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1. The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Author

Xie, J, Liu, L., Mladkova, N., Li, Yifu, Ren, H., Wang, W., Cui, Z., Lin, L., Hu, X., Yu, X, Xu, J, Liu, G., Caliskan, Y., Sidore, C., Balderes, O., Rosen, R.J., Bodria, M., Zanoni, F., Zhang, J.Y., Krithivasan, P., Mehl, K., Marasa, M., Khan, A., Ozay, F., Canetta, P.A., Bomback, A.S., Appel, G.B., Sanna-Cherchi, S., Sampson, M.G., Mariani, L.H., Perkowska-Ptasinska, A., Durlik, M., Mucha, K., Moszczuk, B., Foroncewicz, B., Paczek, L., Habura, I., Ars, E., Ballarin, J., Mani, L.Y., Vogt, B., Ozturk, S., Yildiz, A., Seyahi, N., Arikan, H., Koc, M., Basturk, T., Karahan, G., Akgul, S.U., Sever, M.S., Zhang, D., Santoro, D., Bonomini, M., Londrino, F., Gesualdo, L., Reiterova, J., Tesar, V., Izzi, C., Savoldi, S., Spotti, D., Marcantoni, C., Messa, P., Galliani, M., Roccatello, D., Granata, S., Zaza, G., Lugani, F., Ghiggeri, G., Pisani, I., Allegri, L., Sprangers, B., Park, J.H., Cho, B., Kim, Y.S., Kim, D.K., Suzuki, H, Amoroso, A., Cattran, D.C., Fervenza, F.C., Pani, A., Hamilton, P., Harris, S., Gupta, S., Cheshire, C., Dufek, S., Issler, N., Pepper, R.J., Connolly, J., Powis, S., Bockenhauer, D., Stanescu, H.C., Ashman, N., Loos, R.J., Kenny, E.E., Wuttke, M., Eckardt, K.U., Kottgen, A., Hofstra, J.M., Coenen, M.J.H., Kiemeney, L.A.L.M., Wetzels, J., Chen, N., Kiryluk, K., Xie, J, Liu, L., Mladkova, N., Li, Yifu, Ren, H., Wang, W., Cui, Z., Lin, L., Hu, X., Yu, X, Xu, J, Liu, G., Caliskan, Y., Sidore, C., Balderes, O., Rosen, R.J., Bodria, M., Zanoni, F., Zhang, J.Y., Krithivasan, P., Mehl, K., Marasa, M., Khan, A., Ozay, F., Canetta, P.A., Bomback, A.S., Appel, G.B., Sanna-Cherchi, S., Sampson, M.G., Mariani, L.H., Perkowska-Ptasinska, A., Durlik, M., Mucha, K., Moszczuk, B., Foroncewicz, B., Paczek, L., Habura, I., Ars, E., Ballarin, J., Mani, L.Y., Vogt, B., Ozturk, S., Yildiz, A., Seyahi, N., Arikan, H., Koc, M., Basturk, T., Karahan, G., Akgul, S.U., Sever, M.S., Zhang, D., Santoro, D., Bonomini, M., Londrino, F., Gesualdo, L., Reiterova, J., Tesar, V., Izzi, C., Savoldi, S., Spotti, D., Marcantoni, C., Messa, P., Galliani, M., Roccatello, D., Granata, S., Zaza, G., Lugani, F., Ghiggeri, G., Pisani, I., Allegri, L., Sprangers, B., Park, J.H., Cho, B., Kim, Y.S., Kim, D.K., Suzuki, H, Amoroso, A., Cattran, D.C., Fervenza, F.C., Pani, A., Hamilton, P., Harris, S., Gupta, S., Cheshire, C., Dufek, S., Issler, N., Pepper, R.J., Connolly, J., Powis, S., Bockenhauer, D., Stanescu, H.C., Ashman, N., Loos, R.J., Kenny, E.E., Wuttke, M., Eckardt, K.U., Kottgen, A., Hofstra, J.M., Coenen, M.J.H., Kiemeney, L.A.L.M., Wetzels, J., Chen, N., and Kiryluk, K.

Abstract

Contains fulltext : 220480.pdf (publisher's version ) (Open Access), Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 x 10(-12)) and IRF4 (rs9405192, OR = 1.29, P = 1.4 x 10(-14)), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 x 10(-103)) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 x 10(-49)), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 x 10(-93)), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 x 10(-23) and OR = 3.39, P = 5.2 x 10(-82), respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

Published
2020

2. The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Author

Xie, J, Liu, L., Mladkova, N., Li, Yifu, Ren, H., Wang, W., Cui, Z., Lin, L., Hu, X., Yu, X, Xu, J, Liu, G., Caliskan, Y., Sidore, C., Balderes, O., Rosen, R.J., Bodria, M., Zanoni, F., Zhang, J.Y., Krithivasan, P., Mehl, K., Marasa, M., Khan, A., Ozay, F., Canetta, P.A., Bomback, A.S., Appel, G.B., Sanna-Cherchi, S., Sampson, M.G., Mariani, L.H., Perkowska-Ptasinska, A., Durlik, M., Mucha, K., Moszczuk, B., Foroncewicz, B., Paczek, L., Habura, I., Ars, E., Ballarin, J., Mani, L.Y., Vogt, B., Ozturk, S., Yildiz, A., Seyahi, N., Arikan, H., Koc, M., Basturk, T., Karahan, G., Akgul, S.U., Sever, M.S., Zhang, D., Santoro, D., Bonomini, M., Londrino, F., Gesualdo, L., Reiterova, J., Tesar, V., Izzi, C., Savoldi, S., Spotti, D., Marcantoni, C., Messa, P., Galliani, M., Roccatello, D., Granata, S., Zaza, G., Lugani, F., Ghiggeri, G., Pisani, I., Allegri, L., Sprangers, B., Park, J.H., Cho, B., Kim, Y.S., Kim, D.K., Suzuki, H, Amoroso, A., Cattran, D.C., Fervenza, F.C., Pani, A., Hamilton, P., Harris, S., Gupta, S., Cheshire, C., Dufek, S., Issler, N., Pepper, R.J., Connolly, J., Powis, S., Bockenhauer, D., Stanescu, H.C., Ashman, N., Loos, R.J., Kenny, E.E., Wuttke, M., Eckardt, K.U., Kottgen, A., Hofstra, J.M., Coenen, M.J.H., Kiemeney, L.A.L.M., Wetzels, J., Chen, N., Kiryluk, K., Xie, J, Liu, L., Mladkova, N., Li, Yifu, Ren, H., Wang, W., Cui, Z., Lin, L., Hu, X., Yu, X, Xu, J, Liu, G., Caliskan, Y., Sidore, C., Balderes, O., Rosen, R.J., Bodria, M., Zanoni, F., Zhang, J.Y., Krithivasan, P., Mehl, K., Marasa, M., Khan, A., Ozay, F., Canetta, P.A., Bomback, A.S., Appel, G.B., Sanna-Cherchi, S., Sampson, M.G., Mariani, L.H., Perkowska-Ptasinska, A., Durlik, M., Mucha, K., Moszczuk, B., Foroncewicz, B., Paczek, L., Habura, I., Ars, E., Ballarin, J., Mani, L.Y., Vogt, B., Ozturk, S., Yildiz, A., Seyahi, N., Arikan, H., Koc, M., Basturk, T., Karahan, G., Akgul, S.U., Sever, M.S., Zhang, D., Santoro, D., Bonomini, M., Londrino, F., Gesualdo, L., Reiterova, J., Tesar, V., Izzi, C., Savoldi, S., Spotti, D., Marcantoni, C., Messa, P., Galliani, M., Roccatello, D., Granata, S., Zaza, G., Lugani, F., Ghiggeri, G., Pisani, I., Allegri, L., Sprangers, B., Park, J.H., Cho, B., Kim, Y.S., Kim, D.K., Suzuki, H, Amoroso, A., Cattran, D.C., Fervenza, F.C., Pani, A., Hamilton, P., Harris, S., Gupta, S., Cheshire, C., Dufek, S., Issler, N., Pepper, R.J., Connolly, J., Powis, S., Bockenhauer, D., Stanescu, H.C., Ashman, N., Loos, R.J., Kenny, E.E., Wuttke, M., Eckardt, K.U., Kottgen, A., Hofstra, J.M., Coenen, M.J.H., Kiemeney, L.A.L.M., Wetzels, J., Chen, N., and Kiryluk, K.

Abstract

Contains fulltext : 220480.pdf (publisher's version ) (Open Access), Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 x 10(-12)) and IRF4 (rs9405192, OR = 1.29, P = 1.4 x 10(-14)), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 x 10(-103)) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 x 10(-49)), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 x 10(-93)), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 x 10(-23) and OR = 3.39, P = 5.2 x 10(-82), respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

Published
2020

3. The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Author

Xie, J, Liu, L., Mladkova, N., Li, Yifu, Ren, H., Wang, W., Cui, Z., Lin, L., Hu, X., Yu, X, Xu, J, Liu, G., Caliskan, Y., Sidore, C., Balderes, O., Rosen, R.J., Bodria, M., Zanoni, F., Zhang, J.Y., Krithivasan, P., Mehl, K., Marasa, M., Khan, A., Ozay, F., Canetta, P.A., Bomback, A.S., Appel, G.B., Sanna-Cherchi, S., Sampson, M.G., Mariani, L.H., Perkowska-Ptasinska, A., Durlik, M., Mucha, K., Moszczuk, B., Foroncewicz, B., Paczek, L., Habura, I., Ars, E., Ballarin, J., Mani, L.Y., Vogt, B., Ozturk, S., Yildiz, A., Seyahi, N., Arikan, H., Koc, M., Basturk, T., Karahan, G., Akgul, S.U., Sever, M.S., Zhang, D., Santoro, D., Bonomini, M., Londrino, F., Gesualdo, L., Reiterova, J., Tesar, V., Izzi, C., Savoldi, S., Spotti, D., Marcantoni, C., Messa, P., Galliani, M., Roccatello, D., Granata, S., Zaza, G., Lugani, F., Ghiggeri, G., Pisani, I., Allegri, L., Sprangers, B., Park, J.H., Cho, B., Kim, Y.S., Kim, D.K., Suzuki, H, Amoroso, A., Cattran, D.C., Fervenza, F.C., Pani, A., Hamilton, P., Harris, S., Gupta, S., Cheshire, C., Dufek, S., Issler, N., Pepper, R.J., Connolly, J., Powis, S., Bockenhauer, D., Stanescu, H.C., Ashman, N., Loos, R.J., Kenny, E.E., Wuttke, M., Eckardt, K.U., Kottgen, A., Hofstra, J.M., Coenen, M.J.H., Kiemeney, L.A.L.M., Wetzels, J., Chen, N., Kiryluk, K., Xie, J, Liu, L., Mladkova, N., Li, Yifu, Ren, H., Wang, W., Cui, Z., Lin, L., Hu, X., Yu, X, Xu, J, Liu, G., Caliskan, Y., Sidore, C., Balderes, O., Rosen, R.J., Bodria, M., Zanoni, F., Zhang, J.Y., Krithivasan, P., Mehl, K., Marasa, M., Khan, A., Ozay, F., Canetta, P.A., Bomback, A.S., Appel, G.B., Sanna-Cherchi, S., Sampson, M.G., Mariani, L.H., Perkowska-Ptasinska, A., Durlik, M., Mucha, K., Moszczuk, B., Foroncewicz, B., Paczek, L., Habura, I., Ars, E., Ballarin, J., Mani, L.Y., Vogt, B., Ozturk, S., Yildiz, A., Seyahi, N., Arikan, H., Koc, M., Basturk, T., Karahan, G., Akgul, S.U., Sever, M.S., Zhang, D., Santoro, D., Bonomini, M., Londrino, F., Gesualdo, L., Reiterova, J., Tesar, V., Izzi, C., Savoldi, S., Spotti, D., Marcantoni, C., Messa, P., Galliani, M., Roccatello, D., Granata, S., Zaza, G., Lugani, F., Ghiggeri, G., Pisani, I., Allegri, L., Sprangers, B., Park, J.H., Cho, B., Kim, Y.S., Kim, D.K., Suzuki, H, Amoroso, A., Cattran, D.C., Fervenza, F.C., Pani, A., Hamilton, P., Harris, S., Gupta, S., Cheshire, C., Dufek, S., Issler, N., Pepper, R.J., Connolly, J., Powis, S., Bockenhauer, D., Stanescu, H.C., Ashman, N., Loos, R.J., Kenny, E.E., Wuttke, M., Eckardt, K.U., Kottgen, A., Hofstra, J.M., Coenen, M.J.H., Kiemeney, L.A.L.M., Wetzels, J., Chen, N., and Kiryluk, K.

Abstract

Contains fulltext : 220480.pdf (publisher's version ) (Open Access), Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 x 10(-12)) and IRF4 (rs9405192, OR = 1.29, P = 1.4 x 10(-14)), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 x 10(-103)) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 x 10(-49)), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 x 10(-93)), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 x 10(-23) and OR = 3.39, P = 5.2 x 10(-82), respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

Published
2020

4. Development of a graded index microlens based fiber optical trap and its characterization using principal component analysis.

Author

Nylk, J, Kristensen, M V G, Mazilu, M, Thayil, A K, Mitchell, C A, Campbell, E C, Powis, S J, Gunn-Moore, F J, Dholakia, K, Nylk, J, Kristensen, M V G, Mazilu, M, Thayil, A K, Mitchell, C A, Campbell, E C, Powis, S J, Gunn-Moore, F J, and Dholakia, K

Abstract

We demonstrate a miniaturized single beam fiber optical trapping probe based on a high numerical aperture graded index (GRIN) micro-objective lens. This enables optical trapping at a distance of 200μm from the probe tip. The fiber trapping probe is characterized experimentally using power spectral density analysis and an original approach based on principal component analysis for accurate particle tracking. Its use for biomedical microscopy is demonstrated through optically mediated immunological synapse formation.

Published
2015

5. Development of a graded index microlens based fiber optical trap and its characterization using principal component analysis.

Author

Nylk, J, Kristensen, M V G, Mazilu, M, Thayil, A K, Mitchell, C A, Campbell, E C, Powis, S J, Gunn-Moore, F J, Dholakia, K, Nylk, J, Kristensen, M V G, Mazilu, M, Thayil, A K, Mitchell, C A, Campbell, E C, Powis, S J, Gunn-Moore, F J, and Dholakia, K

Abstract

We demonstrate a miniaturized single beam fiber optical trapping probe based on a high numerical aperture graded index (GRIN) micro-objective lens. This enables optical trapping at a distance of 200μm from the probe tip. The fiber trapping probe is characterized experimentally using power spectral density analysis and an original approach based on principal component analysis for accurate particle tracking. Its use for biomedical microscopy is demonstrated through optically mediated immunological synapse formation.

Published
2015

6. Development of a graded index microlens based fiber optical trap and its characterization using principal component analysis.

Author

Nylk, J, Kristensen, M V G, Mazilu, M, Thayil, A K, Mitchell, C A, Campbell, E C, Powis, S J, Gunn-Moore, F J, Dholakia, K, Nylk, J, Kristensen, M V G, Mazilu, M, Thayil, A K, Mitchell, C A, Campbell, E C, Powis, S J, Gunn-Moore, F J, and Dholakia, K

Abstract

We demonstrate a miniaturized single beam fiber optical trapping probe based on a high numerical aperture graded index (GRIN) micro-objective lens. This enables optical trapping at a distance of 200μm from the probe tip. The fiber trapping probe is characterized experimentally using power spectral density analysis and an original approach based on principal component analysis for accurate particle tracking. Its use for biomedical microscopy is demonstrated through optically mediated immunological synapse formation.

Published
2015

7. Plasma concentrations of mycophenolic acid acyl glucuronide are not associated with diarrhea in renal transplant recipients

Author

Heller, T., van Gelder, T., Budde, K., de Fijter, J. W., Kuypers, D., Arns, W., Schmidt, J., Rostaing, L., Powis, S. H., Claesson, Kerstin, Macphee, I. A .M., Pohanka, E., Engelmayer, J., Brandhorst, G., Oellerich, M., Armstrong, V. W., Heller, T., van Gelder, T., Budde, K., de Fijter, J. W., Kuypers, D., Arns, W., Schmidt, J., Rostaing, L., Powis, S. H., Claesson, Kerstin, Macphee, I. A .M., Pohanka, E., Engelmayer, J., Brandhorst, G., Oellerich, M., and Armstrong, V. W.

Abstract

The aim of this study was to determine whether plasma concentrations of the acyl (AcMPAG) and phenolic (MPAG) glucuronide metabolites of mycophenolic acid (MPA) were related to diarrhoea in renal transplant patients on mycophenolate mofetil (MMF) with cyclosporine (CsA) or tacrolimus (TCL). Blood samples (0, 30, 120 min) were taken at days 3, 10, week 4, months 3, 6 and 12 for determination of MPA, MPAG and AcMPAG. MPA-AUC was estimated using validated algorithms. Two hour AUCs were calculated for MPAG and AcMPAG. Immunosuppressive therapy consisted of CsA/MMF (n= 110) and of TCL/MMF (n= 180). In 70/290 (24%) patients 86 episodes of diarrhoea were recorded during 12 months. Significantly more patients on TCL (31.1%) suffered from diarrhea compared to CsA (12.7%). MMF dose, MPA-AUC and the 2 h AUCs of MPAG and AcMPAG did not differ between patients with and without diarrhoea. Plasma AcMPAG and MPAG concentrations were substantially higher in patients on CsA compared with TCL, while MPA-AUC was lower in the former group. These data support the concept that CsA inhibits the biliary excretion of MPAG and AcMPAG, thereby potentially reducing the risk of intestinal injury through enterohepatic recycling of MPA and its metabolites.

Published
2007
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8. Plasma concentrations of mycophenolic acid acyl glucuronide are not associated with diarrhea in renal transplant recipients

Author

UCL, Heller, T., van Gelder, T., Budde, K., de Fijter, J. W., Kuypers, Delphine, Arns, W., Schmidt, J., Rostaing, L., Powis, S. H., Claesson, K., MacPhee, I. A. M., Pohanka, E., Engelmayer, J., Brandhorst, G., Oellerich, M., Armstrong, V. W., UCL, Heller, T., van Gelder, T., Budde, K., de Fijter, J. W., Kuypers, Delphine, Arns, W., Schmidt, J., Rostaing, L., Powis, S. H., Claesson, K., MacPhee, I. A. M., Pohanka, E., Engelmayer, J., Brandhorst, G., Oellerich, M., and Armstrong, V. W.

Abstract

The aim of this study was to determine whether plasma concentrations of the acyl (AcMPAG) and phenolic (MPAG) glucuronide metabolites of mycophenolic acid (MPA) were related to diarrhoea in renal transplant patients on mycophenolate mofetil (MMF) with cyclosporine (CsA) or tacrolimus (TCL). Blood samples (0, 30, 120 min) were taken at days 3, 10, week 4, months 3, 6 and 12 for determination of MPA, MPAG and AcMPAG. MPA-AUC was estimated using validated algorithms. Two hour AUCs were calculated for MPAG and AcMPAG. Immunosuppressive therapy consisted of CsA/MMF (n = 110) and of TCL/MMF (n = 180). In 70/290 (24%) patients 86 episodes of diarrhoea were recorded during 12 months. Significantly more patients on TCL (31.1%) suffered from diarrhea compared to CsA (12.7%). MMF dose, MPA-AUC and the 2 h AUCs of MPAG and AcMPAG did not differ between patients with and without diarrhoea. Plasma AcMPAG and MPAG concentrations were substantially higher in patients on CsA compared with TCL, while MPA-AUC was lower in the former group. These data support the concept that CsA inhibits the biliary excretion of MPAG and AcMPAG, thereby potentially reducing the risk of intestinal injury through enterohepatic recycling of MPA and its metabolites.

Published
2007

9. Lmp2(+) Proteasomes Are Required for the Presentation of Specific Antigens To Cytotoxic T-lymphocytes

Author

UCL, Sibille, Catherine, Gould, KG., Willardgallo, K., Thomson, S., Rivett, AJ., Powis, S., Butcher, GW., Debaetselier, P., UCL, Sibille, Catherine, Gould, KG., Willardgallo, K., Thomson, S., Rivett, AJ., Powis, S., Butcher, GW., and Debaetselier, P.

Abstract

Background: Major histocompatibility complex (MHC) class I molecules present short peptides generated by intracellular protein degradation to cytotoxic T lymphocytes (CTL). The multisubunit, non-lysosomal proteinases known as proteasomes have been implicated in the generation of these peptides. Two interferon-gamma (IFN-gamma)-inducible proteasome subunits, LMP2 and LMP7, are encoded within the MHC gene cluster in a region associated with antigen presentation. The incorporation of these LMP subunits into proteasomes may alter their activity so as to favour the generation of peptides able to bind to MHC class I molecules. It has been difficult, however, to demonstrate a specific requirement for LMP2 or LMP7 in the presentation of peptide epitopes to CTL. Results: We describe a T-cell lymphoma, termed SP3, that displays a novel selective defect in MHC class I-restricted presentation of influenza virus antigens. Of the MHC-encoded genes implicated in the class I pathway, only LMP2 is underexpressed in SP3 cells. Expression of IFN-gamma in transfected SP3 cells simultaneously restores LMP2 expression and antigen presentation to CTL. Expression of antisense-LMP2 mRNA in these IFN-gamma-transfected cells selectively represses antigen recognition and the induction of surface class I MHC expression. Moreover, the expression of this antisense-LMP2 mRNA in L929 fibroblast cells, which constitutively express LMP2 and have no presentation defect, blocks the presentation of the same influenza virus antigens that SP3 cells are defective in presenting. Conclusions: Our results show that the LMP2 proteasome subunit can directly influence both MHC class I-restricted antigen presentation and class I surface expression.

Published
1995

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