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17 results on '"Vysochinskaya, Vera"'

2. Stable Polymer-Lipid Hybrid Nanoparticles Based on mcl -Polyhydroxyalkanoate and Cationic Liposomes for mRNA Delivery.

Author

Shishlyannikov, Sergey M., Zubkov, Ilya N., Vysochinskaya, Vera V., Gavrilova, Nina V., Dobrovolskaya, Olga A., Elpaeva, Ekaterina A., Maslov, Mikhail A., and Vasin, Andrey

Subjects
BIOPOLYMERS, CATIONIC lipids, ELECTRON microscope techniques, GREEN fluorescent protein, NUCLEIC acids, CATIONIC polymers
Abstract

Background/Objectives: The development of polymer–lipid hybrid nanoparticles (PLNs) is a promising area of research, as it can help increase the stability of cationic lipid carriers. Hybrid PLNs are core–shell nanoparticle structures that combine the advantages of both polymer nanoparticles and liposomes, especially in terms of their physical stability and biocompatibility. Natural polymers such as polyhydroxyalkanoate (PHA) can be used as a matrix for the PLNs' preparation. Methods: In this study, we first obtained stable cationic hybrid PLNs using a cationic liposome (CL) composed of a polycationic lipid 2X3 (1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosane tetrahydrochloride), helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), and the hydrophobic polymer mcl-PHA, which was produced by the soil bacterium Pseudomonas helmantisensis P1. Results: The new polymer-lipid carriers effectively encapsulated and delivered model mRNA-eGFP (enhanced green fluorescent protein mRNA) to BHK-21 cells. We then evaluated the role of mcl-PHA in increasing the stability of cationic PLNs in ionic solutions using dynamic light scattering data, electrophoretic mobility, and transmission electron microscopy techniques. Conclusions: The results showed that increasing the concentration of PBS (phosphate buffered saline) led to a decrease in the stability of the CLs. At high concentrations of PBS, the CLs aggregate. In contrast, the presence of isotonic PBS did not result in the aggregation of PLNs, and the particles remained stable for 120 h when stored at +4 °C. The obtained results show that PLNs hold promise for further in vivo studies on nucleic acid delivery. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Advancements and Future Prospects in Molecular Targeted and siRNA Therapies for Chronic Myeloid Leukemia.

Author

Vysochinskaya, Vera, Dovbysh, Olesya, Gorshkov, Andrey, Brodskaia, Alexandra, Dubina, Michael, Vasin, Andrey, and Zabrodskaya, Yana

Subjects
*CHRONIC myeloid leukemia, *RNA interference, *SMALL interfering RNA, *MYELOPROLIFERATIVE neoplasms, *PROTEIN-tyrosine kinase inhibitors
Abstract

Chronic myeloid leukemia (CML) is an oncological myeloproliferative disorder that accounts for 15 to 20% of all adult leukemia cases. The molecular basis of this disease lies in the formation of a chimeric oncogene BCR–ABL1. The protein product of this gene, p210 BCR–ABL1, exhibits abnormally high constitutive tyrosine kinase activity. Over recent decades, several targeted tyrosine kinase inhibitors (TKIs) directed against BCR–ABL1 have been developed and introduced into clinical practice. These inhibitors suppress BCR–ABL1 activity through various mechanisms. Furthermore, the advent of RNA interference technology has enabled the highly specific inhibition of BCR–ABL1 transcript expression using small interfering RNA (siRNA). This experimental evidence opens avenues for the development of a novel therapeutic strategy for CML, termed siRNA therapy. The review delves into molecular genetic mechanisms underlying the pathogenesis of CML, challenges in CML therapy, potential molecular targets for drug development, and the latest results from the application of siRNAs in in vitro and in vivo CML models. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Cell-penetrating peptide and cationic liposomes mediated siRNA delivery to arrest growth of chronic myeloid leukemia cells in vitro

Author

Vysochinskaya, Vera, primary, Zabrodskaya, Yana, additional, Dovbysh, Olesya, additional, Emelyanov, Anton, additional, Klimenko, Vladimir, additional, Knyazev, Nikolay, additional, Terterov, Ivan, additional, Egorova, Marya, additional, Bogdanov, Alexey, additional, Maslov, Michael, additional, Vasin, Andrey, additional, and Dubina, Michael, additional

Published
2023
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5. Influence of Lipid Composition of Cationic Liposomes 2X3-DOPE on mRNA Delivery into Eukaryotic Cells

Author

Vysochinskaya, Vera, primary, Shishlyannikov, Sergey, additional, Zabrodskaya, Yana, additional, Shmendel, Elena, additional, Klotchenko, Sergey, additional, Dobrovolskaya, Olga, additional, Gavrilova, Nina, additional, Makarova, Darya, additional, Plotnikova, Marina, additional, Elpaeva, Ekaterina, additional, Gorshkov, Andrey, additional, Moshkoff, Dmitry, additional, Maslov, Mikhail, additional, and Vasin, Andrey, additional

Published
2022
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7. Exosomes Released by Influenza-Virus-Infected Cells Carry Factors Capable of Suppressing Immune Defense Genes in Naïve Cells

Author

Zabrodskaya, Yana, primary, Plotnikova, Marina, additional, Gavrilova, Nina, additional, Lozhkov, Alexey, additional, Klotchenko, Sergey, additional, Kiselev, Artem, additional, Burdakov, Vladimir, additional, Ramsay, Edward, additional, Purvinsh, Lada, additional, Egorova, Marja, additional, Vysochinskaya, Vera, additional, Baranovskaya, Irina, additional, Brodskaya, Alexandra, additional, Povalikhin, Roman, additional, and Vasin, Andrey, additional

Published
2022
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8. Influence of Lipid Composition of Cationic Liposomes 2X3-DOPE on mRNA Delivery into Eukaryotic Cells.

Author

Vysochinskaya, Vera, Shishlyannikov, Sergey, Zabrodskaya, Yana, Shmendel, Elena, Klotchenko, Sergey, Dobrovolskaya, Olga, Gavrilova, Nina, Makarova, Darya, Plotnikova, Marina, Elpaeva, Ekaterina, Gorshkov, Andrey, Moshkoff, Dmitry, Maslov, Mikhail, and Vasin, Andrey

Subjects
*CATIONIC lipids, *EUKARYOTIC cells, *MESSENGER RNA, *GENE transfection, *LIPIDS, *LIPOSOMES
Abstract

The design of cationic liposomes for efficient mRNA delivery can significantly improve mRNA-based therapies. Lipoplexes based on polycationic lipid 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosane tetrahydrochloride (2X3) and helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) were formulated in different molar ratios (1:1, 1:2, 1:3) to efficiently deliver model mRNAs to BHK-21 and A549. The objective of this study was to examine the effect of 2X3-DOPE composition as well as lipid-to-mRNA ratio (amino-to-phosphate group ratio, N/P) on mRNA transfection. We found that lipoplex-mediated transfection efficiency depends on both liposome composition and the N/P ratio. Lipoplexes with an N/P ratio of 10/1 showed nanometric hydrodynamic size, positive ζ potential, maximum loading, and transfection efficiency. Liposomes 2X3-DOPE (1:3) provided the superior delivery of both mRNA coding firefly luciferase and mRNA-eGFP into BHK-21 cells and A549 cells, compared with commercial Lipofectamine MessengerMax. [ABSTRACT FROM AUTHOR]

Published
2023
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9. Crystal structures of a llama VHH antibody BCD090-M2 targeting human ErbB3 receptor

Author

Eliseev, Igor E., primary, Yudenko, Anna N., additional, Vysochinskaya, Vera V., additional, Svirina, Anna A., additional, Evstratyeva, Anna V., additional, Drozhzhachih, Maria S., additional, Krendeleva, Elena A., additional, Vladimirova, Anna K., additional, Nemankin, Timofey A., additional, Ekimova, Viktoria M., additional, Ulitin, Andrey B., additional, Lomovskaya, Maria I., additional, Yakovlev, Pavel A., additional, Bukatin, Anton S., additional, Knyazev, Nickolay A., additional, Moiseenko, Fedor V., additional, and Chakchir, Oleg B., additional

Published
2018
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10. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Author

Aung, Tin, Ozaki, Mineo, Lee, Mei Chin, Schlotzer-Schrehardt, Ursula, Thorleifsson, Gudmar, Mizoguchi, Takanori, Igo, Robert P., Jr., Haripriya, Aravind, Williams, Susan E., Astakhov, Yury S., Orr, Andrew C., Burdon, Kathryn P., Nakano, Satoko, Mori, Kazuhiko, Abu-Amero, Khaled, Hauser, Michael, Li, Zheng, Prakadeeswari, Gopalakrishnan, Bailey, Jessica N. Cooke, Cherecheanu, Alina Popa, Kang, Jae H., Nelson, Sarah, Hayashi, Ken, Manabe, Shin-ichi, Kazama, Shigeyasu, Zarnowski, Tomasz, Inoue, Kenji, Irkec, Murat, Coca-Prados, Miguel, Sugiyama, Kazuhisa, Jarvela, Irma, Schlottmann, Patricio, Lerner, S. Fabian, Lamari, Hasnaa, Nilgun, Yildirim, Bikbov, Mukharram, Park, Ki Ho, Cha, Soon Cheol, Yamashiro, Kenji, Zenteno, Juan C., Jonas, Jost B., Kumar, Rajesh S., Perera, Shamira A., Chan, Anita S. Y., Kobakhidze, Nino, George, Ronnie, Vijaya, Lingam, Do, Tan, Edward, Deepak P., de Juan Marcos, Lourdes, Pakravan, Mohammad, Moghimi, Sasan, Ideta, Ryuichi, Bach-Holm, Daniella, Kappelgaard, Per, Wirostko, Barbara, Thomas, Samuel, Gaston, Daniel, Bedard, Karen, Greer, Wenda L., Yang, Zhenglin, Chen, Xueyi, Huang, Lulin, Sang, Jinghong, Jia, Hongyan, Jia, Liyun, Qiao, Chunyan, Zhang, Hui, Liu, Xuyang, Zhao, Bowen, Wang, Ya-Xing, Xu, Liang, Leruez, Stephanie, Reynier, Pascal, Chichua, George, Tabagari, Sergo, Uebe, Steffen, Zenkel, Matthias, Berner, Daniel, Mossboeck, Georg, Weisschuh, Nicole, Hoja, Ursula, Welge-Luessen, Ulrich-Christoph, Mardin, Christian, Founti, Panayiota, Chatzikyriakidou, Anthi, Pappas, Theofanis, Anastasopoulos, Eleftherios, Lambropoulos, Alexandros, Ghosh, Arkasubhra, Shetty, Rohit, Porporato, Natalia, Saravanan, Vijayan, Venkatesh, Rengaraj, Shivkumar, Chandrashekaran, Kalpana, Narendran, Sarangapani, Sripriya, Kanavi, Mozhgan R., Beni, Afsaneh Naderi, Yazdani, Shahin, Lashay, Alireza, Naderifar, Homa, Khatibi, Nassim, Fea, Antonio, Lavia, Carlo, Dallorto, Laura, Rolle, Teresa, Frezzotti, Paolo, Paoli, Daniela, Salvi, Erika, Manunta, Paolo, Mori, Yosai, Miyata, Kazunori, Higashide, Tomomi, Chihara, Etsuo, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Aihara, Makoto, Inatani, Masaru, Miyake, Masahiro, Gotoh, Norimoto, Matsuda, Fumihiko, Yoshimura, Nagahisa, Ikeda, Yoko, Ueno, Morio, Sotozono, Chie, Jeoung, Jin Wook, Sagong, Min, Park, Kyu Hyung, Ahn, Jeeyun, Cruz-Aguilar, Marisa, Ezzouhairi, Sidi M., Rafei, Abderrahman, Chong, Yaan Fun, Ng, Xiao Yu, Goh, Shuang Ru, Chen, Yueming, Yong, Victor H. K., Khan, Muhammad Imran, Olawoye, Olusola O., Ashaye, Adeyinka O., Ugbede, Idakwo, Onakoya, Adeola, Kizor-Akaraiwe, Nkiru, Teekhasaenee, Chaiwat, Suwan, Yanin, Supakontanasan, Wasu, Okeke, Suhanya, Uche, Nkechi J., Asimadu, Ifeoma, Ayub, Humaira, Akhtar, Farah, Kosior-Jarecka, Ewa, Lukasik, Urszula, Lischinsky, Ignacio, Castro, Vania, Perez Grossmann, Rodolfo, Megevand, Gordana Sunaric, Roy, Sylvain, Dervan, Edward, Silke, Eoin, Rao, Aparna, Sahay, Priti, Fornero, Pablo, Cuello, Osvaldo, Sivori, Delia, Zompa, Tamara, Mills, Richard A., Souzeau, Emmanuelle, Mitchell, Paul, Wang, Jie Jin, Hewitt, Alex W., Coote, Michael, Crowston, Jonathan G., Astakhov, Sergei Y., Akopov, Eugeny L., Emelyanov, Anton, Vysochinskaya, Vera, Kazakbaeva, Gyulli, Fayzrakhmanov, Rinat, Al-Obeidan, Saleh A., Owaidhah, Ohoud, Aljasim, Leyla Ali, Chowbay, Balram, Foo, Jia Nee, Soh, Raphael Q., Sim, Kar Seng, Xie, Zhicheng, Cheong, Augustine W. O., Mok, Shi Qi, Soo, Hui Meng, Chen, Xiao Yin, Peh, Su Qin, Heng, Khai Koon, Husain, Rahat, Ho, Su-Ling, Hillmer, Axel M., Cheng, Ching-Yu, Escudero-Dominguez, Francisco A., Gonzalez-Sarmiento, Rogelio, Martinon-Torres, Frederico, Salas, Antonio, Pathanapitoon, Kessara, Hansapinyo, Linda, Wanichwecharugruang, Boonsong, Kitnarong, Naris, Sakuntabhai, Anavaj, Nguyn, Hip X., Nguyn, Giang T. T., Nguyn, TrNh V., Zenz, Werner, Binder, Alexander, Klobassa, Daniela S., Hibberd, Martin L., Davila, Sonia, Herms, Stefan, Nothen, Markus M., Moebus, Susanne, Rautenbach, Robyn M., Ziskind, Ari, Carmichael, Trevor R., Ramsay, Michele, Alvarez, Lydia, Garcia, Montserrat, Gonzalez-Iglesias, Hector, Rodriguez-Calvo, Pedro P., Fernandez-Vega Cueto, Luis, Oguz, Cilingir, Tamcelik, Nevbahar, Atalay, Eray, Batu, Bilge, Aktas, Dilek, Kasim, Burcu, Wilson, M. Roy, Coleman, Anne L., Liu, Yutao, Challa, Pratap, Herndon, Leon, Kuchtey, Rachel W., Kuchtey, John, Curtin, Karen, Chaya, Craig J., Crandall, Alan, Zangwill, Linda M., Wong, Tien Yin, Nakano, Masakazu, Kinoshita, Shigeru, den Hollander, Anneke I., Vesti, Eija, Fingert, John H., Lee, Richard K., Sit, Arthur J., Shingleton, Bradford J., Wang, Ningli, Cusi, Daniele, Qamar, Raheel, Kraft, Peter, Pericak-Vance, Margaret A., Raychaudhuri, Soumya, Heegaard, Steffen, Kivela, Tero, Reis, Andre, Kruse, Friedrich E., Weinreb, Robert N., Pasquale, Louis R., Haines, Jonathan L., Thorsteinsdottir, Unnur, Jonasson, Fridbert, Allingham, R. Rand, Milea, Dan, Ritch, Robert, Kubota, Toshiaki, Tashiro, Kei, Vithana, Eranga N., Micheal, Shazia, Topouzis, Fotis, Craig, Jamie E., Dubina, Michael, Sundaresan, Periasamy, Stefansson, Kari, Wiggs, Janey L., Pasutto, Francesca, Khor, Chiea Chuen, Aung, Tin, Ozaki, Mineo, Lee, Mei Chin, Schlotzer-Schrehardt, Ursula, Thorleifsson, Gudmar, Mizoguchi, Takanori, Igo, Robert P., Jr., Haripriya, Aravind, Williams, Susan E., Astakhov, Yury S., Orr, Andrew C., Burdon, Kathryn P., Nakano, Satoko, Mori, Kazuhiko, Abu-Amero, Khaled, Hauser, Michael, Li, Zheng, Prakadeeswari, Gopalakrishnan, Bailey, Jessica N. Cooke, Cherecheanu, Alina Popa, Kang, Jae H., Nelson, Sarah, Hayashi, Ken, Manabe, Shin-ichi, Kazama, Shigeyasu, Zarnowski, Tomasz, Inoue, Kenji, Irkec, Murat, Coca-Prados, Miguel, Sugiyama, Kazuhisa, Jarvela, Irma, Schlottmann, Patricio, Lerner, S. Fabian, Lamari, Hasnaa, Nilgun, Yildirim, Bikbov, Mukharram, Park, Ki Ho, Cha, Soon Cheol, Yamashiro, Kenji, Zenteno, Juan C., Jonas, Jost B., Kumar, Rajesh S., Perera, Shamira A., Chan, Anita S. Y., Kobakhidze, Nino, George, Ronnie, Vijaya, Lingam, Do, Tan, Edward, Deepak P., de Juan Marcos, Lourdes, Pakravan, Mohammad, Moghimi, Sasan, Ideta, Ryuichi, Bach-Holm, Daniella, Kappelgaard, Per, Wirostko, Barbara, Thomas, Samuel, Gaston, Daniel, Bedard, Karen, Greer, Wenda L., Yang, Zhenglin, Chen, Xueyi, Huang, Lulin, Sang, Jinghong, Jia, Hongyan, Jia, Liyun, Qiao, Chunyan, Zhang, Hui, Liu, Xuyang, Zhao, Bowen, Wang, Ya-Xing, Xu, Liang, Leruez, Stephanie, Reynier, Pascal, Chichua, George, Tabagari, Sergo, Uebe, Steffen, Zenkel, Matthias, Berner, Daniel, Mossboeck, Georg, Weisschuh, Nicole, Hoja, Ursula, Welge-Luessen, Ulrich-Christoph, Mardin, Christian, Founti, Panayiota, Chatzikyriakidou, Anthi, Pappas, Theofanis, Anastasopoulos, Eleftherios, Lambropoulos, Alexandros, Ghosh, Arkasubhra, Shetty, Rohit, Porporato, Natalia, Saravanan, Vijayan, Venkatesh, Rengaraj, Shivkumar, Chandrashekaran, Kalpana, Narendran, Sarangapani, Sripriya, Kanavi, Mozhgan R., Beni, Afsaneh Naderi, Yazdani, Shahin, Lashay, Alireza, Naderifar, Homa, Khatibi, Nassim, Fea, Antonio, Lavia, Carlo, Dallorto, Laura, Rolle, Teresa, Frezzotti, Paolo, Paoli, Daniela, Salvi, Erika, Manunta, Paolo, Mori, Yosai, Miyata, Kazunori, Higashide, Tomomi, Chihara, Etsuo, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Aihara, Makoto, Inatani, Masaru, Miyake, Masahiro, Gotoh, Norimoto, Matsuda, Fumihiko, Yoshimura, Nagahisa, Ikeda, Yoko, Ueno, Morio, Sotozono, Chie, Jeoung, Jin Wook, Sagong, Min, Park, Kyu Hyung, Ahn, Jeeyun, Cruz-Aguilar, Marisa, Ezzouhairi, Sidi M., Rafei, Abderrahman, Chong, Yaan Fun, Ng, Xiao Yu, Goh, Shuang Ru, Chen, Yueming, Yong, Victor H. K., Khan, Muhammad Imran, Olawoye, Olusola O., Ashaye, Adeyinka O., Ugbede, Idakwo, Onakoya, Adeola, Kizor-Akaraiwe, Nkiru, Teekhasaenee, Chaiwat, Suwan, Yanin, Supakontanasan, Wasu, Okeke, Suhanya, Uche, Nkechi J., Asimadu, Ifeoma, Ayub, Humaira, Akhtar, Farah, Kosior-Jarecka, Ewa, Lukasik, Urszula, Lischinsky, Ignacio, Castro, Vania, Perez Grossmann, Rodolfo, Megevand, Gordana Sunaric, Roy, Sylvain, Dervan, Edward, Silke, Eoin, Rao, Aparna, Sahay, Priti, Fornero, Pablo, Cuello, Osvaldo, Sivori, Delia, Zompa, Tamara, Mills, Richard A., Souzeau, Emmanuelle, Mitchell, Paul, Wang, Jie Jin, Hewitt, Alex W., Coote, Michael, Crowston, Jonathan G., Astakhov, Sergei Y., Akopov, Eugeny L., Emelyanov, Anton, Vysochinskaya, Vera, Kazakbaeva, Gyulli, Fayzrakhmanov, Rinat, Al-Obeidan, Saleh A., Owaidhah, Ohoud, Aljasim, Leyla Ali, Chowbay, Balram, Foo, Jia Nee, Soh, Raphael Q., Sim, Kar Seng, Xie, Zhicheng, Cheong, Augustine W. O., Mok, Shi Qi, Soo, Hui Meng, Chen, Xiao Yin, Peh, Su Qin, Heng, Khai Koon, Husain, Rahat, Ho, Su-Ling, Hillmer, Axel M., Cheng, Ching-Yu, Escudero-Dominguez, Francisco A., Gonzalez-Sarmiento, Rogelio, Martinon-Torres, Frederico, Salas, Antonio, Pathanapitoon, Kessara, Hansapinyo, Linda, Wanichwecharugruang, Boonsong, Kitnarong, Naris, Sakuntabhai, Anavaj, Nguyn, Hip X., Nguyn, Giang T. T., Nguyn, TrNh V., Zenz, Werner, Binder, Alexander, Klobassa, Daniela S., Hibberd, Martin L., Davila, Sonia, Herms, Stefan, Nothen, Markus M., Moebus, Susanne, Rautenbach, Robyn M., Ziskind, Ari, Carmichael, Trevor R., Ramsay, Michele, Alvarez, Lydia, Garcia, Montserrat, Gonzalez-Iglesias, Hector, Rodriguez-Calvo, Pedro P., Fernandez-Vega Cueto, Luis, Oguz, Cilingir, Tamcelik, Nevbahar, Atalay, Eray, Batu, Bilge, Aktas, Dilek, Kasim, Burcu, Wilson, M. Roy, Coleman, Anne L., Liu, Yutao, Challa, Pratap, Herndon, Leon, Kuchtey, Rachel W., Kuchtey, John, Curtin, Karen, Chaya, Craig J., Crandall, Alan, Zangwill, Linda M., Wong, Tien Yin, Nakano, Masakazu, Kinoshita, Shigeru, den Hollander, Anneke I., Vesti, Eija, Fingert, John H., Lee, Richard K., Sit, Arthur J., Shingleton, Bradford J., Wang, Ningli, Cusi, Daniele, Qamar, Raheel, Kraft, Peter, Pericak-Vance, Margaret A., Raychaudhuri, Soumya, Heegaard, Steffen, Kivela, Tero, Reis, Andre, Kruse, Friedrich E., Weinreb, Robert N., Pasquale, Louis R., Haines, Jonathan L., Thorsteinsdottir, Unnur, Jonasson, Fridbert, Allingham, R. Rand, Milea, Dan, Ritch, Robert, Kubota, Toshiaki, Tashiro, Kei, Vithana, Eranga N., Micheal, Shazia, Topouzis, Fotis, Craig, Jamie E., Dubina, Michael, Sundaresan, Periasamy, Stefansson, Kari, Wiggs, Janey L., Pasutto, Francesca, and Khor, Chiea Chuen

Abstract

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10−14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10−8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Published
2017

11. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Author

Aung, Tin, primary, Ozaki, Mineo, additional, Lee, Mei Chin, additional, Schlötzer-Schrehardt, Ursula, additional, Thorleifsson, Gudmar, additional, Mizoguchi, Takanori, additional, Igo, Robert P, additional, Haripriya, Aravind, additional, Williams, Susan E, additional, Astakhov, Yury S, additional, Orr, Andrew C, additional, Burdon, Kathryn P, additional, Nakano, Satoko, additional, Mori, Kazuhiko, additional, Abu-Amero, Khaled, additional, Hauser, Michael, additional, Li, Zheng, additional, Prakadeeswari, Gopalakrishnan, additional, Bailey, Jessica N Cooke, additional, Cherecheanu, Alina Popa, additional, Kang, Jae H, additional, Nelson, Sarah, additional, Hayashi, Ken, additional, Manabe, Shin-ichi, additional, Kazama, Shigeyasu, additional, Zarnowski, Tomasz, additional, Inoue, Kenji, additional, Irkec, Murat, additional, Coca-Prados, Miguel, additional, Sugiyama, Kazuhisa, additional, Järvelä, Irma, additional, Schlottmann, Patricio, additional, Lerner, S Fabian, additional, Lamari, Hasnaa, additional, Nilgün, Yildirim, additional, Bikbov, Mukharram, additional, Park, Ki Ho, additional, Cha, Soon Cheol, additional, Yamashiro, Kenji, additional, Zenteno, Juan C, additional, Jonas, Jost B, additional, Kumar, Rajesh S, additional, Perera, Shamira A, additional, Chan, Anita S Y, additional, Kobakhidze, Nino, additional, George, Ronnie, additional, Vijaya, Lingam, additional, Do, Tan, additional, Edward, Deepak P, additional, de Juan Marcos, Lourdes, additional, Pakravan, Mohammad, additional, Moghimi, Sasan, additional, Ideta, Ryuichi, additional, Bach-Holm, Daniella, additional, Kappelgaard, Per, additional, Wirostko, Barbara, additional, Thomas, Samuel, additional, Gaston, Daniel, additional, Bedard, Karen, additional, Greer, Wenda L, additional, Yang, Zhenglin, additional, Chen, Xueyi, additional, Huang, Lulin, additional, Sang, Jinghong, additional, Jia, Hongyan, additional, Jia, Liyun, additional, Qiao, Chunyan, additional, Zhang, Hui, additional, Liu, Xuyang, additional, Zhao, Bowen, additional, Wang, Ya-Xing, additional, Xu, Liang, additional, Leruez, Stéphanie, additional, Reynier, Pascal, additional, Chichua, George, additional, Tabagari, Sergo, additional, Uebe, Steffen, additional, Zenkel, Matthias, additional, Berner, Daniel, additional, Mossböck, Georg, additional, Weisschuh, Nicole, additional, Hoja, Ursula, additional, Welge-Luessen, Ulrich-Christoph, additional, Mardin, Christian, additional, Founti, Panayiota, additional, Chatzikyriakidou, Anthi, additional, Pappas, Theofanis, additional, Anastasopoulos, Eleftherios, additional, Lambropoulos, Alexandros, additional, Ghosh, Arkasubhra, additional, Shetty, Rohit, additional, Porporato, Natalia, additional, Saravanan, Vijayan, additional, Venkatesh, Rengaraj, additional, Shivkumar, Chandrashekaran, additional, Kalpana, Narendran, additional, Sarangapani, Sripriya, additional, Kanavi, Mozhgan R, additional, Beni, Afsaneh Naderi, additional, Yazdani, Shahin, additional, lashay, Alireza, additional, Naderifar, Homa, additional, Khatibi, Nassim, additional, Fea, Antonio, additional, Lavia, Carlo, additional, Dallorto, Laura, additional, Rolle, Teresa, additional, Frezzotti, Paolo, additional, Paoli, Daniela, additional, Salvi, Erika, additional, Manunta, Paolo, additional, Mori, Yosai, additional, Miyata, Kazunori, additional, Higashide, Tomomi, additional, Chihara, Etsuo, additional, Ishiko, Satoshi, additional, Yoshida, Akitoshi, additional, Yanagi, Masahide, additional, Kiuchi, Yoshiaki, additional, Ohashi, Tsutomu, additional, Sakurai, Toshiya, additional, Sugimoto, Takako, additional, Chuman, Hideki, additional, Aihara, Makoto, additional, Inatani, Masaru, additional, Miyake, Masahiro, additional, Gotoh, Norimoto, additional, Matsuda, Fumihiko, additional, Yoshimura, Nagahisa, additional, Ikeda, Yoko, additional, Ueno, Morio, additional, Sotozono, Chie, additional, Jeoung, Jin Wook, additional, Sagong, Min, additional, Park, Kyu Hyung, additional, Ahn, Jeeyun, additional, Cruz-Aguilar, Marisa, additional, Ezzouhairi, Sidi M, additional, Rafei, Abderrahman, additional, Chong, Yaan Fun, additional, Ng, Xiao Yu, additional, Goh, Shuang Ru, additional, Chen, Yueming, additional, Yong, Victor H K, additional, Khan, Muhammad Imran, additional, Olawoye, Olusola O, additional, Ashaye, Adeyinka O, additional, Ugbede, Idakwo, additional, Onakoya, Adeola, additional, Kizor-Akaraiwe, Nkiru, additional, Teekhasaenee, Chaiwat, additional, Suwan, Yanin, additional, Supakontanasan, Wasu, additional, Okeke, Suhanya, additional, Uche, Nkechi J, additional, Asimadu, Ifeoma, additional, Ayub, Humaira, additional, Akhtar, Farah, additional, Kosior-Jarecka, Ewa, additional, Lukasik, Urszula, additional, Lischinsky, Ignacio, additional, Castro, Vania, additional, Grossmann, Rodolfo Perez, additional, Megevand, Gordana Sunaric, additional, Roy, Sylvain, additional, Dervan, Edward, additional, Silke, Eoin, additional, Rao, Aparna, additional, Sahay, Priti, additional, Fornero, Pablo, additional, Cuello, Osvaldo, additional, Sivori, Delia, additional, Zompa, Tamara, additional, Mills, Richard A, additional, Souzeau, Emmanuelle, additional, Mitchell, Paul, additional, Wang, Jie Jin, additional, Hewitt, Alex W, additional, Coote, Michael, additional, Crowston, Jonathan G, additional, Astakhov, Sergei Y, additional, Akopov, Eugeny L, additional, Emelyanov, Anton, additional, Vysochinskaya, Vera, additional, Kazakbaeva, Gyulli, additional, Fayzrakhmanov, Rinat, additional, Al-Obeidan, Saleh A, additional, Owaidhah, Ohoud, additional, Aljasim, Leyla Ali, additional, Chowbay, Balram, additional, Foo, Jia Nee, additional, Soh, Raphael Q, additional, Sim, Kar Seng, additional, Xie, Zhicheng, additional, Cheong, Augustine W O, additional, Mok, Shi Qi, additional, Soo, Hui Meng, additional, Chen, Xiao Yin, additional, Peh, Su Qin, additional, Heng, Khai Koon, additional, Husain, Rahat, additional, Ho, Su-Ling, additional, Hillmer, Axel M, additional, Cheng, Ching-Yu, additional, Escudero-Domínguez, Francisco A, additional, González-Sarmiento, Rogelio, additional, Martinon-Torres, Frederico, additional, Salas, Antonio, additional, Pathanapitoon, Kessara, additional, Hansapinyo, Linda, additional, Wanichwecharugruang, Boonsong, additional, Kitnarong, Naris, additional, Sakuntabhai, Anavaj, additional, Nguyn, Hip X, additional, Nguyn, Giang T T, additional, Nguyn, Trình V, additional, Zenz, Werner, additional, Binder, Alexander, additional, Klobassa, Daniela S, additional, Hibberd, Martin L, additional, Davila, Sonia, additional, Herms, Stefan, additional, Nöthen, Markus M, additional, Moebus, Susanne, additional, Rautenbach, Robyn M, additional, Ziskind, Ari, additional, Carmichael, Trevor R, additional, Ramsay, Michele, additional, Álvarez, Lydia, additional, García, Montserrat, additional, González-Iglesias, Héctor, additional, Rodríguez-Calvo, Pedro P, additional, Fernández-Vega Cueto, Luis, additional, Oguz, Çilingir, additional, Tamcelik, Nevbahar, additional, Atalay, Eray, additional, Batu, Bilge, additional, Aktas, Dilek, additional, Kasım, Burcu, additional, Wilson, M Roy, additional, Coleman, Anne L, additional, Liu, Yutao, additional, Challa, Pratap, additional, Herndon, Leon, additional, Kuchtey, Rachel W, additional, Kuchtey, John, additional, Curtin, Karen, additional, Chaya, Craig J, additional, Crandall, Alan, additional, Zangwill, Linda M, additional, Wong, Tien Yin, additional, Nakano, Masakazu, additional, Kinoshita, Shigeru, additional, den Hollander, Anneke I, additional, Vesti, Eija, additional, Fingert, John H, additional, Lee, Richard K, additional, Sit, Arthur J, additional, Shingleton, Bradford J, additional, Wang, Ningli, additional, Cusi, Daniele, additional, Qamar, Raheel, additional, Kraft, Peter, additional, Pericak-Vance, Margaret A, additional, Raychaudhuri, Soumya, additional, Heegaard, Steffen, additional, Kivelä, Tero, additional, Reis, André, additional, Kruse, Friedrich E, additional, Weinreb, Robert N, additional, Pasquale, Louis R, additional, Haines, Jonathan L, additional, Thorsteinsdottir, Unnur, additional, Jonasson, Fridbert, additional, Allingham, R Rand, additional, Milea, Dan, additional, Ritch, Robert, additional, Kubota, Toshiaki, additional, Tashiro, Kei, additional, Vithana, Eranga N, additional, Micheal, Shazia, additional, Topouzis, Fotis, additional, Craig, Jamie E, additional, Dubina, Michael, additional, Sundaresan, Periasamy, additional, Stefansson, Kari, additional, Wiggs, Janey L, additional, Pasutto, Francesca, additional, and Khor, Chiea Chuen, additional

Published
2017
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12. Erratum: A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome (Nature Genetics (2015) 47 (387-392))

Author

Aung, Tin, Ozaki, Mineo, Mizoguchi, Takanori, Allingham, R. Rand, Zheng, Li, Haripriya, Aravind, Nakano, Satoko, Uebe, Steffen, Harder, Jeffrey M., Chan, Anita S. Y., Lee, Mei Chin, Burdon, Kathryn P., Astakhov, Yury S., Abu Amero, Khaled K., Zenteno, Juan C., Nilgün, Yildirim, Zarnowski, Tomasz, Pakravan, Mohammad, Safieh, Leen Abu, Jia, Liyun, Wang, Ya Xing, Williams, Susan, Paoli, Daniela, Schlottmann, Patricio G., Huang, Lulin, Sim, Kar Seng, Foo, Jia Nee, Nakano, Masakazu, Ikeda, Yoko, Kumar, Rajesh S., Ueno, Morio, Manabe, Shin Ichi, Hayashi, Ken, Kazama, Shigeyasu, Ideta, Ryuichi, Mori, Yosai, Miyata, Kazunori, Sugiyama, Kazuhisa, Higashide, Tomomi, Chihara, Etsuo, Inoue, Kenji, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Aihara, Makoto, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Matsuda, Fumihiko, Yamashiro, Kenji, Gotoh, Norimoto, Miyake, Masahiro, Astakhov, Sergei Y., Osman, Essam A., Al Obeidan, Saleh A., Owaidhah, Ohoud, Al Jasim, Leyla, Shahwan, Sami Al, Fogarty, Rhys A., Leo, Paul, Yetkin, Yaz, Oaiuz, Çilingir, Kanavi, Mozhgan Rezaei, Beni, Afsaneh Naderi, Yazdani, Shahin, Akopov, Evgeny L., Toh, Kai Yee, Howell, Gareth R., Orr, Andrew C., Goh, Yufen, Meah, Wee Yang, Peh, Su Qin, Kosior Jarecka, Ewa, Lukasik, Urszula, Krumbiegel, Mandy, Vithana, Eranga N., Wong, Tien Yin, Liu, Yutao, Koch, Allison E. Ashley, Challa, Pratap, Rautenbach, Robyn M., Mackey, David A., Hewitt, Alex W., Mitchell, Paul, Wang, Jie Jin, Ziskind, Ari, Carmichael, Trevor, Ramakrishnan, Rangappa, Narendran, Kalpana, Venkatesh, Rangaraj, Vijayan, Saravanan, Zhao, Peiquan, Chen, Xueyi, Guadarrama Vallejo, Dalia, Cheng, Ching Yu, Perera, Shamira A., Husain, Rahat, Su Ling, Ho, Welge Luessen, Ulrich Christoph, Mardin, Christian, Schloetzer Schrehardt, Ursula, Hillmer, Axel M., Herms, Stefan, Moebus, Susanne, Nöthen, Markus M., Weisschuh, Nicole, Shetty, Rohit, Ghosh, Arkasubhra, Teo, Yik Ying, Brown, Matthew A., Lischinsky, Ignacio, Crowston, Jonathan G., Coote, Michae, Zhao, Bowen, Sang, Jinghong, Zhang, Nihong, You, Qisheng, Vysochinskaya, Vera, Founti, Panayiota, Chatzikyriakidou, Anthoula, Lambropoulos, Alexandros, Anastasopoulos, Eleftherios, Coleman, Anne L., Wilson, M. Roy, Rhee, Douglas J., Kang, Jae Hee, May Bolchakova, Inna, Heegaard, Steffen, Mori, Kazuhiko, Alward, Wallace L. M., Jonas, Jost B., Liang, Xu, Liebmann, Jeffrey M., Chowbay, Balram, Schaeffeler, Elke, Schwab, Matthias, Lerner, Fabian, Wang, Ningli, Yang, Zhenglin, Frezzotti, Paolo, Kinoshita, Shigeru, Fingert, John H., Inatani, Masaru, Tashiro, Kei, Reis, André, Edward, Deepak P., Pasquale, Louis R., Kubota, Toshiaki, Wiggs, Janey L., Pasutto, Francesca, Topouzis, Fotis, Dubina, Michael, Craig, Jamie E., Yoshimura, Nagahisa, Sundaresan, Periasamy, John, Simon W. M., Ritch, Robert, Hauser, Michael A., and Khor, Chiea Chuen

Subjects
Genetics
Published
2015

13. A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Author

Aung, Tin, Ozaki, Mineo, Mizoguchi, Takanori, Allingham, R Rand, Li, Zheng, Haripriya, Aravind, Nakano, Satoko, Uebe, Steffen, Harder, Jeffrey M, Chan, Anita S Y, Lee, Mei Chin, Burdon, Kathryn P, Astakhov, Yury S, Abu-Amero, Khaled K, Zenteno, Juan C, Nilgün, Yildirim, Zarnowski, Tomasz, Pakravan, Mohammad, Safieh, Leen Abu, Jia, Liyun, Wang, Ya Xing, Williams, Susan, Paoli, Daniela, Schlottmann, Patricio G, Huang, Lulin, Sim, Kar Seng, Foo, Jia Nee, Nakano, Masakazu, Ikeda, Yoko, Kumar, Rajesh S, Ueno, Morio, Manabe, Shin-ichi, Hayashi, Ken, Kazama, Shigeyasu, Ideta, Ryuichi, Mori, Yosai, Miyata, Kazunori, Sugiyama, Kazuhisa, Higashide, Tomomi, Chihara, Etsuo, Inoue, Kenji, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Aihara, Makoto, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Matsuda, Fumihiko, Yamashiro, Kenji, Gotoh, Norimoto, Miyake, Masahiro, Astakhov, Sergei Y, Osman, Essam A, Al-Obeidan, Saleh A, Owaidhah, Ohoud, Al-Jasim, Leyla, Al Shahwan, Sami, Fogarty, Rhys A, Leo, Paul, Yetkin, Yaz, Oguz, Çilingir, Kanavi, Mozhgan Rezaei, Beni, Afsaneh Nederi, Yazdani, Shahin, Akopov, Evgeny L, Toh, Kai-Yee, Howell, Gareth R, Orr, Andrew C, Goh, Yufen, Meah, Wee Yang, Peh, Su Qin, Kosior-Jarecka, Ewa, Lukasik, Urszula, Krumbiegel, Mandy, Vithana, Eranga N, Wong, Tien Yin, Liu, Yutao, Koch, Allison E Ashley, Challa, Pratap, Rautenbach, Robyn M, Mackey, David A, Hewitt, Alex W, Mitchell, Paul, Wang, Jie Jin, Ziskind, Ari, Carmichael, Trevor, Ramakrishnan, Rangappa, Narendran, Kalpana, Venkatesh, Rangaraj, Vijayan, Saravanan, Zhao, Peiquan, Chen, Xueyi, Guadarrama-Vallejo, Dalia, Cheng, Ching Yu, Perera, Shamira A, Husain, Rahat, Ho, Su-Ling, Welge-Luessen, Ulrich-Christoph, Mardin, Christian, Schloetzer-Schrehardt, Ursula, Hillmer, Axel M, Herms, Stefan, Moebus, Susanne, Nöthen, Markus M, Weisschuh, Nicole, Shetty, Rohit, Ghosh, Arkasubhra, Teo, Yik Ying, Brown, Matthew A, Lischinsky, Ignacio, Crowston, Jonathan G, Coote, Michael, Zhao, Bowen, Sang, Jinghong, Zhang, Nihong, You, Qisheng, Vysochinskaya, Vera, Founti, Panayiota, Chatzikyriakidou, Anthoula, Lambropoulos, Alexandros, Anastasopoulos, Eleftherios, Coleman, Anne L, Wilson, M Roy, Rhee, Douglas J, Kang, Jae Hee, May-Bolchakova, Inna, Heegaard, Steffen, Mori, Kazuhiko, Alward, Wallace L M, Jonas, Jost B, Xu, Liang, Liebmann, Jeffrey M, Chowbay, Balram, Schaeffeler, Elke, Schwab, Matthias, Lerner, Fabian, Wang, Ningli, Yang, Zhenglin, Frezzotti, Paolo, Kinoshita, Shigeru, Fingert, John H, Inatani, Masaru, Tashiro, Kei, Reis, André, Edward, Deepak P, Pasquale, Louis R, Kubota, Toshiaki, Wiggs, Janey L, Pasutto, Francesca, Topouzis, Fotis, Dubina, Michael, Craig, Jamie E, Yoshimura, Nagahisa, Sundaresan, Periasamy, John, Simon W M, Ritch, Robert, Hauser, Michael A, Khor, Chiea-Chuen, Rochtchina, Elena, Viswanathan, Ananth C, Wong, Tien Y, Xie, Jing, Sim, Xueling, Inouye, Michael, Holliday, Elizabeth G, Attia, John, Scott, Rodney J, Baird, Paul N, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Wood, Nicholas W, Spencer, Chris C A, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, and Whittaker, Pamela

Subjects
Asian Continental Ancestry Group, Pseudoexfoliation syndrome, Medizin, Locus (genetics), Genome-wide association study, Biology, Inbred C57BL, Exfoliation Syndrome, Polymorphism, Single Nucleotide, Article, Mice, Animals, Calcium Channels, Case-Control Studies, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, Glaucoma, Open-Angle, HEK293 Cells, HeLa Cells, Humans, Japan, MCF-7 Cells, Mice, Inbred C57BL, Tumor Cells, Cultured, Genetics, Asian People, medicine, SNP, Allele, Polymorphism, Cultured, Case-control study, Glaucoma, Odds ratio, Single Nucleotide, medicine.disease, eye diseases, Tumor Cells, Open-Angle, Etiology
Abstract

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Published
2014

14. A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Author

Aung, Tin, Ozaki, Mineo, Mizoguchi, Takanori, Allingham, R. Rand, Li, Zheng, Haripriya, Aravind, Nakano, Satoko, Uebe, Steffen, Harder, Jeffrey M., Chan, Anita S. Y., Lee, Mei Chin, Burdon, Kathryn P., Astakhov, Yury S., Abu-Amero, Khaled K., Zenteno, Juan C., Nilguen, Yildirim, Zarnowski, Tomasz, Pakravan, Mohammad, Abu Safieh, Leen, Jia, Liyun, Wang, Ya Xing, Williams, Susan, Paoli, Daniela, Schlottmann, Patricio G., Huang, Lulin, Sim, Kar Seng, Foo, Jia Nee, Nakano, Masakazu, Ikeda, Yoko, Kumar, Rajesh S., Ueno, Morio, Manabe, Shin-Ichi, Hayashi, Ken, Kazama, Shigeyasu, Ideta, Ryuichi, Mori, Yosai, Miyata, Kazunori, Sugiyama, Kazuhisa, Higashide, Tomomi, Chihara, Etsuo, Inoue, Kenji, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Aihara, Makoto, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Matsuda, Fumihiko, Yamashiro, Kenji, Gotoh, Norimoto, Miyake, Masahiro, Astakhov, Sergei Y., Osman, Essam A., Al-Obeidan, Saleh A., Owaidhah, Ohoud, Al-Jasim, Leyla, Al Shahwan, Sami, Fogarty, Rhys A., Leo, Paul, Yetkin, Yaz, Oguz, Cilingir, Kanavi, Mozhgan Rezaei, Beni, Afsaneh Nederi, Yazdani, Shahin, Akopov, Evgeny L., Toh, Kai-Yee, Howell, Gareth R., Orr, Andrew C., Goh, Yufen, Meah, Wee Yang, Peh, Su Qin, Kosior-Jarecka, Ewa, Lukasik, Urszula, Krumbiegel, Mandy, Vithana, Eranga N., Wong, Tien Yin, Liu, Yutao, Koch, Allison E. Ashley, Challa, Pratap, Rautenbach, Robyn M., Mackey, David A., Hewitt, Alex W., Mitchell, Paul, Wang, Jie Jin, Ziskind, Ari, Carmichael, Trevor, Ramakrishnan, Rangappa, Narendran, Kalpana, Venkatesh, Rangaraj, Vijayan, Saravanan, Zhao, Peiquan, Chen, Xueyi, Guadarrama-Vallejo, Dalia, Cheng, Ching Yu, Perera, Shamira A., Husain, Rahat, Ho, Su-Ling, Welge-Luessen, Ulrich-Christoph, Mardin, Christian, Schloetzer-Schrehardt, Ursula, Hillmer, Axel M., Herms, Stefan, Moebus, Susanne, Noethen, Markus M., Weisschuh, Nicole, Shetty, Rohit, Ghosh, Arkasubhra, Teo, Yik Ying, Brown, Matthew A., Lischinsky, Ignacio, Crowston, Jonathan G., Coote, Michael, Zhao, Bowen, Sang, Jinghong, Zhang, Nihong, You, Qisheng, Vysochinskaya, Vera, Founti, Panayiota, Chatzikyriakidou, Anthoula, Lambropoulos, Alexandros, Anastasopoulos, Eleftherios, Coleman, Anne L., Wilson, M. Roy, Rhee, Douglas J., Kang, Jae Hee, May-Bolchakova, Inna, Heegaard, Steffen, Mori, Kazuhiko, Alward, Wallace L. M., Jonas, Jost B., Xu, Liang, Liebmann, Jeffrey M., Chowbay, Balram, Schaeffeler, Elke, Schwab, Matthias, Lerner, Fabian, Wang, Ningli, Yang, Zhenglin, Frezzotti, Paolo, Kinoshita, Shigeru, Fingert, John H., Inatani, Masaru, Tashiro, Kei, Reis, Andre, Edward, Deepak P., Pasquale, Louis R., Kubota, Toshiaki, Wiggs, Janey L., Pasutto, Francesca, Topouzis, Fotis, Dubina, Michael, Craig, Jamie E., Yoshimura, Nagahisa, Sundaresan, Periasamy, John, Simon W. M., Ritch, Robert, Hauser, Michael A., Khor, Chiea-Chuen, Aung, Tin, Ozaki, Mineo, Mizoguchi, Takanori, Allingham, R. Rand, Li, Zheng, Haripriya, Aravind, Nakano, Satoko, Uebe, Steffen, Harder, Jeffrey M., Chan, Anita S. Y., Lee, Mei Chin, Burdon, Kathryn P., Astakhov, Yury S., Abu-Amero, Khaled K., Zenteno, Juan C., Nilguen, Yildirim, Zarnowski, Tomasz, Pakravan, Mohammad, Abu Safieh, Leen, Jia, Liyun, Wang, Ya Xing, Williams, Susan, Paoli, Daniela, Schlottmann, Patricio G., Huang, Lulin, Sim, Kar Seng, Foo, Jia Nee, Nakano, Masakazu, Ikeda, Yoko, Kumar, Rajesh S., Ueno, Morio, Manabe, Shin-Ichi, Hayashi, Ken, Kazama, Shigeyasu, Ideta, Ryuichi, Mori, Yosai, Miyata, Kazunori, Sugiyama, Kazuhisa, Higashide, Tomomi, Chihara, Etsuo, Inoue, Kenji, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Aihara, Makoto, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Matsuda, Fumihiko, Yamashiro, Kenji, Gotoh, Norimoto, Miyake, Masahiro, Astakhov, Sergei Y., Osman, Essam A., Al-Obeidan, Saleh A., Owaidhah, Ohoud, Al-Jasim, Leyla, Al Shahwan, Sami, Fogarty, Rhys A., Leo, Paul, Yetkin, Yaz, Oguz, Cilingir, Kanavi, Mozhgan Rezaei, Beni, Afsaneh Nederi, Yazdani, Shahin, Akopov, Evgeny L., Toh, Kai-Yee, Howell, Gareth R., Orr, Andrew C., Goh, Yufen, Meah, Wee Yang, Peh, Su Qin, Kosior-Jarecka, Ewa, Lukasik, Urszula, Krumbiegel, Mandy, Vithana, Eranga N., Wong, Tien Yin, Liu, Yutao, Koch, Allison E. Ashley, Challa, Pratap, Rautenbach, Robyn M., Mackey, David A., Hewitt, Alex W., Mitchell, Paul, Wang, Jie Jin, Ziskind, Ari, Carmichael, Trevor, Ramakrishnan, Rangappa, Narendran, Kalpana, Venkatesh, Rangaraj, Vijayan, Saravanan, Zhao, Peiquan, Chen, Xueyi, Guadarrama-Vallejo, Dalia, Cheng, Ching Yu, Perera, Shamira A., Husain, Rahat, Ho, Su-Ling, Welge-Luessen, Ulrich-Christoph, Mardin, Christian, Schloetzer-Schrehardt, Ursula, Hillmer, Axel M., Herms, Stefan, Moebus, Susanne, Noethen, Markus M., Weisschuh, Nicole, Shetty, Rohit, Ghosh, Arkasubhra, Teo, Yik Ying, Brown, Matthew A., Lischinsky, Ignacio, Crowston, Jonathan G., Coote, Michael, Zhao, Bowen, Sang, Jinghong, Zhang, Nihong, You, Qisheng, Vysochinskaya, Vera, Founti, Panayiota, Chatzikyriakidou, Anthoula, Lambropoulos, Alexandros, Anastasopoulos, Eleftherios, Coleman, Anne L., Wilson, M. Roy, Rhee, Douglas J., Kang, Jae Hee, May-Bolchakova, Inna, Heegaard, Steffen, Mori, Kazuhiko, Alward, Wallace L. M., Jonas, Jost B., Xu, Liang, Liebmann, Jeffrey M., Chowbay, Balram, Schaeffeler, Elke, Schwab, Matthias, Lerner, Fabian, Wang, Ningli, Yang, Zhenglin, Frezzotti, Paolo, Kinoshita, Shigeru, Fingert, John H., Inatani, Masaru, Tashiro, Kei, Reis, Andre, Edward, Deepak P., Pasquale, Louis R., Kubota, Toshiaki, Wiggs, Janey L., Pasutto, Francesca, Topouzis, Fotis, Dubina, Michael, Craig, Jamie E., Yoshimura, Nagahisa, Sundaresan, Periasamy, John, Simon W. M., Ritch, Robert, Hauser, Michael A., and Khor, Chiea-Chuen

Abstract

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10−11). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: ORA allele = 9.87, P = 2.13 × 10−217; non-Japanese: ORA allele = 0.49, P = 2.35 × 10−31). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Published
2015

15. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Author

Daniele Cusi, Etsuo Chihara, Leyla Al-Jasim, Ya Xing Wang, Tero Kivelä, Jinghong Sang, Adeyinka O. Ashaye, Bowen Zhao, Tan Do, Susanne Moebus, Ursula Schlötzer-Schrehardt, Shamira A. Perera, Augustine W O Cheong, Afsaneh Naderi Beni, Francisco A. Escudero-Domínguez, Yoshiaki Kiuchi, Tomomi Higashide, DS Klobassa, Friedrich E. Kruse, Nicole Weisschuh, Chunyan Qiao, Muhammad Imran Khan, Martin L. Hibberd, Arthur J. Sit, Jamie E Craig, Akitoshi Yoshida, Periasamy Sundaresan, Humaira Ayub, Kathryn P. Burdon, Jonathan G Crowston, Kazunori Miyata, Marisa Cruz-Aguilar, Markus M. Nöthen, Hasnaa Lamari, Michael A. Hauser, Louis R. Pasquale, Anneke I. den Hollander, Eija Vesti, Ursula Hoja, Raphael Q Soh, Burcu Kasım, Adeola O Onakoya, Rachel W. Kuchtey, Eugeny L. Akopov, Liang Xu, Juan Carlos Zenteno, Chaiwat Teekhasaenee, Saleh A. Al-Obeidan, Eleftherios Anastasopoulos, Anita S Y Chan, Nagahisa Yoshimura, John Kuchtey, Naris Kitnarong, Yaan Fun Chong, Boonsong Wanichwecharugruang, R.R. Fayzrakhmanov, Paul Mitchell, N Kalpana, Unnur Thorsteinsdottir, Kei Tashiro, Rajesh Kumar, Jin Wook Jeoung, Deepak P. Edward, Frederico Martinon-Torres, Bilge Batu, Anavaj Sakuntabhai, Robert N. Weinreb, Héctor González-Iglesias, Sasan Moghimi, Jia Nee Foo, Nkechi J Uche, Karen Curtin, Kenji Inoue, Lingam Vijaya, Makoto Aihara, Dilek Aktas, Norimoto Gotoh, Wasu Supakontanasan, Laura Dallorto, Takako Sugimoto, Jonathan L. Haines, Olusola Olawoye, Janey L. Wiggs, Sripriya Sarangapani, Craig J. Chaya, Theofanis Pappas, Fotis Topouzis, Eranga N. Vithana, Steffen Heegaard, Fridbert Jonasson, Kazuhiko Mori, Idakwo Ugbede, Hongyan Jia, Anthi Chatzikyriakidou, Robert P. Igo, Soon Cheol Cha, Yueming Chen, Su-Ling Ho, Zhenglin Yang, Jost B. Jonas, Francesca Pasutto, Ken Hayashi, Rahat Husain, Georg Mossböck, S Fabian Lerner, R. Rand Allingham, Priti Sahay, Fumihiko Matsuda, Yanin Suwan, Teresa Rolle, Robert Ritch, Peter Kraft, Trevor R. Carmichael, Kar Seng Sim, Raheel Qamar, Gordana Sunaric Megevand, Tomasz Zarnowski, Shazia Micheal, Scott Thomas, Paolo Frezzotti, Vera Vysochinskaya, Linda M. Zangwill, Alina Popa Cherecheanu, Tin Aung, Jessica N. Cooke Bailey, Kyu Hyung Park, Edward Dervan, Suhanya Okeke, Pablo Fornero, Sidi M Ezzouhairi, Pascal Reynier, Gudmar Thorleifsson, Michael V. Dubina, Kazuhisa Sugiyama, Sylvain Roy, Per Kappelgaard, Mineo Ozaki, Vijayan Saravanan, Carlo Lavia, Wenda L. Greer, Takanori Mizoguchi, Alireza Lashay, A. Binder, Daniel Berner, Su Qin Peh, Balram Chowbay, Nino Kobakhidze, Ifeoma N. Asimadu, Delia Sivori, Gopalakrishnan Prakadeeswari, Alexandros Lambropoulos, Michael Coote, Sergei Y. Astakhov, Shahin Yazdani, Dan Milea, Montserrat García, Lydia Álvarez, Kenji Yamashiro, Soumya Raychaudhuri, Pratap Challa, Aparna Rao, Jae H. Kang, Khai Koon Heng, Richard K. Lee, Tien Yin Wong, Alex W. Hewitt, Yoko Ikeda, Kessara Pathanapitoon, Panayiota Founti, Daniella Bach-Holm, Emmanuelle Souzeau, Margaret A. Pericak-Vance, Michèle Ramsay, Nkiru Kizor-Akaraiwe, Yosai Mori, Antonio Maria Fea, Chandrashekaran Shivkumar, Xiao Yu Ng, Jie Jin Wang, Erika Salvi, Giang T T Nguyn, Steffen Uebe, Tamara Zompa, Anne L. Coleman, Werner Zenz, Min Sagong, Luis Fernández-Vega Cueto, Farah Akhtar, Susan Williams, Sarah C. Nelson, Bradford J. Shingleton, Ryuichi Ideta, Leon W. Herndon, Zheng Li, Murat Irkec, M. Roy Wilson, Ewa Kosior-Jarecka, Christian Y. Mardin, Mozhgan Rezaei Kanavi, Tsutomu Ohashi, Abderrahman Rafei, Rengaraj Venkatesh, Stefan Herms, George Chichua, Mohammad Pakravan, Robyn M. Rautenbach, Shi Qi Mok, Trình V Nguyn, Patricio G. Schlottmann, Nassim Khatibi, Daniel Gaston, Masaru Inatani, Morio Ueno, Mukharram M. Bikbov, Eoin Silke, Homa Naderifar, Linda Hansapinyo, Paolo Manunta, Z. Xie, Urszula Lukasik, Eray Atalay, Lulin Huang, Xuyang Liu, Chie Sotozono, Shuang Ru Goh, John H. Fingert, Richard A. Mills, Khaled K. Abu-Amero, Xiao Yin Chen, Matthias Zenkel, Sergo Tabagari, Irma Järvelä, Xueyi Chen, Stéphanie Leruez, Yury S. Astakhov, Sonia Davila, Yildirim Nilgün, Ronnie George, Shin-ichi Manabe, Miguel Coca-Prados, Masahiro Miyake, Ignacio Lischinsky, Rogelio González-Sarmiento, Arkasubhra Ghosh, A. Emelyanov, Çilingir Oguz, Masakazu Nakano, Rohit Shetty, Karen Bedard, Toshiya Sakurai, Yutao Liu, Barbara M Wirostko, Hui Zhang, Ulrich-Christoph Welge-Luessen, Toshiaki Kubota, Vania Castro, Hip X Nguyn, Liyun Jia, Ari Ziskind, Hideki Chuman, Andrew C. Orr, Satoko Nakano, Daniela Paoli, Masahide Yanagi, Aravind Haripriya, Kari Stefansson, Pedro Pablo Rodríguez-Calvo, Hui Meng Soo, Chiea Chuen Khor, Gyulli M. Kazakbaeva, Osvaldo Cuello, Mei Chin Lee, Ki Ho Park, Natalia Porporato, Lourdes de Juan Marcos, Ching-Yu Cheng, Shigeyasu Kazama, Shigeru Kinoshita, Axel M. Hillmer, Alan S. Crandall, Victor H. K. Yong, Ohoud Owaidhah, Rodolfo Perez Grossmann, Jeeyun Ahn, André Reis, Nevbahar Tamçelik, Satoshi Ishiko, Antonio Salas, Ningli Wang, Singapore Eye Research Institute [Singapore] (SERI), Ozaki Eye Hospital [Miyazaki], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), deCODE genetics [Reykjavik], Mizoguchi Eye Hospital [Sasebo], Case Western Reserve University [Cleveland], Aravind Eye Hospital [Madurai, India], University of the Witwatersrand [Johannesburg] (WITS), Pavlov First Saint Petersburg State Medical University [St. Petersburg], Dalhousie University [Halifax], Flinders University [Adelaide, Australia], Kyoto Prefectural University of Medicine [Kyoto, Japon], King Saud University [Riyadh] (KSU), Genome Institute of Singapore (GIS), Aravind Medical Research Foundation (AMRF), Université de Médecine Carol Davila, Harvard Medical School [Boston] (HMS), University of Washington [Seattle], Hayashi Eye Hospital [Fukuoka], Shinjo Eye Clinic [Nagoya], Medical University of Lublin, Inoue Eye Hospital [Tokyo], Hacettepe University = Hacettepe Üniversitesi, Universidad de Oviedo [Oviedo], Kanazawa University (KU), Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Organizacion Medica de Investigacion (OMI BUENOS AIRES), Fundacion para el Estudio del Glaucoma [Buenos Aires], Chercheur indépendant, Eskisehir Osmangazi University, Ufa Eye Research Institute [Bashkortostan], Seoul National University Hospital, Yeungnam University [South Korea], Kyoto University, Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Universität Heidelberg [Heidelberg] = Heidelberg University, Birla Institute of Scientific Research (BISR), B. M. Birla Science and Technology Center, Faculty of Computer Science, Department of Pathology and Immunology, Geneva University Hospital (HUG), Key Laboratory for Information System Security, ministry of education, Numerical modeling and high performance computing for evolution problems in complex domains and heterogeneous media (NACHOS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (LJAD), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institute of Human Genetics [Erlangen, Allemagne], Department of Ophthalmology, School of Medicine [Thessaloniki, Grèce], Aristotle University of Thessaloniki, Università degli Studi di Siena = University of Siena (UNISI), Department of Medicine, Surgery, and Dentistry, University of Milano, Japan Advanced Institute of Science and Technology (JAIST), Etudes génomiques trans-ethniques des maladies multifactorielles, Kyoto University-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Archaeogenetics Laboratory, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Rheinische Friedrich-Wilhelms-Universität Bonn, University of Kentucky (UK), Helsinki University Eye Hospital, Turku University Hospital, Turku, Finland, COMSATS Institute of Information Technology (CIIT), Department of Epidemiology, Harvard School of Public Health, University of Miami Leonard M. Miller School of Medicine (UMMSM), Brigham and Women's Hospital [Boston], Department of Neuroscience and Pharmacology, Section of Eye Pathology, University of Copenhagen, University of Copenhagen = Københavns Universitet (UCPH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of California [San Diego] (UC San Diego), University of California (UC), University of Iceland [Reykjavik], New York Eye and Ear Infirmary of Mount Sinai [New York] (NYEE), Oita University Faculty of Medicine [Oita, Japon], Radboud University Medical Center [Nijmegen], Oogheelkunde, RS: FHML non-thematic output, Kyoto University [Kyoto], Universidad Nacional Autónoma de México (UNAM), Universität Heidelberg [Heidelberg], Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (JAD), Dipartimento di Scienze oftalmologiche e Neurochirurgiche, Universita' degli Studi di Siena, Siena, Kyoto University [Kyoto]-Institut National de la Santé et de la Recherche Médicale (INSERM), Rothschild Hospital, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Kentucky, University of Copenhagen = Københavns Universitet (KU), University of California, Aung, Tin, Ozaki, Mineo, Lee, Mei Chin, Schlötzer Schrehardt, Ursula, Thorleifsson, Gudmar, Mizoguchi, Takanori, Igo, Robert P, Haripriya, Aravind, Williams, Susan E, Astakhov, Yury S, Orr, Andrew C, Burdon, Kathryn P, Nakano, Satoko, Mori, Kazuhiko, Abu Amero, Khaled, Hauser, Michael, Li, Zheng, Prakadeeswari, Gopalakrishnan, Bailey, Jessica N. Cooke, Cherecheanu, Alina Popa, Kang, Jae H, Nelson, Sarah, Hayashi, Ken, Manabe, Shin Ichi, Kazama, Shigeyasu, Zarnowski, Tomasz, Inoue, Kenji, Irkec, Murat, Coca Prados, Miguel, Sugiyama, Kazuhisa, Järvelä, Irma, Schlottmann, Patricio, Lerner, S. Fabian, Lamari, Hasnaa, Nilgün, Yildirim, Bikbov, Mukharram, Park, Ki Ho, Cha, Soon Cheol, Yamashiro, Kenji, Zenteno, Juan C, Jonas, Jost B, Kumar, Rajesh S, Perera, Shamira A, Chan, Anita S. Y, Kobakhidze, Nino, George, Ronnie, Vijaya, Lingam, Do, Tan, Edward, Deepak P, de Juan Marcos, Lourde, Pakravan, Mohammad, Moghimi, Sasan, Ideta, Ryuichi, Bach Holm, Daniella, Kappelgaard, Per, Wirostko, Barbara, Thomas, Samuel, Gaston, Daniel, Bedard, Karen, Greer, Wenda L, Yang, Zhenglin, Chen, Xueyi, Huang, Lulin, Sang, Jinghong, Jia, Hongyan, Jia, Liyun, Qiao, Chunyan, Zhang, Hui, Liu, Xuyang, Zhao, Bowen, Wang, Ya Xing, Xu, Liang, Leruez, Stéphanie, Reynier, Pascal, Chichua, George, Tabagari, Sergo, Uebe, Steffen, Zenkel, Matthia, Berner, Daniel, Mossböck, Georg, Weisschuh, Nicole, Hoja, Ursula, Welge Luessen, Ulrich Christoph, Mardin, Christian, Founti, Panayiota, Chatzikyriakidou, Anthi, Pappas, Theofani, Anastasopoulos, Eleftherio, Lambropoulos, Alexandro, Ghosh, Arkasubhra, Shetty, Rohit, Porporato, Natalia, Saravanan, Vijayan, Venkatesh, Rengaraj, Shivkumar, Chandrashekaran, Kalpana, Narendran, Sarangapani, Sripriya, Kanavi, Mozhgan R, Beni, Afsaneh Naderi, Yazdani, Shahin, Lashay, Alireza, Naderifar, Homa, Khatibi, Nassim, Fea, Antonio, Lavia, Carlo, Dallorto, Laura, Rolle, Teresa, Frezzotti, Paolo, Paoli, Daniela, Salvi, Erika, Manunta, Paolo, Mori, Yosai, Miyata, Kazunori, Higashide, Tomomi, Chihara, Etsuo, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Aihara, Makoto, Inatani, Masaru, Miyake, Masahiro, Gotoh, Norimoto, Matsuda, Fumihiko, Yoshimura, Nagahisa, Ikeda, Yoko, Ueno, Morio, Sotozono, Chie, Jeoung, Jin Wook, Sagong, Min, Park, Kyu Hyung, Ahn, Jeeyun, Cruz Aguilar, Marisa, Ezzouhairi, Sidi M, Rafei, Abderrahman, Chong, Yaan Fun, Ng, Xiao Yu, Goh, Shuang Ru, Chen, Yueming, Yong, Victor H. K, Khan, Muhammad Imran, Olawoye, Olusola O, Ashaye, Adeyinka O, Ugbede, Idakwo, Onakoya, Adeola, Kizor Akaraiwe, Nkiru, Teekhasaenee, Chaiwat, Suwan, Yanin, Supakontanasan, Wasu, Okeke, Suhanya, Uche, Nkechi J, Asimadu, Ifeoma, Ayub, Humaira, Akhtar, Farah, Kosior Jarecka, Ewa, Lukasik, Urszula, Lischinsky, Ignacio, Castro, Vania, Grossmann, Rodolfo Perez, Megevand, Gordana Sunaric, Roy, Sylvain, Dervan, Edward, Silke, Eoin, Rao, Aparna, Sahay, Priti, Fornero, Pablo, Cuello, Osvaldo, Sivori, Delia, Zompa, Tamara, Mills, Richard A, Souzeau, Emmanuelle, Mitchell, Paul, Wang, Jie Jin, Hewitt, Alex W, Coote, Michael, Crowston, Jonathan G, Astakhov, Sergei Y, Akopov, Eugeny L, Emelyanov, Anton, Vysochinskaya, Vera, Kazakbaeva, Gyulli, Fayzrakhmanov, Rinat, Al Obeidan, Saleh A, Owaidhah, Ohoud, Aljasim, Leyla Ali, Chowbay, Balram, Foo, Jia Nee, Soh, Raphael Q, Sim, Kar Seng, Xie, Zhicheng, Cheong, Augustine W. O, Mok, Shi Qi, Soo, Hui Meng, Chen, Xiao Yin, Peh, Su Qin, Heng, Khai Koon, Husain, Rahat, Ho, Su Ling, Hillmer, Axel M, Cheng, Ching Yu, Escudero Domínguez, Francisco A, González Sarmiento, Rogelio, Martinon Torres, Frederico, Salas, Antonio, Pathanapitoon, Kessara, Hansapinyo, Linda, Wanichwecharugruang, Boonsong, Kitnarong, Nari, Sakuntabhai, Anavaj, Nguyn, Hip X, Nguyn, Giang T. T, Nguyn, Trình V, Zenz, Werner, Binder, Alexander, Klobassa, Daniela S, Hibberd, Martin L, Davila, Sonia, Herms, Stefan, Nöthen, Markus M, Moebus, Susanne, Rautenbach, Robyn M, Ziskind, Ari, Carmichael, Trevor R, Ramsay, Michele, Álvarez, Lydia, García, Montserrat, González Iglesias, Héctor, Rodríguez Calvo, Pedro P, Cueto, Luis Fernández Vega, Oguz, Çilingir, Tamcelik, Nevbahar, Atalay, Eray, Batu, Bilge, Aktas, Dilek, Kasım, Burcu, Wilson, M. Roy, Coleman, Anne L, Liu, Yutao, Challa, Pratap, Herndon, Leon, Kuchtey, Rachel W, Kuchtey, John, Curtin, Karen, Chaya, Craig J, Crandall, Alan, Zangwill, Linda M, Wong, Tien Yin, Nakano, Masakazu, Kinoshita, Shigeru, den Hollander, Anneke I, Vesti, Eija, Fingert, John H, Lee, Richard K, Sit, Arthur J, Shingleton, Bradford J, Wang, Ningli, Cusi, Daniele, Qamar, Raheel, Kraft, Peter, Pericak Vance, Margaret A, Raychaudhuri, Soumya, Heegaard, Steffen, Kivelä, Tero, Reis, André, Kruse, Friedrich E, Weinreb, Robert N, Pasquale, Louis R, Haines, Jonathan L, Thorsteinsdottir, Unnur, Jonasson, Fridbert, Allingham, R. Rand, Milea, Dan, Ritch, Robert, Kubota, Toshiaki, Tashiro, Kei, Vithana, Eranga N, Micheal, Shazia, Topouzis, Foti, Craig, Jamie E, Dubina, Michael, Sundaresan, Periasamy, Stefansson, Kari, Wiggs, Janey L, Pasutto, Francesca, Khor, Chiea Chuen, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and University of Helsinki

Subjects
0301 basic medicine, Male, Calcium Channels/genetics, Messenger, Medizin, PSEUDOEXFOLIATION SYNDROME, Genome-wide association study, BLOOD-PRESSURE, Disease, Exfoliation Syndrome, Eye, Exfoliation Syndrome/ethnology/genetics, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, PARKINSONS-DISEASE, 80 and over, ta319, Missense mutation, Genetics, Aged, 80 and over, Amino Acid Oxidoreductases/genetics/physiology, Alleles, Amino Acid Oxidoreductases, Amino Acid Substitution, Asian Continental Ancestry Group, Calcium Channels, Cell Adhesion, Extracellular Matrix, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Haplotypes, Humans, Molecular Chaperones, RNA, Messenger, Spheroids, Cellular, Genome-Wide Association Study, Mutation, Missense, Point Mutation, Metaanalysis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, ALZHEIMERS-DISEASE, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Molecular Chaperones/biosynthesis/genetics, Biology, SYNONYMOUS MUTATIONS, ta3111, Article, 03 medical and health sciences, Asian People, Asian Continental Ancestry Group/genetics, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Allele, Risk factor, GENOME-WIDE ASSOCIATION, Eye/metabolism, Aged, Genetic association, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Haplotype, Individuals, Glaucoma, Odds ratio, Extracellular Matrix/metabolism, RNA, Messenger/biosynthesis, MACULAR DEGENERATION, RISK LOCI, eye diseases, COMMON SEQUENCE VARIANTS, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, 030221 ophthalmology & optometry, RNA, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cellular, Spheroids, Missense, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Polymorphisms, purl.org/pe-repo/ocde/ford#1.06.07 [https], INFLAMMATORY-BOWEL-DISEASE
Abstract

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Published
2017
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16. Corrigendum: a common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome.

Author

Aung T, Ozaki M, Mizoguchi T, Allingham RR, Li Z, Haripriya A, Nakano S, Uebe S, Harder JM, Chan AS, Lee MC, Burdon KP, Astakhov YS, Abu-Amero KK, Zenteno JC, Nilgün Y, Zarnowski T, Pakravan M, Safieh LA, Jia L, Wang YX, Williams S, Paoli D, Schlottmann PG, Huang L, Sim KS, Foo JN, Nakano M, Ikeda Y, Kumar RS, Ueno M, Manabe S, Hayashi K, Kazama S, Ideta R, Mori Y, Miyata K, Sugiyama K, Higashide T, Chihara E, Inoue K, Ishiko S, Yoshida A, Yanagi M, Kiuchi Y, Aihara M, Ohashi T, Sakurai T, Sugimoto T, Chuman H, Matsuda F, Yamashiro K, Gotoh N, Miyake M, Astakhov SY, Osman EA, Al-Obeidan SA, Owaidhah O, Al-Jasim L, Shahwan SA, Fogarty RA, Leo P, Yetkin Y, Oğuz Ç, Kanavi MR, Beni AN, Yazdani S, Akopov EL, Toh KY, Howell GR, Orr AC, Goh Y, Meah WY, Peh SQ, Kosior-Jarecka E, Lukasik U, Krumbiegel M, Vithana EN, Wong TY, Liu Y, Koch AE, Challa P, Rautenbach RM, Mackey DA, Hewitt AW, Mitchell P, Wang JJ, Ziskind A, Carmichael T, Ramakrishnan R, Narendran K, Venkatesh R, Vijayan S, Zhao P, Chen X, Guadarrama-Vallejo D, Cheng CY, Perera SA, Husain R, Ho SL, Welge-Luessen UC, Mardin C, Schloetzer-Schrehardt U, Hillmer AM, Herms S, Moebus S, Nöthen MM, Weisschuh N, Shetty R, Ghosh A, Teo YY, Brown MA, Lischinsky I, Crowston JG, Coote M, Zhao B, Sang J, Zhang N, You Q, Vysochinskaya V, Founti P, Chatzikyriakidou A, Lambropoulos A, Anastasopoulos E, Coleman AL, Wilson MR, Rhee DJ, Kang JH, May-Bolchakova I, Heegaard S, Mori K, Alward WL, Jonas JB, Xu L, Liebmann JM, Chowbay B, Schaeffeler E, Schwab M, Lerner F, Wang N, Yang Z, Frezzotti P, Kinoshita S, Fingert JH, Inatani M, Tashiro K, Reis A, Edward DP, Pasquale LR, Kubota T, Wiggs JL, Pasutto F, Topouzis F, Dubina M, Craig JE, Yoshimura N, Sundaresan P, John SW, Ritch R, Hauser MA, and Khor CC

Published
2015
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17. A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome.

Author

Aung T, Ozaki M, Mizoguchi T, Allingham RR, Li Z, Haripriya A, Nakano S, Uebe S, Harder JM, Chan AS, Lee MC, Burdon KP, Astakhov YS, Abu-Amero KK, Zenteno JC, Nilgün Y, Zarnowski T, Pakravan M, Safieh LA, Jia L, Wang YX, Williams S, Paoli D, Schlottmann PG, Huang L, Sim KS, Foo JN, Nakano M, Ikeda Y, Kumar RS, Ueno M, Manabe S, Hayashi K, Kazama S, Ideta R, Mori Y, Miyata K, Sugiyama K, Higashide T, Chihara E, Inoue K, Ishiko S, Yoshida A, Yanagi M, Kiuchi Y, Aihara M, Ohashi T, Sakurai T, Sugimoto T, Chuman H, Matsuda F, Yamashiro K, Gotoh N, Miyake M, Astakhov SY, Osman EA, Al-Obeidan SA, Owaidhah O, Al-Jasim L, Al Shahwan S, Fogarty RA, Leo P, Yetkin Y, Oğuz Ç, Kanavi MR, Beni AN, Yazdani S, Akopov EL, Toh KY, Howell GR, Orr AC, Goh Y, Meah WY, Peh SQ, Kosior-Jarecka E, Lukasik U, Krumbiegel M, Vithana EN, Wong TY, Liu Y, Koch AE, Challa P, Rautenbach RM, Mackey DA, Hewitt AW, Mitchell P, Wang JJ, Ziskind A, Carmichael T, Ramakrishnan R, Narendran K, Venkatesh R, Vijayan S, Zhao P, Chen X, Guadarrama-Vallejo D, Cheng CY, Perera SA, Husain R, Ho SL, Welge-Luessen UC, Mardin C, Schloetzer-Schrehardt U, Hillmer AM, Herms S, Moebus S, Nöthen MM, Weisschuh N, Shetty R, Ghosh A, Teo YY, Brown MA, Lischinsky I, Crowston JG, Coote M, Zhao B, Sang J, Zhang N, You Q, Vysochinskaya V, Founti P, Chatzikyriakidou A, Lambropoulos A, Anastasopoulos E, Coleman AL, Wilson MR, Rhee DJ, Kang JH, May-Bolchakova I, Heegaard S, Mori K, Alward WL, Jonas JB, Xu L, Liebmann JM, Chowbay B, Schaeffeler E, Schwab M, Lerner F, Wang N, Yang Z, Frezzotti P, Kinoshita S, Fingert JH, Inatani M, Tashiro K, Reis A, Edward DP, Pasquale LR, Kubota T, Wiggs JL, Pasutto F, Topouzis F, Dubina M, Craig JE, Yoshimura N, Sundaresan P, John SW, Ritch R, Hauser MA, and Khor CC

Subjects
Animals, Asian People genetics, Asian People statistics & numerical data, Case-Control Studies, Chromosome Mapping, Exfoliation Syndrome epidemiology, Genetic Predisposition to Disease, Genome-Wide Association Study, Glaucoma, Open-Angle epidemiology, Glaucoma, Open-Angle genetics, HEK293 Cells, HeLa Cells, Humans, Japan epidemiology, MCF-7 Cells, Mice, Mice, Inbred C57BL, Tumor Cells, Cultured, Calcium Channels genetics, Exfoliation Syndrome genetics, Polymorphism, Single Nucleotide
Abstract

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Published
2015
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