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9. Comparative whole transcriptome analysis of Parkinson's disease focusing on the efficacy of zonisamide.

Author

Tatsuhiko Naito, Wataru Satake, Pei-Chieng Cha, Kazuhiro Kobayashi, Miho Murata, Tatsushi Toda, Naito, Tatsuhiko, Satake, Wataru, Cha, Pei-Chieng, Kobayashi, Kazuhiro, Murata, Miho, and Toda, Tatsushi

Subjects
DRUG therapy for Parkinson's disease, RESEARCH, ANTIPARKINSONIAN agents, RESEARCH methodology, EVALUATION research, COMPARATIVE studies, PARKINSON'S disease, GENE expression profiling
Abstract

Objective: Interindividual variations in responsiveness to zonisamide in patients with Parkinson's disease (PD) have been observed in clinical settings. To decipher the molecular mechanisms determining the efficacy of zonisamide, we conducted whole transcriptome sequencing analysis of patients with PD.Methods: We selected 23 super-responders (SRs) and 25 non-responders (NRs) to zonisamide from patients with PD who had participated in a previous clinical trial for the approval of zonisamide for the treatment of 'wearing-off'. Whole transcriptome analysis of peripheral blood was conducted on samples taken before and 12 weeks after zonisamide treatment. We performed differential gene expression analysis to compare between the SRs and NRs at each time point.Results: Differentially expressed genes in the pre-treatment samples were significantly enriched for glutamatergic synapses and insulin-like growth factor binding (Padj=7.8 × 10-3 and 0.029, respectively). The gene sets associated with these functions changed more dynamically by treatment in SRs than NRs (p=7.2 × 10-3 and 8.2 × 10-3, respectively).Conclusions: Our results suggest that the efficacy of zonisamide in PD patients is associated with glutamate-related synaptic modulation and p53-mediated dopaminergic neural loss. Their transcriptomic differences could be captured before treatment, which would lead to the realisation of future personalised treatment. [ABSTRACT FROM AUTHOR]

Published
2022
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10. In silico drug screening by using genome-wide association study (GWAS)-data repurposed dabrafenib, an anti-melanoma drug, for Parkinson’s disease (P3.8-031)

Author

Uenaka, Takeshi, primary, Satake, Wataru, additional, Cha, Pei-Chieng, additional, Hayakawa, Hideki, additional, Baba, Kousuke, additional, Jiang, Shiying, additional, Kobayashi, Kazuhiro, additional, Kanagawa, Motoi, additional, Okada, Yukinori, additional, Mochizuki, Hideki, additional, and Toda, Tatsushi, additional

Published
2019
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12. In silico drug screening by using genome-wide association study data repurposed dabrafenib, an anti-melanoma drug, for Parkinson’s disease

Author

Uenaka, Takeshi, primary, Satake, Wataru, additional, Cha, Pei-Chieng, additional, Hayakawa, Hideki, additional, Baba, Kousuke, additional, Jiang, Shiying, additional, Kobayashi, Kazuhiro, additional, Kanagawa, Motoi, additional, Okada, Yukinori, additional, Mochizuki, Hideki, additional, and Toda, Tatsushi, additional

Published
2018
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13. Treatment of a case of severe insulin resistance as a result of a PIK3R1 mutation with a sodium-glucose cotransporter 2 inhibitor

Author

Hamaguchi, Tetsushi, primary, Hirota, Yushi, additional, Takeuchi, Takehito, additional, Nakagawa, Yasushi, additional, Matsuoka, Atsuko, additional, Matsumoto, Masaaki, additional, Awano, Hiroyuki, additional, Iijima, Kazumoto, additional, Cha, Pei Chieng, additional, Satake, Wataru, additional, Toda, Tatsushi, additional, and Ogawa, Wataru, additional

Published
2018
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14. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study

Author

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

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

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

Author

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

Published
2017
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16. A de novo mutation of the MYH7 gene in a large Chinese family with autosomal dominant myopathy

Author

Oda, Tetsuya, primary, Xiong, Hui, additional, Kobayashi, Kazuhiro, additional, Wang, Shuo, additional, Satake, Wataru, additional, Jiao, Hui, additional, Yang, Yanling, additional, Cha, Pei-Chieng, additional, Hayashi, Yukiko K, additional, Nishino, Ichizo, additional, Suzuki, Yutaka, additional, Sugano, Sumio, additional, Wu, Xiru, additional, and Toda, Tatsushi, additional

Published
2015
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21. Single nucleotide polymorphism in ABCG2 is associated with irinotecan-induced severe myelosuppression

Author

Cha, Pei-Chieng, primary, Mushiroda, Taisei, additional, Zembutsu, Hitoshi, additional, Harada, Hiromasa, additional, Shinoda, Noriyuki, additional, Kawamoto, Shunji, additional, Shimoyama, Rai, additional, Nishidate, Toshihiko, additional, Furuhata, Tomohisa, additional, Sasaki, Kazuaki, additional, Hirata, Koichi, additional, and Nakamura, Yusuke, additional

Published
2009
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22. TUBB3 E410K Syndrome With Childhood-Onset Nonalcoholic Steatohepatitis.

Author

Mori J, Umemura A, Satake W, Cha PC, Suzuki Y, Itoh K, and Chiyonobu T

Subjects
Age of Onset, Child, Female, Humans, Non-alcoholic Fatty Liver Disease genetics, Prognosis, Exome Sequencing, Mutation, Non-alcoholic Fatty Liver Disease pathology, Tubulin genetics
Abstract

Context: Nonalcoholic fatty liver disease (NAFLD) is becoming a major issue worldwide, even in children. Multiple parallel hits hypothesis has been suggested as progress of NAFLD, but the mechanism of NAFLD is not completely understood. β-Tubulin is essential in mitoses, neuronal migration, and axon guidance during neuronal development. Pathogenic variants in the TUBB3 gene were shown to be associated with a wide spectrum of neurological abnormalities, but not accompanied by hepatic complications, such as NAFLD., Objective: This work aims to examine the association between TUBB3 mutation and nonalcoholic steatohepatitis (NASH)., Methods: An 11-year-old girl has been followed up as having atypical Möbius syndrome since infancy, as she was born with bilateral ptosis, paralytic strabismus, and facial weakness. At age 7 years, she was diagnosed with TUBB3 E410K syndrome by whole-exome sequencing. At age 10 years, her blood examination revealed elevated liver transaminase levels, which persisted for almost 2 years. She underwent liver biopsy, the results of which were suggestive of NASH., Results: The expression of TUBB3 was absent, but that of tyrosine hydroxylase (TH) was present in the parenchymal nerve fibers of the liver. On the other hand, in comparison with an autopsy case of NASH and a normal control, these showed coexpression of TUBB3 and TH in the liver., Conclusion: We report the first case of TUBB3 E410K syndrome accompanied by NASH. This case suggests that the TUBB3 mutation may be associated with the pathogenesis and progression of NASH in humans., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2022
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23. 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 TR, Hemani G, Mangino M, Ellis HP, Kurian KM, Pooley KA, Eeles RA, Lee JE, Fang S, 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 NC, 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 D, Petersen GM, Risch HA, Klein AP, Han J, Abnet CC, Freedman ND, 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 DA, Hunt K, Arking DE, Ashar FN, Sotoodehnia N, Woo D, Rosand J, Comeau ME, Brown WM, Silverman EK, Hokanson JE, Cho MH, Hui J, Ferreira MA, Thompson PJ, Morrison AC, Felix JF, Smith NL, Christiano AM, Petukhova L, Betz RC, Fan X, Zhang X, Zhu C, Langefeld CD, Thompson SD, Wang F, 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 C, Zheng W, Shu XO, Reis A, Uebe S, Hüffmeier U, Kawamura Y, Otowa T, Sasaki T, Hibberd ML, Davila S, Xie G, Siminovitch K, Bei JX, Zeng YX, Försti A, Chen B, Landi S, Franke A, Fischer A, Ellinghaus D, Flores C, Noth I, Ma SF, Foo JN, Liu J, 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 AW, Barr RG, Kahali B, Speliotes E, Yerges-Armstrong LM, Cheng CY, Jonas JB, Wong TY, Fogh I, Lin K, Powell JF, Rice K, Relton CL, Martin RM, and Davey Smith G

Subjects
Adult, Aged, Aged, 80 and over, Cardiovascular Diseases genetics, Female, Genome-Wide Association Study, Germ-Line Mutation, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment methods, Telomere genetics, Genetic Predisposition to Disease genetics, Mendelian Randomization Analysis methods, Neoplasms genetics, Telomere Homeostasis genetics
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
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