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3. P06-13: Machine learning in predicting genotoxicity biomarkers based on the exposure to air pollutants in colder and warmer periods in the general population of Zagreb (Croatia)

Author

Matković, K., primary, Delić, L., additional, Jurič, A., additional, Davila, S., additional, Milić, M., additional, Jakovljević, I., additional, Kašuba, V., additional, Pehnec, G., additional, Hopf, N.B., additional, Guseva Canu, I., additional, Brčić Karačonji, I., additional, Gajski, G., additional, and Gerić, M., additional

Published
2023
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4. P03-02: The use of buccal micronucleus cytome assay as an additional biomarker in the assessment of exposure to air pollutants in colder and warmer periods in the chronically exposed Zagreb (Croatia) residents

Author

Milić, M., primary, Kašuba, V., additional, Matković, K., additional, Delić, L., additional, Jakovljević, I., additional, Davila, S., additional, Pehnec, G., additional, Guseva Canu, I., additional, Hopf, N.B., additional, Gerić, M., additional, and Gajski, G., additional

Published
2023
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7. Quality of Life of Patients Treated with Radiotherapy in an Upper Middle-Income Country

Author

De Falla, V., primary, Figueroa, F.J., additional, Michalski, J.M., additional, van Rheenen, J., additional, Gay, H.A., additional, Ruiz Furlan, E.A., additional, Kihn, A., additional, Hugo, G.D., additional, Sobrevilla, L., additional, Garcia, M., additional, Davila, S., additional, Powderly, W.G., additional, Velarde, A., additional, Sun, B., additional, Lee, K., additional, Huang, Y., additional, Ma, K.S.K., additional, Najera, K.D., additional, García, C., additional, Reyes, F.E., additional, Ixquiac, M., additional, and Henke, L.E., additional

Published
2022
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10. Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

Author

Kumar, Vikrant, Pouw, R.B., Autio, M.I., Sagmeister, M.G., Phua, Z. Yang, Borghini, L., Wright, V.J., Hoggart, C., Pan, B., Tan, A., Binder, A., Brouwer, M.C.T., Pinnock, E., Groot, R. de, Hazelzet, J., Emonts, M., Flier, M. van der, Reiter, K., Nöthen, M.M., Hoffmann, P., consortium, E., Schlapbach, L.J., Bellos, E., Anderson, S., Secka, F., Martinón-Torres, F., Salas, A., Fink, C., Carrol, E.D., Pollard, A.J., Coin, L.J., Zenz, W., Wouters, D., Ang, L. Teng, Hibberd, M.L., Levin, M., Kuijpers, T.W., Davila, S., Kumar, Vikrant, Pouw, R.B., Autio, M.I., Sagmeister, M.G., Phua, Z. Yang, Borghini, L., Wright, V.J., Hoggart, C., Pan, B., Tan, A., Binder, A., Brouwer, M.C.T., Pinnock, E., Groot, R. de, Hazelzet, J., Emonts, M., Flier, M. van der, Reiter, K., Nöthen, M.M., Hoffmann, P., consortium, E., Schlapbach, L.J., Bellos, E., Anderson, S., Secka, F., Martinón-Torres, F., Salas, A., Fink, C., Carrol, E.D., Pollard, A.J., Coin, L.J., Zenz, W., Wouters, D., Ang, L. Teng, Hibberd, M.L., Levin, M., Kuijpers, T.W., and Davila, S.

Abstract

Contains fulltext : 282924.pdf (Publisher’s version ) (Open Access)

Published
2022

11. Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

Author

Kumar, V, Pouw, RB, Autio, M, Sagmeister, MG, Phua, ZY, Borghini, L, Wright, VJ, Hoggart, C, Pan, B, Tan, AKY, Binder, A, Brouwer, MC, Pinnock, E, De Groot, R, Hazelzet, J, Emonts, M, van der Flier, M, Reiter, K, Nothen, MM, Hoffmann, P, Schlapbach, LJ, Bellos, E, Anderson, S, Secka, F, Martinon-Torres, F, Salas, A, Fink, C, Carrol, ED, Pollard, AJ, Coin, LJ, Zenz, W, Wouters, D, Ang, LT, Hibberd, ML, Levin, M, Kuijpers, TW, Davila, S, Kumar, V, Pouw, RB, Autio, M, Sagmeister, MG, Phua, ZY, Borghini, L, Wright, VJ, Hoggart, C, Pan, B, Tan, AKY, Binder, A, Brouwer, MC, Pinnock, E, De Groot, R, Hazelzet, J, Emonts, M, van der Flier, M, Reiter, K, Nothen, MM, Hoffmann, P, Schlapbach, LJ, Bellos, E, Anderson, S, Secka, F, Martinon-Torres, F, Salas, A, Fink, C, Carrol, ED, Pollard, AJ, Coin, LJ, Zenz, W, Wouters, D, Ang, LT, Hibberd, ML, Levin, M, Kuijpers, TW, and Davila, S

Abstract

Neisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls. We identified a CFHR3 SNP that provides protection from MD (rs75703017, p value = 1.1 × 10-16) by decreasing the concentration of FH in the blood (p value = 1.4 × 10-11). We subsequently used dual-luciferase studies and CRISPR gene editing to establish that deletion of rs75703017 increased FH expression in hepatocyte by preventing promotor inhibition. Our data suggest that reduced concentrations of FH in the blood confer protection from MD; with reduced access to FH, N. meningitidis is less able to shield itself from complement-mediated killing.

Published
2022

12. Analysis of clinically relevant variants from ancestrally diverse Asian genomes.

Author

Chan, SH, Bylstra, Y, Teo, JX, Kuan, JL, Bertin, N, Gonzalez-Porta, M, Hebrard, M, Tirado-Magallanes, R, Tan, JHJ, Jeyakani, J, Li, Z, Chai, JF, Chong, YS, Davila, S, Goh, LL, Lee, ES, Wong, E, Wong, TY, SG10K_Health Consortium, Prabhakar, S, Liu, J, Cheng, C-Y, Eisenhaber, B, Karnani, N, Leong, KP, Sim, X, Yeo, KK, Chambers, JC, Tai, E-S, Tan, P, Jamuar, SS, Ngeow, J, Lim, WK, Chan, SH, Bylstra, Y, Teo, JX, Kuan, JL, Bertin, N, Gonzalez-Porta, M, Hebrard, M, Tirado-Magallanes, R, Tan, JHJ, Jeyakani, J, Li, Z, Chai, JF, Chong, YS, Davila, S, Goh, LL, Lee, ES, Wong, E, Wong, TY, SG10K_Health Consortium, Prabhakar, S, Liu, J, Cheng, C-Y, Eisenhaber, B, Karnani, N, Leong, KP, Sim, X, Yeo, KK, Chambers, JC, Tai, E-S, Tan, P, Jamuar, SS, Ngeow, J, and Lim, WK

Abstract

Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population.

Published
2022

22. Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population.

Author

Chang, X, Gurung, RL, Wang, L, Jin, A, Li, Z, Wang, R, Beckman, KB, Adams-Haduch, J, Meah, WY, Sim, KS, Lim, WK, Davila, S, Tan, P, Teo, JX, Yeo, KK, M, Y, Liu, S, Lim, SC, Liu, J, van Dam, RM, Friedlander, Y, Koh, W-P, Yuan, J-M, Khor, CC, Heng, C-K, Dorajoo, R, Chang, X, Gurung, RL, Wang, L, Jin, A, Li, Z, Wang, R, Beckman, KB, Adams-Haduch, J, Meah, WY, Sim, KS, Lim, WK, Davila, S, Tan, P, Teo, JX, Yeo, KK, M, Y, Liu, S, Lim, SC, Liu, J, van Dam, RM, Friedlander, Y, Koh, W-P, Yuan, J-M, Khor, CC, Heng, C-K, and Dorajoo, R

Abstract

The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10-14-6.94×10-10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR95%CI = 1.544 (1.173, 2.032), PAdj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR95%CI = 1.123 (1.051, 1.201), Padj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.

Published
2021

26. Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Author

Borghini, L., Png, E., Binder, A., Wright, V.J., Pinnock, E., Groot, R. de, Hazelzet, J., Emonts, M., Flier, M. van der, Philipsen, H.L.A., Schlapbach, L.J., Anderson, S., Secka, F., Salas, A., Fink, C., Carrol, E.D., Pollard, A.J., Coin, L.J., Kuijpers, T.W., Martinon-Torres, F., Zenz, W., Levin, M., Hibberd, M.L., Davila, S., Neeleman, C., Deuren, M. van, Kunze, W., Schermann, P., Borghini, L., Png, E., Binder, A., Wright, V.J., Pinnock, E., Groot, R. de, Hazelzet, J., Emonts, M., Flier, M. van der, Philipsen, H.L.A., Schlapbach, L.J., Anderson, S., Secka, F., Salas, A., Fink, C., Carrol, E.D., Pollard, A.J., Coin, L.J., Kuijpers, T.W., Martinon-Torres, F., Zenz, W., Levin, M., Hibberd, M.L., Davila, S., Neeleman, C., Deuren, M. van, Kunze, W., and Schermann, P.

Abstract

Contains fulltext : 204148.pdf (publisher's version ) (Open Access), Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.

Published
2019

27. ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder

Author

Williams, L.B., Javed, A., Sabri, A., Morgan, D.J. (Denise), Huff, C.D., Grigg, J.R., Heng, X.T., Khng, A.J., Hollink, I.H.I.M. (Iris), Morrison, M. A., Owen, L.A., Anderson, K.C. (Kenneth), Kinard, K., Greenlees, R. (R.), Novacic, D., Sen, H.N., Zein, W.M., Rodgers, G.M., Vitale, A.T., Haider, N.B., Hillmer, A.M., Ng, P.C., Shankaracharya, ., Cheng, A., Zheng, L.D., Gillies, M.C. (Mark), Slegtenhorst, M.A. (Marjon) van, Hagen, P.M. (Martin) van, Missotten, T. (Tom), Farley, G.L., Polo, M., Malatack, J., Curtin, J., Martin, F. (F.), Arbuckle, S. (Susan), Alexander, SI, Chircop, M., Davila, S. (Sonia), Digre, K.B., Jamieson, R.V., DeAngelis, M.M. (Margaret), Williams, L.B., Javed, A., Sabri, A., Morgan, D.J. (Denise), Huff, C.D., Grigg, J.R., Heng, X.T., Khng, A.J., Hollink, I.H.I.M. (Iris), Morrison, M. A., Owen, L.A., Anderson, K.C. (Kenneth), Kinard, K., Greenlees, R. (R.), Novacic, D., Sen, H.N., Zein, W.M., Rodgers, G.M., Vitale, A.T., Haider, N.B., Hillmer, A.M., Ng, P.C., Shankaracharya, ., Cheng, A., Zheng, L.D., Gillies, M.C. (Mark), Slegtenhorst, M.A. (Marjon) van, Hagen, P.M. (Martin) van, Missotten, T. (Tom), Farley, G.L., Polo, M., Malatack, J., Curtin, J., Martin, F. (F.), Arbuckle, S. (Susan), Alexander, SI, Chircop, M., Davila, S. (Sonia), Digre, K.B., Jamieson, R.V., and DeAngelis, M.M. (Margaret)

Abstract

Purpose: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. Methods: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members. Results: We found the heterozygous missense variant in the ɑkinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis. Conclusion: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.

Published
2019
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28. Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Author

Borghini, L, Png, E, Binder, A, Wright, VJ, Pinnock, E, de Groot, R, Hazelzet, J, Emonts, M, Van der Flier, M, Schlapbach, LJ, Anderson, S, Secka, F, Salas, A, Fink, C, Carrol, ED, Pollard, AJ, Coin, LJ, Kuijpers, TW, Martinon-Torres, F, Zenz, W, Levin, M, Hibberd, ML, Davila, S, Gormley, S, Hamilton, S, Herberg, J, Hourmat, B, Hoggart, C, Kaforou, M, Sancho-Shimizu, V, Abdulla, A, Agapow, P, Bartlett, M, Bellos, E, Eleftherohorinou, H, Galassini, R, Inwald, D, Mashbat, M, Menikou, S, Mustafa, S, Nadel, S, Rahman, R, Thakker, C, Bokhandi, S, Power, S, Barham, H, Pathan, N, Ridout, J, White, D, Thurston, S, Faust, S, Patel, S, McCorkell, J, Davies, P, Cratev, L, Navarra, H, Carter, S, Ramaiah, R, Patel, R, Tuffrey, C, Gribbin, A, McCready, S, Peters, M, Hardy, K, Standing, F, O'Neill, L, Abelake, E, Deep, A, Nsirim, E, Willis, L, Young, Z, Royad, C, White, S, Fortune, PM, Hudnott, P, Alvez Gonzalez, F, Barral-Arca, R, Cebey-Lopez, M, Jose Curras-Tuala, M, Garcia, N, Garcia Vicente, L, Gomez-Carballa, A, Gomez Rial, J, Grela Beiroa, A, Justicia Grande, A, Leborans Iglesias, P, Martinez Santos, AE, Martinon-Torres, N, Martinon Sanchez, JM, Mosquera Perez, B, Obando Pacheco, P, Pardo-Seco, J, Pischedda, S, Rivero Calle, I, Rodriguez-Tenreiro, C, Redondo-Collazo, L, Seren Fernandez, S, Porto Silva, MDS, Vega, A, Beatriz Reyes, S, Leon Leon, MC, Navarro Mingorance, A, Gabaldo Barrios, X, Onate Vergara, E, Concha Torre, A, Vivanco, A, Fernandez, R, Gimenez Sanchez, F, Sanchez Forte, M, Rojo, P, Ruiz Contreras, J, Palacios, A, Navarro, M, Alvarez Alvarez, C, Jose Lozano, M, Carreras, E, Brio Sanagustin, S, Neth, O, Martinez Padilla, MDC, Prieto Tato, LM, Guillen, S, Fernandez Silveira, L, Moreno, D, van Furth, AMT, van der Flier, M, Boeddha, NP, Driessen, GJA, Pajkrt, D, Sanders, EAM, van de Beek, D, van der Ende, A, Philipsen, HLA, Adeel, AOA, Breukels, MA, Brinkman, DMC, de Korte, CCMM, de Vries, E, de Waal, WJ, Dekkers, R, Dings-Lammertink, A, Doedens, RA, Donker, AE, Dousma, M, Faber, TE, Gerrits, GPJM, Gerver, JAM, Heidema, J, Homan-van der Veen, J, Jacobs, MAM, Jansen, NJG, Kawczynski, P, Klucovska, K, Kneyber, MCJ, Koopman-Keemink, Y, Langenhorst, VJ, Leusink, J, Loza, BF, Merth, IT, Miedema, CJ, Neeleman, C, Noordzij, JG, Obihara, CC, van Overbeek-van Gils, ALT, Poortman, GH, Potgieter, ST, Potjewijd, J, Rosias, PPR, Sprong, T, ten Tussher, GW, Thio, BJ, Tramper-Stranders, GA, van Deuren, M, van der Meer, H, van Kuppevelt, AJM, van Wermeskerken, AM, Verwijs, WA, Wolfs, TFW, Agyeman, P, Aebi, C, Berger, C, Giannoni, E, Stocker, M, Posfay-Barbe, KM, Heininger, U, Bernhard-Stirnemann, S, Niederer-Loher, A, Kahlert, C, Hasters, P, Relly, C, Baer, W, Paulus, S, Frederick, H, Jennings, R, Johnston, J, Kenwright, R, Agbeko, R, Bojang, K, Sarr, I, Kebbeh, N, Sey, G, Saidykhan, M, Cole, F, Thomas, G, Antonio, M, Walcher, W, Geishofer, G, Klobassa, D, Martin, M, Pfurtscheller, K, Reiter, K, Roedl, S, Zobel, G, Zoehrer, B, Toepke, B, Fucik, P, Gabriel, M, Penzien, JM, Diab, G, Miething, R, Deeg, KH, Hammer, J, Varnholt, V, Schmidt, A, Bindl, L, Sillaber, U, Huemer, C, Meier, P, Simic-Schleicher, G, Markart, M, Pfau, E, Broede, H, Ausserer, B, Kalhoff, H, Arpe, V, Schweitzer-Krantz, S, Kasper, J-M, Loranth, K, Bittrich, HJ, Simma, B, Klinge, J, Fedlmaier, M, Weigand, N, Herting, E, Grube, R, Fusch, C, Gruber, A, Schimmel, U, Knaufer-Schiefer, S, Laessig, W, Hennenberger, A, von der Wense, A, Tillmann, R, Schwarick, J, Sitzmann, FC, Streif, W, Mueller, H, Kurnik, P, Groneck, P, Weiss, U, Groeblacher-Roth, H, Bensch, J, Moser, R, Schwarz, R, Lenz, K, Hofmann, T, Goepel, W, Schulz, D, Berger, T, Hauser, E, Foerster, KM, Peters, J, Nicolai, TH, Kumlien, B, Beckmann, R, Seitz, C, Hueseman, D, Schuermann, R, Ta, VH, Weikmann, E, Evert, W, Hautz, J, Seidenberg, J, Wocko, L, Luigs, P, Reiter, H-L, Quietzach, J, Koenig, M, Herrmann, J, Mitter, H, Seidler, E, Maak, B, Sperl, W, Zwiauer, K, Meissl, M, Koch, R, Cremer, M, Breuer, HA, Goerke, W, Nossal, R, Pernice, W, Brangenberg, R, Salzer, HR, Koch, H, Schaller, G, Paky, F, Strasser, F, Eitelberger, F, Sontheimer, D, Lischka, A, Kronberger, M, Dilch, A, Scheibenpflug, C, Bruckner, R, Mahler, K, Runge, K, Kunze, W, Schermann, P, Borghini, L, Png, E, Binder, A, Wright, VJ, Pinnock, E, de Groot, R, Hazelzet, J, Emonts, M, Van der Flier, M, Schlapbach, LJ, Anderson, S, Secka, F, Salas, A, Fink, C, Carrol, ED, Pollard, AJ, Coin, LJ, Kuijpers, TW, Martinon-Torres, F, Zenz, W, Levin, M, Hibberd, ML, Davila, S, Gormley, S, Hamilton, S, Herberg, J, Hourmat, B, Hoggart, C, Kaforou, M, Sancho-Shimizu, V, Abdulla, A, Agapow, P, Bartlett, M, Bellos, E, Eleftherohorinou, H, Galassini, R, Inwald, D, Mashbat, M, Menikou, S, Mustafa, S, Nadel, S, Rahman, R, Thakker, C, Bokhandi, S, Power, S, Barham, H, Pathan, N, Ridout, J, White, D, Thurston, S, Faust, S, Patel, S, McCorkell, J, Davies, P, Cratev, L, Navarra, H, Carter, S, Ramaiah, R, Patel, R, Tuffrey, C, Gribbin, A, McCready, S, Peters, M, Hardy, K, Standing, F, O'Neill, L, Abelake, E, Deep, A, Nsirim, E, Willis, L, Young, Z, Royad, C, White, S, Fortune, PM, Hudnott, P, Alvez Gonzalez, F, Barral-Arca, R, Cebey-Lopez, M, Jose Curras-Tuala, M, Garcia, N, Garcia Vicente, L, Gomez-Carballa, A, Gomez Rial, J, Grela Beiroa, A, Justicia Grande, A, Leborans Iglesias, P, Martinez Santos, AE, Martinon-Torres, N, Martinon Sanchez, JM, Mosquera Perez, B, Obando Pacheco, P, Pardo-Seco, J, Pischedda, S, Rivero Calle, I, Rodriguez-Tenreiro, C, Redondo-Collazo, L, Seren Fernandez, S, Porto Silva, MDS, Vega, A, Beatriz Reyes, S, Leon Leon, MC, Navarro Mingorance, A, Gabaldo Barrios, X, Onate Vergara, E, Concha Torre, A, Vivanco, A, Fernandez, R, Gimenez Sanchez, F, Sanchez Forte, M, Rojo, P, Ruiz Contreras, J, Palacios, A, Navarro, M, Alvarez Alvarez, C, Jose Lozano, M, Carreras, E, Brio Sanagustin, S, Neth, O, Martinez Padilla, MDC, Prieto Tato, LM, Guillen, S, Fernandez Silveira, L, Moreno, D, van Furth, AMT, van der Flier, M, Boeddha, NP, Driessen, GJA, Pajkrt, D, Sanders, EAM, van de Beek, D, van der Ende, A, Philipsen, HLA, Adeel, AOA, Breukels, MA, Brinkman, DMC, de Korte, CCMM, de Vries, E, de Waal, WJ, Dekkers, R, Dings-Lammertink, A, Doedens, RA, Donker, AE, Dousma, M, Faber, TE, Gerrits, GPJM, Gerver, JAM, Heidema, J, Homan-van der Veen, J, Jacobs, MAM, Jansen, NJG, Kawczynski, P, Klucovska, K, Kneyber, MCJ, Koopman-Keemink, Y, Langenhorst, VJ, Leusink, J, Loza, BF, Merth, IT, Miedema, CJ, Neeleman, C, Noordzij, JG, Obihara, CC, van Overbeek-van Gils, ALT, Poortman, GH, Potgieter, ST, Potjewijd, J, Rosias, PPR, Sprong, T, ten Tussher, GW, Thio, BJ, Tramper-Stranders, GA, van Deuren, M, van der Meer, H, van Kuppevelt, AJM, van Wermeskerken, AM, Verwijs, WA, Wolfs, TFW, Agyeman, P, Aebi, C, Berger, C, Giannoni, E, Stocker, M, Posfay-Barbe, KM, Heininger, U, Bernhard-Stirnemann, S, Niederer-Loher, A, Kahlert, C, Hasters, P, Relly, C, Baer, W, Paulus, S, Frederick, H, Jennings, R, Johnston, J, Kenwright, R, Agbeko, R, Bojang, K, Sarr, I, Kebbeh, N, Sey, G, Saidykhan, M, Cole, F, Thomas, G, Antonio, M, Walcher, W, Geishofer, G, Klobassa, D, Martin, M, Pfurtscheller, K, Reiter, K, Roedl, S, Zobel, G, Zoehrer, B, Toepke, B, Fucik, P, Gabriel, M, Penzien, JM, Diab, G, Miething, R, Deeg, KH, Hammer, J, Varnholt, V, Schmidt, A, Bindl, L, Sillaber, U, Huemer, C, Meier, P, Simic-Schleicher, G, Markart, M, Pfau, E, Broede, H, Ausserer, B, Kalhoff, H, Arpe, V, Schweitzer-Krantz, S, Kasper, J-M, Loranth, K, Bittrich, HJ, Simma, B, Klinge, J, Fedlmaier, M, Weigand, N, Herting, E, Grube, R, Fusch, C, Gruber, A, Schimmel, U, Knaufer-Schiefer, S, Laessig, W, Hennenberger, A, von der Wense, A, Tillmann, R, Schwarick, J, Sitzmann, FC, Streif, W, Mueller, H, Kurnik, P, Groneck, P, Weiss, U, Groeblacher-Roth, H, Bensch, J, Moser, R, Schwarz, R, Lenz, K, Hofmann, T, Goepel, W, Schulz, D, Berger, T, Hauser, E, Foerster, KM, Peters, J, Nicolai, TH, Kumlien, B, Beckmann, R, Seitz, C, Hueseman, D, Schuermann, R, Ta, VH, Weikmann, E, Evert, W, Hautz, J, Seidenberg, J, Wocko, L, Luigs, P, Reiter, H-L, Quietzach, J, Koenig, M, Herrmann, J, Mitter, H, Seidler, E, Maak, B, Sperl, W, Zwiauer, K, Meissl, M, Koch, R, Cremer, M, Breuer, HA, Goerke, W, Nossal, R, Pernice, W, Brangenberg, R, Salzer, HR, Koch, H, Schaller, G, Paky, F, Strasser, F, Eitelberger, F, Sontheimer, D, Lischka, A, Kronberger, M, Dilch, A, Scheibenpflug, C, Bruckner, R, Mahler, K, Runge, K, Kunze, W, and Schermann, P

Abstract

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.

Published
2019

29. ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder

Author

Williams, LB, Javed, A, Sabri, A, Morgan, DJ, Huff, CD, Grigg, JR, Heng, XT, Khng, AJ, Hollink, Iris, Morrison, M A, Owen, LA, Anderson, K, Kinard, K, Greenlees, R, Novacic, D, Sen, HN, Zein, WM, Rodgers, GM, Vitale, AT, Haider, NB, Hillmer, AM, Ng, PC, Shankaracharya, Cheng, A, Zheng, LD, Gillies, MC, van Slegtenhorst, M, van Hagen, P.M., Missotten, T, Farley, GL, Polo, M, Malatack, J, Curtin, J, Martin, F, Arbuckle, S, Alexander, SI, Chircop, M, Davila, S, Digre, KB, Jamieson, RV, DeAngelis, MM, Williams, LB, Javed, A, Sabri, A, Morgan, DJ, Huff, CD, Grigg, JR, Heng, XT, Khng, AJ, Hollink, Iris, Morrison, M A, Owen, LA, Anderson, K, Kinard, K, Greenlees, R, Novacic, D, Sen, HN, Zein, WM, Rodgers, GM, Vitale, AT, Haider, NB, Hillmer, AM, Ng, PC, Shankaracharya, Cheng, A, Zheng, LD, Gillies, MC, van Slegtenhorst, M, van Hagen, P.M., Missotten, T, Farley, GL, Polo, M, Malatack, J, Curtin, J, Martin, F, Arbuckle, S, Alexander, SI, Chircop, M, Davila, S, Digre, KB, Jamieson, RV, and DeAngelis, MM

Published
2019

33. PCN16 COST ESTIMATE ANALYSIS OF ABIRATERONE PLUS PREDNISONE (AAP) AND ENZALUTAMIDE (ENZ) IN INSURED METASTATIC CASTRATION RESISTANT PROSTATE CANCER PATIENTS IN ARGENTINA: EVIREPRO DATABASE

Author

Schmilovich, A., primary, Arroyo Davila, S., additional, Jewtuchowicz, H., additional, Wilks, E., additional, Catalan, M., additional, Lopez, J., additional, Garcia, M., additional, Magallanes, D., additional, Barreiro, D., additional, Costantino, G., additional, Jalil, J., additional, and Traine, G., additional

Published
2019
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34. Human pharyngeal microbiota in age-related macular degeneration.

Author

Clark, SJ, Ho, EXP, Cheung, CMG, Sim, S, Chu, CW, Wilm, A, Lin, CB, Mathur, R, Wong, D, Chan, CM, Bhagarva, M, Laude, A, Lim, TH, Wong, TY, Cheng, CY, Davila, S, Hibberd, M, Clark, SJ, Ho, EXP, Cheung, CMG, Sim, S, Chu, CW, Wilm, A, Lin, CB, Mathur, R, Wong, D, Chan, CM, Bhagarva, M, Laude, A, Lim, TH, Wong, TY, Cheng, CY, Davila, S, and Hibberd, M

Abstract

BACKGROUND: While the aetiology of age-related macular degeneration (AMD)-a major blinding disease-remains unknown, the disease is strongly associated with variants in the complement factor H (CFH) gene. CFH variants also confer susceptibility to invasive infection with several bacterial colonizers of the nasopharyngeal mucosa. This shared susceptibility locus implicates complement deregulation as a common disease mechanism, and suggests the possibility that microbial interactions with host complement may trigger AMD. In this study, we address this possibility by testing the hypothesis that AMD is associated with specific microbial colonization of the human nasopharynx. RESULTS: High-throughput Illumina sequencing of the V3-V6 region of the microbial 16S ribosomal RNA gene was used to comprehensively and accurately describe the human pharyngeal microbiome, at genus level, in 245 AMD patients and 386 controls. Based on mean and differential microbial abundance analyses, we determined an overview of the pharyngeal microbiota, as well as candidate genera (Prevotella and Gemella) suggesting an association towards AMD health and disease conditions. CONCLUSIONS: Utilizing an extensive study population from Singapore, our results provided an accurate description of the pharyngeal microbiota profiles in AMD health and disease conditions. Through identification of candidate genera that are different between conditions, we provide preliminary evidence for the existence of microbial triggers for AMD. Ethical approval for this study was obtained through the Singapore Health Clinical Institutional Review Board, reference numbers R799/63/2010 and 2010/585/A.

Published
2018

35. Principios del desastre

Author

Dávila S. and Dávila S.

Abstract

Principios del desastre es el primer libro de poemas de Dávila S. Luces y sombras Tus ojos son esos orbesverdesque parpadeanen medio de la noche,deslumbrando las acerasy los cielos,mostrando ese suspirode luz que te define. ¿Podrá mi oscuridadluchar contra el vacíode tenerte sin tenerte,sin ser mío el tiemposuficiente, en estos ojostuyos que hoy me entienden?Tus labios parecensaber todas las respuestas.

Published
2017

36. What motivates rural riverine residents to adopt toilets? Findings from Central Amazon

Author

João Paulo Borges Pedro, Cássio Augusto da Silva Oliveira, Maria Cecília Rosinski Lima Gomes, Ana Claudeíse Silva do Nascimento, Dávila Suelen Souza Corrêa, and Marcos Von Sperling

Subjects
saneamento, pesquisa qualitativa, várzea, áreas alagadas, ods 6, Environmental sciences, GE1-350
Abstract

In the Brazilian Amazon, almost 4 million people lack access to adequate sanitation services, and part of this population still practices open defecation. To contribute to successful public policies, this article explores the factors that motivate rural riverine residents from Central Amazon to adopt and/or use toilets. From interviews, Focus Group Discussion and Content Analysis, it was verified that the main motivations are comfort and convenience in using a toilet and the protection it offers against dangerous animals or when it is raining. It was also found that privacy is a strong and authentic motivation for women, and that it meets the Sustainable Development Goals. These results contribute to regionalized sanitation programs, which must take into account the opinion of those who benefit from the implementation of sanitation social technologies.

Published
2023
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37. Association between telomere length and risk of cancer and non-neoplastic diseases: A Mendelian randomization study

Author

Collaboration, Telomeres Mendelian Randomization, Haycock, P, Burgess, S, Nounu, A, Zheng, J, Okoli, G, Bowden, J, Wade, K, Timpson, N, Evans, D, Willeit, P, Aviv, A, Gaunt, T, Hemani, G, Mangino, M, Ellis, H, Kurian, K, Pooley, K, Eeles, R, Lee, J, Fang, S, Chen, W, Law, M, Bowdler, L, Iles, M, Yang, Q, Worrall, B, Markus, H, Hung, R, Amos, C, Spurdle, A, Thompson, D, O'Mara, T, Wolpin, B, Amundadottir, L, Stolzenberg-Solomon, R, Trichopoulou, A, Onland-Moret, N, Lund, E, Duell, E, Canzian, F, Severi, G, Overvad, K, Gunter, M, Tumino, R, Svenson, U, van Rij, A, Baas, A, Bown, M, Samani, N, van t'Hof, F, Tromp, G, Jones, G, Kuivaniemi, H, Elmore, J, Johansson, M, Mckay, J, Scelo, G, Carreras-Torres, R, Gaborieau, V, Brennan, P, Bracci, P, Neale, R, Olson, S, Gallinger, S, Li, D, Petersen, G, Risch, H, Klein, A, Han, J, Abnet, C, Freedman, N, Taylor, P, Maris, J, Aben, K, Kiemeney, L, Vermeulen, S, Wiencke, J, Walsh, K, Wrensch, M, Rice, T, Turnbull, C, Litchfield, K, Paternoster, L, Standl, M, Abecasis, G, SanGiovanni, J, Li, Y, Mijatovic, V, Sapkota, Y, Low, S, Zondervan, K, Montgomery, G, Nyholt, D, van Heel, D, Hunt, K, Arking, D, Ashar, F, Sotoodehnia, N, Woo, D, Rosand, J, Comeau, M, Brown, W, Silverman, E, Hokanson, J, Cho, M, Hui, J, Ferreira, M, Thompson, P, Morrison, A, Felix, J, Smith, N, Christiano, A, Petukhova, L, Betz, R, Fan, X, Zhang, X, Zhu, C, Langefeld, C, Thompson, S, Wang, F, Lin, X, Schwartz, D, Fingerlin, T, Rotter, J, Cotch, M, Jensen, R, Munz, M, Dommisch, H, Schaefer, A, Han, F, Ollila, H, Hillary, R, Albagha, O, Ralston, S, Zeng, C, Zheng, W, Shu, X, Reis, A, Uebe, S, Hüffmeier, U, Kawamura, Y, Otowa, T, Sasaki, T, Hibberd, M, Davila, S, Xie, G, Siminovitch, K, Bei, J, Zeng, Y, Försti, A, Chen, B, Landi, S, Franke, A, Fischer, A, Ellinghaus, D, Flores, C, Noth, I, Ma, S, Foo, J, Liu, J, Kim, J, Cox, D, Delattre, O, Mirabeau, O, Skibola, C, Tang, C, Garcia-Barcelo, M, Chang, K, Su, W, Chang, Y, Martin, N, Gordon, S, Wade, T, Lee, C, Kubo, M, Cha, P, Nakamura, Y, Levy, D, Kimura, M, Hwang, S, Hunt, S, Spector, T, Soranzo, N, Manichaikul, A, Barr, R, Kahali, B, Speliotes, E, Yerges-Armstrong, L, Cheng, C, Jonas, J, Wong, T, Fogh, I, Lin, K, Powell, J, Rice, K, Relton, C, Martin, R, Davey Smith, G, Erasmus MC other, Epidemiology, and Pediatrics

Subjects
0301 basic medicine, Adult, Male, Cancer Research, Single-nucleotide polymorphism, Genome-wide association study, Disease, Bioinformatics, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, Telomere Homeostasis, SDG 3 - Good Health and Well-being, Neoplasms, Mendelian randomization, Journal Article, medicine, Humans, Genetic Predisposition to Disease, Càncer, Germ-Line Mutation, Aged, Cancer, Aged, 80 and over, business.industry, Nucleotides, Odds ratio, Mendelian Randomization Analysis, Middle Aged, Telomere, medicine.disease, Nucleòtids, 030104 developmental biology, Stem cell division, Oncology, Cardiovascular Diseases, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, ICEP, business, Genome-Wide Association Study, Bristol Population Health Science Institute
Abstract

Importance The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. Data Sources Genomewide association studies (GWAS) published up to January 15, 2015. Study Selection GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. Data Extraction and Synthesis Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. Main Outcomes and Measures Odds ratios (ORs) and 95%confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. Results Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95%CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95%CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95%CI, 0.49-0.81]), celiac disease (OR, 0.42 [95%CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95%CI, 0.05-0.15]). Conclusions and Relevance It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Published
2017

39. Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study

Author

Haycock, P. (Philip), Burgess, S. (Stephen), Nounu, A. (Aayah), Zheng, J. (Jie), Okoli, G.N. (George N.), Bowden, J., Wade, K.H. (Kaitlin Hazel), Timpson, N.J. (Nicholas J.), Evans, D.M. (David M.), Willeit, P. (Peter), Aviv, A. (Abraham), Gaunt, T.R. (Tom), Hemani, G., Mangino, M. (Massimo), Ellis, H.P. (Hayley Patricia), Kurian, K.M. (Kathreena M.), Pooley, K.A. (Karen A.), Eeles, R. (Rosalind), Lee, J.E. (Jeffrey E.), Fang, S. (Shenying), Chen, W.V. (Wei V.), Law, M.H. (Matthew H.), Bowdler, L.M. (Lisa M.), Iles, M.M. (Mark M.), Yang, Q. (Qiong Fang), Worrall, B.B. (Bradford B.), Markus, H.S. (Hugh), Hung, R.J. (Rayjean J.), Amos, W., Spurdle, A.B. (Amanda), Thompson, D. (Deborah), O'Mara, T.A. (Tracy A.), Wolpin, B. (Brian), Amundadottir, L. (Laufey), Stolzenberg-Solomon, R. (Rachael), Trichopoulou, A. (Antonia), Onland-Moret, N.C. (Charlotte), Lund, E. (Eiliv), Duell, E.J. (Eric), Canzian, F. (Federico), Severi, G. (Gianluca), Overvad, K. (Kim), Gunter, M.J. (Marc J.), Tumino, R. (Rosario), Svenson, U. (Ulrika), Rij, A.M. (Andre) van, Baas, A.F. (Annette), Bown, N., Samani, N.J. (Nilesh), Van t'Hof, F.N.G. (Femke N.G.), Tromp, G. (Gerard), Jones, G.T. (Gregory T.), Kuivaniemi, H. (Helena), Elmore, J.R. (James R.), Johansson, M. (Mattias), Mckay, J. (James), Scelo, G. (Ghislaine), Carreras-Torres, R. (Robert), Gaborieau, V. (Valerie), Brennan, P. (Paul), Bracci, P.M. (Paige M.), Neale, R.E. (Rachel E.), Olson, S.H. (Sara H.), Gallinger, S. (Steve), Li, D. (Donghui), Olson, S.H. (Sara), Risch, H. (Harvey), Klein, A.P. (Alison P.), Han, J., Abnet, C.C. (Christian C.), Freedman, N.D. (Neal D.), Taylor, P.R. (Phil R.), Maris, J.M. (John), Aben, K.K.H. (Katja), Kiemeney, L.A.L.M. (Bart), Vermeulen, S.H.H.M. (Sita), Wiencke, J.K. (John K.), Walsh, K.M. (Kyle M.), Wrensch, M. (Margaret), Rice, T. (Terri), Turnbull, C. (Clare), Litchfield, K. (Kevin), Paternoster, L. (Lavinia), Standl, M. (Marie), Abecasis, G.R. (Gonçalo), SanGiovanni, J.P. (John Paul), Li, Y. (Yong), Mijatovic, V. (Vladan), Sapkota, Y. (Yadav), Low, S.-K. (Siew-Kee), Zondervan, K.T. (Krina), Montgomery, G.W. (Grant W.), Nyholt, D.R. (Dale), Heel, D.A. (David) van, Hunt, K. (Karen), Arking, D.E. (Dan), Ashar, F.N. (Foram N.), Sotoodehnia, N. (Nona), Woo, D. (Daniel), Rosand, J. (Jonathan), Comeau, M.E. (Mary E.), Brown, W.M. (W. Mark), Silverman, E. (Edwin), Hokanson, J.E. (John E.), Cho, M.H. (Michael), Hui, J. (Jennie), Ferreira, M.A. (Manuel A.), Thompson, P.J. (Philip J.), Morrison, A.C. (Alanna), Felix, J.F. (Janine F.), Smith, N.L. (Nicholas L.), Christiano, A.M. (Angela), Petukhova, L. (Lynn), Betz, R.C. (Regina), Fan, X. (Xing), Zhang, X. (Xuejun), Zhu, C. (Caihong), Langefeld, C.D. (Carl), Thompson, S.D. (Susan D.), Wang, F. (Feijie), Lin, X. (Xu), Schwartz, D.A. (David A.), Fingerlin, T.E. (Tasha E.), Rotter, J.I. (Jerome I.), Cotch, M.F. (Mary Frances), Jensen, R.A. (Richard A.), Munz, M. (Matthias), Dommisch, H. (Henrik), Schaefer, A. (Antje), Han, F. (Fang), Ollila, H.M., Hillary, R.P. (Ryan P.), Albagha, O.M.E. (Omar M.), Ralston, S.H. (Stuart), Zeng, C. (Chenjie), Zheng, W. (Wei), Shu, X.-O. (Xiao-Ou), Reis, A. (André), Uebe, S. (Steffen), Hüffmeier, U. (Ulrike), Kawamura, Y. (Yoshiya), Otowa, T. (Takeshi), Sasaki, T. (Tsukasa), Hibberd, M.L. (Martin), Davila, S. (Sonia), Xie, G. (Gang), Siminovitch, K.A. (Katherine), Bei, J.-X. (Jin-Xin), Zeng, Y.X., Försti, A. (Asta), Chen, B. (Bowang), Landi, S. (Stefano), Franke, A. (Andre), Fischer, A. (Annegret), Ellinghaus, D. (David), Flores, C. (Carlos), Noth, I. (Imre), Ma, S.-F. (Shwu-Fan), Foo, J.-N. (Jia-Nee), Liu, J. (Jianjun), Kim, J.-W. (Jong-Won), Cox, D.G. (David), Delattre, O. (Olivier), Mirabeau, O. (Olivier), Skibola, C.F. (Christine F.), Tang, C.S. (Clara S.), Garcia-Barcelo, M., Chang, K.-P. (Kai-Ping), Su, W.-H. (Wen-Hui), Chang, Y.-S. (Yu-Sun), Martin, N.G. (Nicholas G.), Gordon, S.D. (Scott D.), Wade, T.D. (Tracey D.), Lee, C. (Chaeyoung), Kubo, M. (Michiaki), Cha, P.-C. (Pei-Chieng), Nakamura, Y. (Yusuke), Levy, D. (Daniel), Kimura, M. (Masayuki), Hwang, S.-J. (Shih-Jen), Hunt, S.C. (Steven), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Manichaikul, A.W. (Ani W.), Barr, R.G. (Graham), Kahali, B. (Bratati), Speliotes, E.K. (Elizabeth), Yerges-Armstrong, L.M. (Laura), Cheng, C-Y. (Ching-Yu), Jonas, J.B. (Jost B.), Wong, T.Y. (Tien Yin), Fogh, I. (Isabella), Lin, K. (Kuang), Powell, J. (John), Rice, K. (Kenneth), Relton, C.L. (Caroline), Martin, R.M. (Richard M.), Smith, A.V. (Davey), Haycock, P. (Philip), Burgess, S. (Stephen), Nounu, A. (Aayah), Zheng, J. (Jie), Okoli, G.N. (George N.), Bowden, J., Wade, K.H. (Kaitlin Hazel), Timpson, N.J. (Nicholas J.), Evans, D.M. (David M.), Willeit, P. (Peter), Aviv, A. (Abraham), Gaunt, T.R. (Tom), Hemani, G., Mangino, M. (Massimo), Ellis, H.P. (Hayley Patricia), Kurian, K.M. (Kathreena M.), Pooley, K.A. (Karen A.), Eeles, R. (Rosalind), Lee, J.E. (Jeffrey E.), Fang, S. (Shenying), Chen, W.V. (Wei V.), Law, M.H. (Matthew H.), Bowdler, L.M. (Lisa M.), Iles, M.M. (Mark M.), Yang, Q. (Qiong Fang), Worrall, B.B. (Bradford B.), Markus, H.S. (Hugh), Hung, R.J. (Rayjean J.), Amos, W., Spurdle, A.B. (Amanda), Thompson, D. (Deborah), O'Mara, T.A. (Tracy A.), Wolpin, B. (Brian), Amundadottir, L. (Laufey), Stolzenberg-Solomon, R. (Rachael), Trichopoulou, A. (Antonia), Onland-Moret, N.C. (Charlotte), Lund, E. (Eiliv), Duell, E.J. (Eric), Canzian, F. (Federico), Severi, G. (Gianluca), Overvad, K. (Kim), Gunter, M.J. (Marc J.), Tumino, R. (Rosario), Svenson, U. (Ulrika), Rij, A.M. (Andre) van, Baas, A.F. (Annette), Bown, N., Samani, N.J. (Nilesh), Van t'Hof, F.N.G. (Femke N.G.), Tromp, G. (Gerard), Jones, G.T. (Gregory T.), Kuivaniemi, H. (Helena), Elmore, J.R. (James R.), Johansson, M. (Mattias), Mckay, J. (James), Scelo, G. (Ghislaine), Carreras-Torres, R. (Robert), Gaborieau, V. (Valerie), Brennan, P. (Paul), Bracci, P.M. (Paige M.), Neale, R.E. (Rachel E.), Olson, S.H. (Sara H.), Gallinger, S. (Steve), Li, D. (Donghui), Olson, S.H. (Sara), Risch, H. (Harvey), Klein, A.P. (Alison P.), Han, J., Abnet, C.C. (Christian C.), Freedman, N.D. (Neal D.), Taylor, P.R. (Phil R.), Maris, J.M. (John), Aben, K.K.H. (Katja), Kiemeney, L.A.L.M. (Bart), Vermeulen, S.H.H.M. (Sita), Wiencke, J.K. (John K.), Walsh, K.M. (Kyle M.), Wrensch, M. (Margaret), Rice, T. (Terri), Turnbull, C. (Clare), Litchfield, K. (Kevin), Paternoster, L. (Lavinia), Standl, M. (Marie), Abecasis, G.R. (Gonçalo), SanGiovanni, J.P. (John Paul), Li, Y. (Yong), Mijatovic, V. (Vladan), Sapkota, Y. (Yadav), Low, S.-K. (Siew-Kee), Zondervan, K.T. (Krina), Montgomery, G.W. (Grant W.), Nyholt, D.R. (Dale), Heel, D.A. (David) van, Hunt, K. (Karen), Arking, D.E. (Dan), Ashar, F.N. (Foram N.), Sotoodehnia, N. (Nona), Woo, D. (Daniel), Rosand, J. (Jonathan), Comeau, M.E. (Mary E.), Brown, W.M. (W. Mark), Silverman, E. (Edwin), Hokanson, J.E. (John E.), Cho, M.H. (Michael), Hui, J. (Jennie), Ferreira, M.A. (Manuel A.), Thompson, P.J. (Philip J.), Morrison, A.C. (Alanna), Felix, J.F. (Janine F.), Smith, N.L. (Nicholas L.), Christiano, A.M. (Angela), Petukhova, L. (Lynn), Betz, R.C. (Regina), Fan, X. (Xing), Zhang, X. (Xuejun), Zhu, C. (Caihong), Langefeld, C.D. (Carl), Thompson, S.D. (Susan D.), Wang, F. (Feijie), Lin, X. (Xu), Schwartz, D.A. (David A.), Fingerlin, T.E. (Tasha E.), Rotter, J.I. (Jerome I.), Cotch, M.F. (Mary Frances), Jensen, R.A. (Richard A.), Munz, M. (Matthias), Dommisch, H. (Henrik), Schaefer, A. (Antje), Han, F. (Fang), Ollila, H.M., Hillary, R.P. (Ryan P.), Albagha, O.M.E. (Omar M.), Ralston, S.H. (Stuart), Zeng, C. (Chenjie), Zheng, W. (Wei), Shu, X.-O. (Xiao-Ou), Reis, A. (André), Uebe, S. (Steffen), Hüffmeier, U. (Ulrike), Kawamura, Y. (Yoshiya), Otowa, T. (Takeshi), Sasaki, T. (Tsukasa), Hibberd, M.L. (Martin), Davila, S. (Sonia), Xie, G. (Gang), Siminovitch, K.A. (Katherine), Bei, J.-X. (Jin-Xin), Zeng, Y.X., Försti, A. (Asta), Chen, B. (Bowang), Landi, S. (Stefano), Franke, A. (Andre), Fischer, A. (Annegret), Ellinghaus, D. (David), Flores, C. (Carlos), Noth, I. (Imre), Ma, S.-F. (Shwu-Fan), Foo, J.-N. (Jia-Nee), Liu, J. (Jianjun), Kim, J.-W. (Jong-Won), Cox, D.G. (David), Delattre, O. (Olivier), Mirabeau, O. (Olivier), Skibola, C.F. (Christine F.), Tang, C.S. (Clara S.), Garcia-Barcelo, M., Chang, K.-P. (Kai-Ping), Su, W.-H. (Wen-Hui), Chang, Y.-S. (Yu-Sun), Martin, N.G. (Nicholas G.), Gordon, S.D. (Scott D.), Wade, T.D. (Tracey D.), Lee, C. (Chaeyoung), Kubo, M. (Michiaki), Cha, P.-C. (Pei-Chieng), Nakamura, Y. (Yusuke), Levy, D. (Daniel), Kimura, M. (Masayuki), Hwang, S.-J. (Shih-Jen), Hunt, S.C. (Steven), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Manichaikul, A.W. (Ani W.), Barr, R.G. (Graham), Kahali, B. (Bratati), Speliotes, E.K. (Elizabeth), Yerges-Armstrong, L.M. (Laura), Cheng, C-Y. (Ching-Yu), Jonas, J.B. (Jost B.), Wong, T.Y. (Tien Yin), Fogh, I. (Isabella), Lin, K. (Kuang), Powell, J. (John), Rice, K. (Kenneth), Relton, C.L. (Caroline), Martin, R.M. (Richard M.), and Smith, A.V. (Davey)

Abstract

IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer ca

Published
2017
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40. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study

Author

Haycock, PC, Burgess, S, Nounu, A, Zheng, J, Okoli, GN, Bowden, J, Wade, KH, Timpson, NJ, Evans, DM, Willeit, P, Aviv, A, Gaunt, T, Hemani, G, Mangino, M, Ellis, HP, Kurian, KM, Pooley, KA, Eeles, RA, Lee, JE, Fang, SY, Chen, WV, Law, MH, Bowdler, LM, Iles, MM, Yang, Q, Worrall, BB, Markus, HS, Hung, RJ, Amos, CI, Spurdle, AB, Thompson, DJ, O'Mara, TA, Wolpin, B, Amundadottir, L, Stolzenberg-Solomon, R, Trichopoulou, A, Onland-Moret, C, Lund, E, Duell, EJ, Canzian, F, Severi, G, Overvad, K, Gunter, MJ, Tumino, R, Svenson, U, van Rij, A, Baas, AF, Bown, MJ, Samani, NJ, van t'Hof, FNG, Tromp, G, Jones, GT, Kuivaniemi, H, Elmore, JR, Johansson, M, Mckay, J, Scelo, G, Carreras-Torres, R, Gaborieau, V, Brennan, P, Bracci, PM, Neale, RE, Olson, SH, Gallinger, S, Li, DH, Petersen, GM, Risch, HA, Klein, AP, Han, JL, Abnet, CC, Freedman, N D, Taylor, PR, Maris, JM, Aben, KK, Kiemeney, LA, Vermeulen, SH, Wiencke, JK, Walsh, KM, Wrensch, M, Rice, T, Turnbull, C, Litchfield, K, Paternoster, L, Standl, M, Abecasis, GR, SanGiovanni, JP, Li, Y, Mijatovic, V, Sapkota, Y, Low, SK, Zondervan, KT, Montgomery, GW, Nyholt, DR, van Heel, D A, Hunt, K, Arking, DE, Ashar, FN, Sotoodehnia, N, Woo, D, Rosand, J, Comeau, ME, Brown, W M, Silverman, EK, Hokanson, JE, Cho, MH, Hui, J, Ferreira, MA, Thompson, PJ, Morrison, AC, Felix, Janine, Smith, NL, Christiano, AM, Petukhova, L, Betz, RC, Fan, X, Zhang, XJ, Zhu, CH, Langefeld, CD, Thompson, SD, Wang, FJ, Lin, X, Schwartz, DA, Fingerlin, T, Rotter, JI, Cotch, MF, Jensen, RA, Munz, M, Dommisch, H, Schaefer, AS, Han, F, Ollila, HM, Hillary, RP, Albagha, O, Ralston, SH, Zeng, CJ, Zheng, W, Shu, XO, Reis, A, Uebe, S, Huffmeier, U, Kawamura, Y, Otowa, T, Sasaki, T, Hibberd, ML, Davila, S, Xie, G, Siminovitch, K, Bei, JX, Zeng, YX, Forsti, A, Chen, B (Bowang), Landi, S, Franke, A, Fischer, A, Ellinghaus, D, Flores, C, Noth, I, Ma, SF, Foo, JN, Liu, JJ, Kim, JW, Cox, DG, Delattre, O, Mirabeau, O, Skibola, CF, Tang, CS, Garcia-Barcelo, M, Chang, KP, Su, WH, Chang, YS, Martin, NG, Gordon, S, Wade, TD, Lee, C, Kubo, M, Cha, PC, Nakamura, Y, Levy, D, Kimura, M, Hwang, SJ, Hunt, S, Spector, T, Soranzo, N, Manichaikul, A, Barr, G, Kahali, B, Speliotes, E, Yerges-Armstrong, L, Cheng, CY (Ching-Yu), Jonas, JB, Wong, TY, Fogh, I, Lin, K, Powell, JF, Rice, K, Relton, CL, Martin, RM, Smith, GD, Haycock, PC, Burgess, S, Nounu, A, Zheng, J, Okoli, GN, Bowden, J, Wade, KH, Timpson, NJ, Evans, DM, Willeit, P, Aviv, A, Gaunt, T, Hemani, G, Mangino, M, Ellis, HP, Kurian, KM, Pooley, KA, Eeles, RA, Lee, JE, Fang, SY, Chen, WV, Law, MH, Bowdler, LM, Iles, MM, Yang, Q, Worrall, BB, Markus, HS, Hung, RJ, Amos, CI, Spurdle, AB, Thompson, DJ, O'Mara, TA, Wolpin, B, Amundadottir, L, Stolzenberg-Solomon, R, Trichopoulou, A, Onland-Moret, C, Lund, E, Duell, EJ, Canzian, F, Severi, G, Overvad, K, Gunter, MJ, Tumino, R, Svenson, U, van Rij, A, Baas, AF, Bown, MJ, Samani, NJ, van t'Hof, FNG, Tromp, G, Jones, GT, Kuivaniemi, H, Elmore, JR, Johansson, M, Mckay, J, Scelo, G, Carreras-Torres, R, Gaborieau, V, Brennan, P, Bracci, PM, Neale, RE, Olson, SH, Gallinger, S, Li, DH, Petersen, GM, Risch, HA, Klein, AP, Han, JL, Abnet, CC, Freedman, N D, Taylor, PR, Maris, JM, Aben, KK, Kiemeney, LA, Vermeulen, SH, Wiencke, JK, Walsh, KM, Wrensch, M, Rice, T, Turnbull, C, Litchfield, K, Paternoster, L, Standl, M, Abecasis, GR, SanGiovanni, JP, Li, Y, Mijatovic, V, Sapkota, Y, Low, SK, Zondervan, KT, Montgomery, GW, Nyholt, DR, van Heel, D A, Hunt, K, Arking, DE, Ashar, FN, Sotoodehnia, N, Woo, D, Rosand, J, Comeau, ME, Brown, W M, Silverman, EK, Hokanson, JE, Cho, MH, Hui, J, Ferreira, MA, Thompson, PJ, Morrison, AC, Felix, Janine, Smith, NL, Christiano, AM, Petukhova, L, Betz, RC, Fan, X, Zhang, XJ, Zhu, CH, Langefeld, CD, Thompson, SD, Wang, FJ, Lin, X, Schwartz, DA, Fingerlin, T, Rotter, JI, Cotch, MF, Jensen, RA, Munz, M, Dommisch, H, Schaefer, AS, Han, F, Ollila, HM, Hillary, RP, Albagha, O, Ralston, SH, Zeng, CJ, Zheng, W, Shu, XO, Reis, A, Uebe, S, Huffmeier, U, Kawamura, Y, Otowa, T, Sasaki, T, Hibberd, ML, Davila, S, Xie, G, Siminovitch, K, Bei, JX, Zeng, YX, Forsti, A, Chen, B (Bowang), Landi, S, Franke, A, Fischer, A, Ellinghaus, D, Flores, C, Noth, I, Ma, SF, Foo, JN, Liu, JJ, Kim, JW, Cox, DG, Delattre, O, Mirabeau, O, Skibola, CF, Tang, CS, Garcia-Barcelo, M, Chang, KP, Su, WH, Chang, YS, Martin, NG, Gordon, S, Wade, TD, Lee, C, Kubo, M, Cha, PC, Nakamura, Y, Levy, D, Kimura, M, Hwang, SJ, Hunt, S, Spector, T, Soranzo, N, Manichaikul, A, Barr, G, Kahali, B, Speliotes, E, Yerges-Armstrong, L, Cheng, CY (Ching-Yu), Jonas, JB, Wong, TY, Fogh, I, Lin, K, Powell, JF, Rice, K, Relton, CL, Martin, RM, and Smith, GD

Published
2017

41. Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies

Author

Martinon-Torres, F, Png, E, Khor, CC, Davila, S, Wright, VJ, Sim, KS, Vega, A, Fachal, L, Inwald, D, Nadel, S, Carrol, ED, Martinon-Torres, N, Marcos Alonso, S, Carracedo, A, Morteruel, E, Lopez-Bayon, J, Concha Torre, A, Calvo Monge, C, Gonzalez de Aguilar, PA, Esteban Torne, E, del Carmen Martinez-Padilla, M, Maria Martinon-Sanchez, J, Levin, M, Hibberd, ML, Salas, A, Martinon-Torres, F, Png, E, Khor, CC, Davila, S, Wright, VJ, Sim, KS, Vega, A, Fachal, L, Inwald, D, Nadel, S, Carrol, ED, Martinon-Torres, N, Marcos Alonso, S, Carracedo, A, Morteruel, E, Lopez-Bayon, J, Concha Torre, A, Calvo Monge, C, Gonzalez de Aguilar, PA, Esteban Torne, E, del Carmen Martinez-Padilla, M, Maria Martinon-Sanchez, J, Levin, M, Hibberd, ML, and Salas, A

Abstract

Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association (P-value ≤ 5 × 10-8) in 20 variants located at the CFH gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR) = 0.62, 95% confidence interval (C.I.) = 0.52-0.73; P-value = 9.62 × 10-9). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR = 0.64, 95% C.I.) = 0.55-0.76, P-value = 3.25 × 10-8). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.

Published
2016

44. New loci and coding variants confer risk for age-related macular degeneration in East Asians.

Author

Cheng, C-Y, Yamashiro, K, Chen, LJ, Ahn, J, Huang, L, Cheung, CMG, Miyake, M, Cackett, PD, Yeo, IY, Laude, A, Mathur, R, Pang, J, Sim, KS, Koh, AH, Chen, P, Lee, SY, Wong, D, Chan, CM, Loh, BK, Sun, Y, Davila, S, Nakata, I, Nakanishi, H, Akagi-Kurashige, Y, Gotoh, N, Tsujikawa, A, Matsuda, F, Mori, K, Yoneya, S, Sakurada, Y, Iijima, H, Iida, T, Honda, S, Lai, TYY, Tam, POS, Chen, H, Tang, S, Ding, X, Wen, F, Lu, F, Zhang, X, Shi, Y, Zhao, P, Zhao, B, Sang, J, Gong, B, Dorajoo, R, Yuan, J-M, Koh, W-P, van Dam, RM, Friedlander, Y, Lin, Y, Hibberd, ML, Foo, JN, Wang, N, Wong, CH, Tan, GS, Park, SJ, Bhargava, M, Gopal, L, Naing, T, Liao, J, Ong, PG, Mitchell, P, Zhou, P, Xie, X, Liang, J, Mei, J, Jin, X, Saw, S-M, Ozaki, M, Mizoguchi, T, Kurimoto, Y, Woo, SJ, Chung, H, Yu, H-G, Shin, JY, Park, DH, Kim, IT, Chang, W, Sagong, M, Lee, S-J, Kim, HW, Lee, JE, Li, Y, Liu, J, Teo, YY, Heng, CK, Lim, TH, Yang, S-K, Song, K, Vithana, EN, Aung, T, Bei, JX, Zeng, YX, Tai, ES, Li, XX, Yang, Z, Park, K-H, Pang, CP, Yoshimura, N, Wong, TY, Khor, CC, Cheng, C-Y, Yamashiro, K, Chen, LJ, Ahn, J, Huang, L, Cheung, CMG, Miyake, M, Cackett, PD, Yeo, IY, Laude, A, Mathur, R, Pang, J, Sim, KS, Koh, AH, Chen, P, Lee, SY, Wong, D, Chan, CM, Loh, BK, Sun, Y, Davila, S, Nakata, I, Nakanishi, H, Akagi-Kurashige, Y, Gotoh, N, Tsujikawa, A, Matsuda, F, Mori, K, Yoneya, S, Sakurada, Y, Iijima, H, Iida, T, Honda, S, Lai, TYY, Tam, POS, Chen, H, Tang, S, Ding, X, Wen, F, Lu, F, Zhang, X, Shi, Y, Zhao, P, Zhao, B, Sang, J, Gong, B, Dorajoo, R, Yuan, J-M, Koh, W-P, van Dam, RM, Friedlander, Y, Lin, Y, Hibberd, ML, Foo, JN, Wang, N, Wong, CH, Tan, GS, Park, SJ, Bhargava, M, Gopal, L, Naing, T, Liao, J, Ong, PG, Mitchell, P, Zhou, P, Xie, X, Liang, J, Mei, J, Jin, X, Saw, S-M, Ozaki, M, Mizoguchi, T, Kurimoto, Y, Woo, SJ, Chung, H, Yu, H-G, Shin, JY, Park, DH, Kim, IT, Chang, W, Sagong, M, Lee, S-J, Kim, HW, Lee, JE, Li, Y, Liu, J, Teo, YY, Heng, CK, Lim, TH, Yang, S-K, Song, K, Vithana, EN, Aung, T, Bei, JX, Zeng, YX, Tai, ES, Li, XX, Yang, Z, Park, K-H, Pang, CP, Yoshimura, N, Wong, TY, and Khor, CC

Abstract

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10(-22)). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l(-1) (P=5.82 × 10(-21)) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10(-18)), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10(-11)) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10(-8)). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.

Published
2015

45. Application of infrared thermography during bone healing

Author

Haluzan, D., Dobric, I., Stipic, J., Ehrenfreund, T., Goran Augustin, Davila, S., Božek, Jelena, and Grgić, Mislav

Subjects
Bone healing, Thermography, Temperature changes
Abstract

Introduction: Infrared thermography is a diagnostic method that could be used in follow up of patients with bone fractures. Studies on the application of thermography in traumatology are extremely scarce. The authors have tried to determine whether infrared thermography could be a diagnostic tool for different stages of bone healing progress. The basic principle is that because of metabolism increase and increase in blood flow around the fracture the temperature of surrounding tissue is increasing. Material and methods: The authors have examined 10 patients of mean age 67.3±8.0 (range=54-78) with fractures of distal radius in typical place. For all measurements Flir ThermaCam B2 (FLIR Systems, Inc., Oregon, USA) was used. We performed thermographic recording on the 7th day after fracture, 21st day after fracture, after the treatment with conservative immobilization had finished approximately 6 weeks after fracture. We used the other healthy hand as comparison. Results: According to our preliminary findings on 10 patients we have found statistically significant temperature changes during different stages of bone healing. We found about 1.3°C temperature difference between fractured and healthy hand. Conclusion: During this research statistically significant temperature changes have been found. Infrared thermography could be a used as a good follow up method in traumatology but further investigations are needed on more patients and a longer time period.

Published
2012

46. cnvCapSeq: detecting copy number variation in long-range targeted resequencing data

Author

Bellos, E, Kumar, V, Lin, C, Maggi, J, Phua, ZY, Cheng, C-Y, Cheung, CMG, Hibberd, ML, Wong, TY, Coin, LJM, Davila, S, Bellos, E, Kumar, V, Lin, C, Maggi, J, Phua, ZY, Cheng, C-Y, Cheung, CMG, Hibberd, ML, Wong, TY, Coin, LJM, and Davila, S

Abstract

Targeted resequencing technologies have allowed for efficient and cost-effective detection of genomic variants in specific regions of interest. Although capture sequencing has been primarily used for investigating single nucleotide variants and indels, it has the potential to elucidate a broader spectrum of genetic variation, including copy number variants (CNVs). Various methods exist for detecting CNV in whole-genome and exome sequencing datasets. However, no algorithms have been specifically designed for contiguous target sequencing, despite its increasing importance in clinical and research applications. We have developed cnvCapSeq, a novel method for accurate and sensitive CNV discovery and genotyping in long-range targeted resequencing. cnvCapSeq was benchmarked using a simulated contiguous capture sequencing dataset comprising 21 genomic loci of various lengths. cnvCapSeq was shown to outperform the best existing exome CNV method by a wide margin both in terms of sensitivity (92.0 versus 48.3%) and specificity (99.8 versus 70.5%). We also applied cnvCapSeq to a real capture sequencing cohort comprising a contiguous 358 kb region that contains the Complement Factor H gene cluster. In this dataset, cnvCapSeq identified 41 samples with CNV, including two with duplications, with a genotyping accuracy of 99%, as ascertained by quantitative real-time PCR.

Published
2014

47. NOVELTY OF PERIOSTAL CIRCULATION

Author

Antabak A, Bekić M, Augustin G, Crkvenac A, Davila S, Seiwhert S

Subjects
PERIOSTAL CIRCULATION, fracture
Abstract

radi se o originalnoj doktorskoj dizertaciji. Ispituje se cirkulacija periosta nakon prijelom i primjene različite vrste osteosintetske pločice. Zaključak rada je da originalna autorska pločica najmanje oštećuje perisotalnu cirkulaciju.

Published
2006

49. Replication and Meta-Analysis of GWAS Identified Susceptibility Loci in Kawasaki Disease Confirm the Importance of B Lymphoid Tyrosine Kinase (BLK) in Disease Susceptibility

Author

Huang, L-M, Chang, C-J, Kuo, H-C, Chang, J-S, Lee, J-K, Tsai, F-J, Khor, CC, Chang, L-C, Chen, S-P, Ko, T-M, Liu, Y-M, Chen, Y-J, Hong, YM, Jang, GY, Hibberd, ML, Kuijpers, T, Burgner, D, Levin, M, Burns, JC, Davila, S, Chen, Y-T, Chen, C-H, Wu, J-Y, Lee, Y-C, Huang, L-M, Chang, C-J, Kuo, H-C, Chang, J-S, Lee, J-K, Tsai, F-J, Khor, CC, Chang, L-C, Chen, S-P, Ko, T-M, Liu, Y-M, Chen, Y-J, Hong, YM, Jang, GY, Hibberd, ML, Kuijpers, T, Burgner, D, Levin, M, Burns, JC, Davila, S, Chen, Y-T, Chen, C-H, Wu, J-Y, and Lee, Y-C

Abstract

The BLK and CD40 loci have been associated with Kawasaki disease (KD) in two genome-wide association studies (GWAS) conducted in a Taiwanese population of Han Chinese ancestry (Taiwanese) and in Japanese cohorts. Here we build on these findings with replication studies of the BLK and CD40 loci in populations of Korean and European descent. The BLK region was significantly associated with KD susceptibility in both populations. Within the BLK gene the rs2736340-located linkage disequilibrium (LD ) comprising the promoter and first intron was strongly associated with KD, with the combined results of Asian studies including Taiwanese, Japanese, and Korean populations (2,539 KD patients and 7,021 controls) providing very compelling evidence of association (rs2736340, OR = 1.498, 1.354-1.657; P = 4.74×10(-31)). We determined the percentage of B cells present in the peripheral blood mononuclear cell (PBMC) population and the expression of BLK in the peripheral blood leukocytes (leukocytes) of KD patients during the acute and convalescent stages. The percentage of B cells in the PBMC population and the expression of BLK in leukocytes were induced in patients in the acute stage of KD. In B cell lines derived from KD patients, and in purified B cells from KD patients obtained during the acute stage, those with the risk allele of rs2736340 expressed significantly lower levels of BLK. These results suggest that peripheral B cells play a pathogenic role during the acute stage of KD. Decreased BLK expression in peripheral blood B cells may alter B cell function and predispose individuals to KD. These associative data suggest a role for B cells during acute KD. Understanding the functional implications may facilitate the development of B cell-mediated therapy for KD.

Published
2013

50. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

Author

Eyre, S, Bowes, J, Diogo, D, Lee, A, Barton, A, Martin, P, Zhernakova, A, Stahl, E, Viatte, S, McAllister, K, Amos, CI, Padyukov, L, Toes, REM, Huizinga, TWJ, Wijmenga, C, Trynka, G, Franke, L, Westra, H-J, Alfredsson, L, Hu, X, Sandor, C, de Bakker, PIW, Davila, S, Khor, CC, Heng, KK, Andrews, R, Edkins, S, Hunt, SE, Langford, C, Symmons, D, Concannon, P, Onengut-Gumuscu, S, Rich, SS, Deloukas, P, Gonzalez-Gay, MA, Rodriguez-Rodriguez, L, Arlsetig, L, Martin, J, Rantapaa-Dahlqvist, S, Plenge, RM, Raychaudhuri, S, Klareskog, L, Gregersen, PK, Worthington, J, Eyre, S, Bowes, J, Diogo, D, Lee, A, Barton, A, Martin, P, Zhernakova, A, Stahl, E, Viatte, S, McAllister, K, Amos, CI, Padyukov, L, Toes, REM, Huizinga, TWJ, Wijmenga, C, Trynka, G, Franke, L, Westra, H-J, Alfredsson, L, Hu, X, Sandor, C, de Bakker, PIW, Davila, S, Khor, CC, Heng, KK, Andrews, R, Edkins, S, Hunt, SE, Langford, C, Symmons, D, Concannon, P, Onengut-Gumuscu, S, Rich, SS, Deloukas, P, Gonzalez-Gay, MA, Rodriguez-Rodriguez, L, Arlsetig, L, Martin, J, Rantapaa-Dahlqvist, S, Plenge, RM, Raychaudhuri, S, Klareskog, L, Gregersen, PK, and Worthington, J

Abstract

Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

Published
2012

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