (ESRD) and proteinuria. First, a total of 1142 patients with ESRD, admitted for renal transplantation, and 1186 donors were genotyped for SNPs rs7918972 and rs1801239 (case-control study). The rs7918972 minor allele frequency (MAF) was higher in ESRD patients comparing to kidney donors, implicating an increased risk for ESRD (OR 1.39, p = 0.0004) in native kidneys. Second, after transplantation recipients were followed for 5.8 [3.8-9.2] years (longitudinal study) documenting ESRD in transplanted kidneys--graft failure (GF). During post-transplant follow-up 92 (9.6%) cases of death-censored GF occurred. Donor rs7918972 MAF, representing genotype of the transplanted kidney, was 16.3% in GF vs 10.7% in cases with functioning graft. Consistently, a multivariate Cox regression analysis showed that donor rs7918972 is a predictor of GF, although statistical significance was not reached (HR 1.53, p = 0.055). There was no association of recipient rs7918972 with GF. Rs1801239 was not associated with ESRD or GF. In line with an association with the outcome, donor rs7918972 was associated with elevated proteinuria levels cross-sectionally at 1 year after transplantation. Thus, we identified CUBN rs7918972 as a novel risk variant for renal function loss in two independent settings: ESRD in native kidneys and GF in transplanted kidneys.