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1. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

Author

Kato, N. (Norihiro), Loh, M. (Marie), Takeuchi, F. (Fumihiko), Verweij, N. (Niek), Wang, X. (Xu), Zhang, W. (Weihua), NKelly, T. (Tanika), Saleheen, D., Lehne, B. (Benjamin), Leach, I.M. (Irene Mateo), Drong, A. (Alexander), Abbott, J. (James), Wahl, S. (Simone), Tan, S.-T. (Sian-Tsung), Scott, W.R. (William R.), Campanella, G. (Gianluca), Chadeau-Hyam, M. (Marc), Afzal, U. (Uzma), Ahluwalia, T.S. (Tarunveer Singh), Bonder, M.J. (Marc), Chen, P. (Ping), Dehghan, A. (Abbas), Edwards, T.L. (Todd L.), Esko, T. (Tõnu), Go, M.J. (Min Jin), Harris, S.E. (Sarah), Hartiala, J. (Jaana), Kasela, S. (Silva), Kasturiratne, A. (Anuradhani), Khor, C.C., Kleber, M.E. (Marcus), Li, H. (Huaixing), Mok, Z.Y. (Zuan Yu), Nakatochi, M. (Masahiro), Sapari, N.S. (Nur Sabrina), Saxena, R. (Richa), Stewart, A.F. (Alexandre F.), Stolk, L. (Lisette), Tabara, Y. (Yasuharu), Teh, A.L. (Ai Ling), Wu, Y. (Ying), Wu, J.-Y. (Jer-Yuarn), Zhang, Y. (Yi), Aits, I. (Imke), Da Silva Couto Alves, A. (Alexessander), Das, S. (Shikta), Dorajoo, R. (Rajkumar), CHopewell, J. (Jemma), Kim, Y.K. (Yun Kyoung), WKoivula, R. (Robert), Luan, J. (Jian'An), Lyytikäinen, L.-P. (Leo-Pekka), NNguyen, Q. (Quang), Pereira, M.A. (Mark A), Postmus, D. (Douwe), TRaitakari, O. (Olli), Scannell Bryan, M. (Molly), Scott, R.A. (Robert), Sorice, R., Tragante, V. (Vinicius), Traglia, M. (Michela), White, J. (Jon), Yamamoto, K. (Ken), Zhang, Y. (Yonghong), Adair, L.S. (Linda), Ahmed, A. (Alauddin), Akiyama, K. (Koichi), Asif, R. (Rasheed), Aung, T. (Tin), Barroso, I.E. (Inês), Bjonnes, A. (Andrew), Braun, T.R. (Timothy R.), Cai, H. (Hui), Chang, L.-C. (Li-Ching), Chen, C.-H., Cheng, C-Y. (Ching-Yu), Chong, Y.-S. (Yap-Seng), Collins, F.S. (Francis), Courtney, R. (Regina), Davies, G. (Gail), Delgado, G., Do, L.D. (Loi D.), Doevendans, P.A. (Pieter), Gansevoort, R.T. (Ron), Gao, Y. (Ying), Grammer, T.B. (Tanja B), Grarup, N. (Niels), Grewal, J. (Jagvir), Gu, D. (D.), SWander, G. (Gurpreet), Hartikainen, A.L., Hazen, S.L. (Stanley), He, J. (Jing), Heng, C.K. (Chew-Kiat), Hixso, E.J.A. (E. James Ames), Hofman, A. (Albert), Hsu, C. (Chris), Huang, W. (Wei), Husemoen, L.L.N. (Lise Lotte), Hwang, J.-Y. (Joo-Yeon), Ichihara, S. (Sahoko), Igase, M. (Michiya), Isono, M. (Masato), Justesen, J.M. (Johanne M.), Katsuya, T. (Tomohiro), GKibriya, M. (Muhammad), Kim, Y.J., Kishimoto, M. (Miyako), Koh, W.-P. (Woon-Puay), Kohara, K. (Katsuhiko), Kumari, M. (Meena), Kwek, K. (Kenneth), Lee, N.R. (Nanette), Lee, J. (Jeannette), Liao, J. (Jie), Lieb, W. (Wolfgang), Liewald, D.C.M. (David), Matsubara, T. (Tatsuaki), Matsushita, Y. (Yumi), Meitinger, T. (Thomas), Mihailov, E. (Evelin), Milani, L. (Lili), Mills, R. (Rebecca), Mononen, K. (Kari), Müller-Nurasyid, M. (Martina), Nabika, T. (Toru), Nakashima, E. (Eitaro), Ng, H.K. (Hong Kiat), Nikus, K. (Kjell), Nutile, T., Ohkubo, T. (Takayoshi), Ohnaka, K. (Keizo), Parish, S. (Sarah), Paternoster, L. (Lavinia), Peng, H. (Hao), Peters, A. (Annette), TPham, S. (Son), Pinidiyapathirage, M.J. (Mohitha J.), Rahman, M. (Mahfuzar), Rakugi, H. (Hiromi), Rolandsson, O. (Olov), Rozario, M.A. (Michelle Ann), Ruggiero, D., Sala, C. (Cinzia), Sarju, R. (Ralhan), Shimokawa, K. (Kazuro), Snieder, H. (Harold), Sparsø, T. (Thomas), Spiering, W. (Wilko), Starr, J.M. (John), Stott, D.J. (David J.), OStram, D. (Daniel), Sugiyama, T. (Takao), Szymczak, S. (Silke), Tang, W.H.W. (W.H. Wilson), Tong, L. (Lin), Trompet, S. (Stella), Turjanmaa, V. (Väinö), Ueshima, H. (Hirotsugu), Uitterlinden, A.G. (André), Umemura, S. (Satoshi), Vaarasmaki, M. (Marja), Dam, R.M. (Rob Mvan), Gilst, W.H. (Wiek) van, Veldhuisen, D.J. (Dirk) van, Viikari, J. (Jorma), Waldenberger, M. (Melanie), Wang, Y. (Yiqin), Wang, A. (Aili), Wilson, R. (Rory), Wong, T.Y. (Tien Yin), Xiang, Y.-B. (Yong-Bing), Yamaguchi, S. (Shuhei), Ye, X. (Xingwang), Young, R. (Robin), Young, T.L. (Terri), Yuan, J.-M. (Jian-Min), Zhou, X. (Xueya), Asselbergs, F.W. (Folkert), Ciullo, M., Clarke, R. (Robert), Deloukas, P. (Panagiotis), Franke, A. (Andre), Paul, W.F. (W. Frank), Franks, S. (Steve), Friedlander, Y. (Yechiel), Gross, M.D. (Myron D.), Guo, Z. (Zhirong), Hansen, T. (T.), Jarvelin, M.-R. (Marjo-Riitta), Jørgensen, T. (Torben), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kajio, H. (Hiroshi), Kivimaki, M. (Mika), Lee, J.-Y. (Jong-Young), Lehtimäki, T. (Terho), Linneberg, A. (Allan), Miki, T. (Tetsuro), Pedersen, O. (Oluf), Samani, N.J. (Nilesh), Sørensen, T.I.A. (Thorkild), Takayanagi, R. (Ryoichi), Toniolo, D. (Daniela), Ahsan, H. (Habibul), Allayee, H. (Hooman), Chen, Y.-T. (Yuan-Tsong), Danesh, J. (John), Deary, I.J. (Ian), Franco, O.H. (Oscar), Franke, L. (Lude), THeijman, B. (Bastiaan), Holbrook, J.D. (Joanna D.), Isaacs, A.J. (Aaron), Kim, B.-J. (Bong-Jo), Lin, X. (Xu), Liu, J. (Jianjun), März, W. (Winfried), Metspalu, A. (Andres), Mohlke, K.L. (Karen), Sangher, K., Harambir, D. (Dharambir), Shu, X.-O. (Xiao-Ou), Meurs, J.B.J. (Joyce) van, Vithana, E.N. (Eranga), Wickremasinghe, A.R. (Ananda), Wijmenga, C. (Cisca), Wolffenbuttel, B.H.W. (Bruce H.W.), Yokota, M. (Mitsuhiro), Zheng, W. (Wei), Zhu, D. (Dingliang), Vineis, P. (Paolo), Kyrtopoulos, S.A. (Soterios A.), Kleinjans, J.C.S. (Jos C.S.), McCarthy, M.I. (Mark), Soong, R. (Richie), Gieger, C. (Christian), Scott, J. (James), Teo, Y.Y. (Yik Ying), He, J. (Jiang), Elliott, P. (Paul), Tai, E.S. (Shyong), Harst, P. (Pim) van der, Kooner, J.S. (Jaspal S.), Chambers, J.C. (John), Kato, N. (Norihiro), Loh, M. (Marie), Takeuchi, F. (Fumihiko), Verweij, N. (Niek), Wang, X. (Xu), Zhang, W. (Weihua), NKelly, T. (Tanika), Saleheen, D., Lehne, B. (Benjamin), Leach, I.M. (Irene Mateo), Drong, A. (Alexander), Abbott, J. (James), Wahl, S. (Simone), Tan, S.-T. (Sian-Tsung), Scott, W.R. (William R.), Campanella, G. (Gianluca), Chadeau-Hyam, M. (Marc), Afzal, U. (Uzma), Ahluwalia, T.S. (Tarunveer Singh), Bonder, M.J. (Marc), Chen, P. (Ping), Dehghan, A. (Abbas), Edwards, T.L. (Todd L.), Esko, T. (Tõnu), Go, M.J. (Min Jin), Harris, S.E. (Sarah), Hartiala, J. (Jaana), Kasela, S. (Silva), Kasturiratne, A. (Anuradhani), Khor, C.C., Kleber, M.E. (Marcus), Li, H. (Huaixing), Mok, Z.Y. (Zuan Yu), Nakatochi, M. (Masahiro), Sapari, N.S. (Nur Sabrina), Saxena, R. (Richa), Stewart, A.F. (Alexandre F.), Stolk, L. (Lisette), Tabara, Y. (Yasuharu), Teh, A.L. (Ai Ling), Wu, Y. (Ying), Wu, J.-Y. (Jer-Yuarn), Zhang, Y. (Yi), Aits, I. (Imke), Da Silva Couto Alves, A. (Alexessander), Das, S. (Shikta), Dorajoo, R. (Rajkumar), CHopewell, J. (Jemma), Kim, Y.K. (Yun Kyoung), WKoivula, R. (Robert), Luan, J. (Jian'An), Lyytikäinen, L.-P. (Leo-Pekka), NNguyen, Q. (Quang), Pereira, M.A. (Mark A), Postmus, D. (Douwe), TRaitakari, O. (Olli), Scannell Bryan, M. (Molly), Scott, R.A. (Robert), Sorice, R., Tragante, V. (Vinicius), Traglia, M. (Michela), White, J. (Jon), Yamamoto, K. (Ken), Zhang, Y. (Yonghong), Adair, L.S. (Linda), Ahmed, A. (Alauddin), Akiyama, K. (Koichi), Asif, R. (Rasheed), Aung, T. (Tin), Barroso, I.E. (Inês), Bjonnes, A. (Andrew), Braun, T.R. (Timothy R.), Cai, H. (Hui), Chang, L.-C. (Li-Ching), Chen, C.-H., Cheng, C-Y. (Ching-Yu), Chong, Y.-S. (Yap-Seng), Collins, F.S. (Francis), Courtney, R. (Regina), Davies, G. (Gail), Delgado, G., Do, L.D. (Loi D.), Doevendans, P.A. (Pieter), Gansevoort, R.T. (Ron), Gao, Y. (Ying), Grammer, T.B. (Tanja B), Grarup, N. (Niels), Grewal, J. (Jagvir), Gu, D. (D.), SWander, G. (Gurpreet), Hartikainen, A.L., Hazen, S.L. (Stanley), He, J. (Jing), Heng, C.K. (Chew-Kiat), Hixso, E.J.A. (E. James Ames), Hofman, A. (Albert), Hsu, C. (Chris), Huang, W. (Wei), Husemoen, L.L.N. (Lise Lotte), Hwang, J.-Y. (Joo-Yeon), Ichihara, S. (Sahoko), Igase, M. (Michiya), Isono, M. (Masato), Justesen, J.M. (Johanne M.), Katsuya, T. (Tomohiro), GKibriya, M. (Muhammad), Kim, Y.J., Kishimoto, M. (Miyako), Koh, W.-P. (Woon-Puay), Kohara, K. (Katsuhiko), Kumari, M. (Meena), Kwek, K. (Kenneth), Lee, N.R. (Nanette), Lee, J. (Jeannette), Liao, J. (Jie), Lieb, W. (Wolfgang), Liewald, D.C.M. (David), Matsubara, T. (Tatsuaki), Matsushita, Y. (Yumi), Meitinger, T. (Thomas), Mihailov, E. (Evelin), Milani, L. (Lili), Mills, R. (Rebecca), Mononen, K. (Kari), Müller-Nurasyid, M. (Martina), Nabika, T. (Toru), Nakashima, E. (Eitaro), Ng, H.K. (Hong Kiat), Nikus, K. (Kjell), Nutile, T., Ohkubo, T. (Takayoshi), Ohnaka, K. (Keizo), Parish, S. (Sarah), Paternoster, L. (Lavinia), Peng, H. (Hao), Peters, A. (Annette), TPham, S. (Son), Pinidiyapathirage, M.J. (Mohitha J.), Rahman, M. (Mahfuzar), Rakugi, H. (Hiromi), Rolandsson, O. (Olov), Rozario, M.A. (Michelle Ann), Ruggiero, D., Sala, C. (Cinzia), Sarju, R. (Ralhan), Shimokawa, K. (Kazuro), Snieder, H. (Harold), Sparsø, T. (Thomas), Spiering, W. (Wilko), Starr, J.M. (John), Stott, D.J. (David J.), OStram, D. (Daniel), Sugiyama, T. (Takao), Szymczak, S. (Silke), Tang, W.H.W. (W.H. Wilson), Tong, L. (Lin), Trompet, S. (Stella), Turjanmaa, V. (Väinö), Ueshima, H. (Hirotsugu), Uitterlinden, A.G. (André), Umemura, S. (Satoshi), Vaarasmaki, M. (Marja), Dam, R.M. (Rob Mvan), Gilst, W.H. (Wiek) van, Veldhuisen, D.J. (Dirk) van, Viikari, J. (Jorma), Waldenberger, M. (Melanie), Wang, Y. (Yiqin), Wang, A. (Aili), Wilson, R. (Rory), Wong, T.Y. (Tien Yin), Xiang, Y.-B. (Yong-Bing), Yamaguchi, S. (Shuhei), Ye, X. (Xingwang), Young, R. (Robin), Young, T.L. (Terri), Yuan, J.-M. (Jian-Min), Zhou, X. (Xueya), Asselbergs, F.W. (Folkert), Ciullo, M., Clarke, R. (Robert), Deloukas, P. (Panagiotis), Franke, A. (Andre), Paul, W.F. (W. Frank), Franks, S. (Steve), Friedlander, Y. (Yechiel), Gross, M.D. (Myron D.), Guo, Z. (Zhirong), Hansen, T. (T.), Jarvelin, M.-R. (Marjo-Riitta), Jørgensen, T. (Torben), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kajio, H. (Hiroshi), Kivimaki, M. (Mika), Lee, J.-Y. (Jong-Young), Lehtimäki, T. (Terho), Linneberg, A. (Allan), Miki, T. (Tetsuro), Pedersen, O. (Oluf), Samani, N.J. (Nilesh), Sørensen, T.I.A. (Thorkild), Takayanagi, R. (Ryoichi), Toniolo, D. (Daniela), Ahsan, H. (Habibul), Allayee, H. (Hooman), Chen, Y.-T. (Yuan-Tsong), Danesh, J. (John), Deary, I.J. (Ian), Franco, O.H. (Oscar), Franke, L. (Lude), THeijman, B. (Bastiaan), Holbrook, J.D. (Joanna D.), Isaacs, A.J. (Aaron), Kim, B.-J. (Bong-Jo), Lin, X. (Xu), Liu, J. (Jianjun), März, W. (Winfried), Metspalu, A. (Andres), Mohlke, K.L. (Karen), Sangher, K., Harambir, D. (Dharambir), Shu, X.-O. (Xiao-Ou), Meurs, J.B.J. (Joyce) van, Vithana, E.N. (Eranga), Wickremasinghe, A.R. (Ananda), Wijmenga, C. (Cisca), Wolffenbuttel, B.H.W. (Bruce H.W.), Yokota, M. (Mitsuhiro), Zheng, W. (Wei), Zhu, D. (Dingliang), Vineis, P. (Paolo), Kyrtopoulos, S.A. (Soterios A.), Kleinjans, J.C.S. (Jos C.S.), McCarthy, M.I. (Mark), Soong, R. (Richie), Gieger, C. (Christian), Scott, J. (James), Teo, Y.Y. (Yik Ying), He, J. (Jiang), Elliott, P. (Paul), Tai, E.S. (Shyong), Harst, P. (Pim) van der, Kooner, J.S. (Jaspal S.), and Chambers, J.C. (John)

Abstract

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10 -11 to 5.0 × 10 -21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10 -6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Published
2015
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2. The birth and development of clinical physiology in Finland.

Author

Laitinen T, Sovijärvi A, Malmberg P, Turjanmaa V, and Hartiala J

Subjects
Finland, Humans, Sweden, Hospitals, University
Abstract

The specialty of clinical physiology was established in Finland about 20 years later than in Sweden. In the early 1960s, six physicians working mainly in preclinical departments of physiology were certified as specialists in clinical physiology. Many of the first specialists working in hospitals received specialist training in Sweden. The first hospital laboratories of clinical physiology were established in Tampere Central Hospital and Turku University Hospital in 1968. Thereafter, laboratories of clinical physiology were also established in Helsinki University Hospital and in Kuopio University Hospital and later also in most central hospitals. After clinical physiology laboratories were set up in hospitals and the number of specialists increased, the specialty gradually had more impact in clinical work. In the 1999 reform, nuclear medicine, which had previously been a subspecialty, was combined with clinical physiology. Arto Uusitalo was nominated the first professor of clinical physiology in Tampere University in 1984. The first professor in Helsinki University was Anssi Sovijärvi (1994), in Kuopio University Esko Länsimies (1998), and in Turku University Jaakko Hartiala (2003). Today, at four universities professors of clinical physiology and nuclear medicine lead research and medical education in this specialty. The hospital laboratories have modern equipment, which promotes multidisciplinary research with clinicians in fruitful collaboration. The Finnish Society of Clinical Physiology was founded in 1975. Today, it has about 160 members, about half of whom are specialists in the field. On its 40th anniversary, the Society decided to publish the history of clinical physiology in Finland., (© 2022 The Authors. Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Published
2022
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3. The Duke treadmill score with bicycle ergometer: Exercise capacity is the most important predictor of cardiovascular mortality.

Author

Salokari E, Laukkanen JA, Lehtimaki T, Kurl S, Kunutsor S, Zaccardi F, Viik J, Lehtinen R, Nikus K, Kööbi T, Turjanmaa V, Kähönen M, and Nieminen T

Subjects
Adult, Aged, Cardiovascular Diseases physiopathology, Cause of Death, Female, Finland epidemiology, Humans, Male, Middle Aged, Predictive Value of Tests, Prognosis, Risk Assessment, Risk Factors, Time Factors, Bicycling, Cardiovascular Diseases diagnosis, Cardiovascular Diseases mortality, Exercise Test, Exercise Tolerance
Abstract

Background: The Duke treadmill score, a widely used treadmill testing tool, is a weighted index combining exercise time or capacity, maximum ST-segment deviation and exercise-induced angina. No previous studies have investigated whether the Duke treadmill score and its individual components based on bicycle exercise testing predict cardiovascular death., Design: Two populations with a standard bicycle testing were used: 3936 patients referred for exercise testing (2371 men, age 56 ± 13 years) from the Finnish Cardiovascular Study (FINCAVAS) and a population-based sample of 2683 men (age 53 ± 5.1 years) from the Kuopio Ischaemic Heart Disease study (KIHD)., Methods: Cox regression was applied for risk prediction with cardiovascular mortality as the primary endpoint., Results: In FINCAVAS, during a median 6.3-year (interquartile range (IQR) 4.5-8.2) follow-up period, 180 patients (4.6%) experienced cardiovascular mortality. In KIHD, 562 patients (21.0%) died from cardiovascular causes during the median follow-up of 24.1 (IQR 18.0-26.2) years. The Duke treadmill score was associated with cardiovascular mortality in both populations (FINCAVAS, adjusted hazard ratio (HR) 3.15 for highest vs. lowest Duke treadmill score tertile, 95% confidence interval (CI) 1.83-5.42, P < 0.001; KIHD, adjusted HR 1.71, 95% CI 1.34-2.18, P < 0.001). However, after progressive adjustment for the Duke treadmill score components, the score was not associated with cardiovascular mortality in either study population, as exercise capacity in metabolic equivalents of task was the dominant harbinger of poor prognosis., Conclusions: The Duke treadmill score is associated with cardiovascular mortality among patients who have undergone bicycle exercise testing, but metabolic equivalents of task, a component of the Duke treadmill score, proved to be a superior predictor.

Published
2019
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4. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.

Author

Kato N, Loh M, Takeuchi F, Verweij N, Wang X, Zhang W, Kelly TN, Saleheen D, Lehne B, Leach IM, Drong AW, Abbott J, Wahl S, Tan ST, Scott WR, Campanella G, Chadeau-Hyam M, Afzal U, Ahluwalia TS, Bonder MJ, Chen P, Dehghan A, Edwards TL, Esko T, Go MJ, Harris SE, Hartiala J, Kasela S, Kasturiratne A, Khor CC, Kleber ME, Li H, Yu Mok Z, Nakatochi M, Sapari NS, Saxena R, Stewart AFR, Stolk L, Tabara Y, Teh AL, Wu Y, Wu JY, Zhang Y, Aits I, Da Silva Couto Alves A, Das S, Dorajoo R, Hopewell JC, Kim YK, Koivula RW, Luan J, Lyytikäinen LP, Nguyen QN, Pereira MA, Postmus I, Raitakari OT, Scannell Bryan M, Scott RA, Sorice R, Tragante V, Traglia M, White J, Yamamoto K, Zhang Y, Adair LS, Ahmed A, Akiyama K, Asif R, Aung T, Barroso I, Bjonnes A, Braun TR, Cai H, Chang LC, Chen CH, Cheng CY, Chong YS, Collins R, Courtney R, Davies G, Delgado G, Do LD, Doevendans PA, Gansevoort RT, Gao YT, Grammer TB, Grarup N, Grewal J, Gu D, Wander GS, Hartikainen AL, Hazen SL, He J, Heng CK, Hixson JE, Hofman A, Hsu C, Huang W, Husemoen LLN, Hwang JY, Ichihara S, Igase M, Isono M, Justesen JM, Katsuya T, Kibriya MG, Kim YJ, Kishimoto M, Koh WP, Kohara K, Kumari M, Kwek K, Lee NR, Lee J, Liao J, Lieb W, Liewald DCM, Matsubara T, Matsushita Y, Meitinger T, Mihailov E, Milani L, Mills R, Mononen N, Müller-Nurasyid M, Nabika T, Nakashima E, Ng HK, Nikus K, Nutile T, Ohkubo T, Ohnaka K, Parish S, Paternoster L, Peng H, Peters A, Pham ST, Pinidiyapathirage MJ, Rahman M, Rakugi H, Rolandsson O, Ann Rozario M, Ruggiero D, Sala CF, Sarju R, Shimokawa K, Snieder H, Sparsø T, Spiering W, Starr JM, Stott DJ, Stram DO, Sugiyama T, Szymczak S, Tang WHW, Tong L, Trompet S, Turjanmaa V, Ueshima H, Uitterlinden AG, Umemura S, Vaarasmaki M, van Dam RM, van Gilst WH, van Veldhuisen DJ, Viikari JS, Waldenberger M, Wang Y, Wang A, Wilson R, Wong TY, Xiang YB, Yamaguchi S, Ye X, Young RD, Young TL, Yuan JM, Zhou X, Asselbergs FW, Ciullo M, Clarke R, Deloukas P, Franke A, Franks PW, Franks S, Friedlander Y, Gross MD, Guo Z, Hansen T, Jarvelin MR, Jørgensen T, Jukema JW, Kähönen M, Kajio H, Kivimaki M, Lee JY, Lehtimäki T, Linneberg A, Miki T, Pedersen O, Samani NJ, Sørensen TIA, Takayanagi R, Toniolo D, Ahsan H, Allayee H, Chen YT, Danesh J, Deary IJ, Franco OH, Franke L, Heijman BT, Holbrook JD, Isaacs A, Kim BJ, Lin X, Liu J, März W, Metspalu A, Mohlke KL, Sanghera DK, Shu XO, van Meurs JBJ, Vithana E, Wickremasinghe AR, Wijmenga C, Wolffenbuttel BHW, Yokota M, Zheng W, Zhu D, Vineis P, Kyrtopoulos SA, Kleinjans JCS, McCarthy MI, Soong R, Gieger C, Scott J, Teo YY, He J, Elliott P, Tai ES, van der Harst P, Kooner JS, and Chambers JC

Subjects
Adult, Aged, Aged, 80 and over, Asian People genetics, Cardiovascular Diseases blood, Cardiovascular Diseases ethnology, Cardiovascular Diseases genetics, Female, Genetic Predisposition to Disease ethnology, Genetic Predisposition to Disease genetics, Genetic Variation, Genotype, Humans, Male, Middle Aged, Natriuretic Peptide, Brain blood, Peptide Fragments blood, Polymorphism, Single Nucleotide, Regression Analysis, Risk Factors, White People genetics, Blood Pressure genetics, DNA Methylation, Genetic Loci genetics, Genome-Wide Association Study methods
Abstract

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Published
2015
Full Text
View/download PDF

5. Prognostic capacity of a clinically indicated exercise test for cardiovascular mortality is enhanced by combined analysis of exercise capacity, heart rate recovery and T-wave alternans.

Author

Minkkinen M, Nieminen T, Verrier RL, Leino J, Lehtimäki T, Viik J, Lehtinen R, Nikus K, Kööbi T, Turjanmaa V, and Kähönen M

Subjects
Action Potentials, Adult, Aged, Cardiovascular Diseases physiopathology, Cause of Death, Chi-Square Distribution, Female, Finland, Humans, Linear Models, Male, Middle Aged, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Recovery of Function, Risk Assessment, Risk Factors, Time Factors, Cardiovascular Diseases diagnosis, Cardiovascular Diseases mortality, Electrocardiography, Exercise Test, Exercise Tolerance, Heart Conduction System physiopathology, Heart Rate
Abstract

Background: Exercise capacity, heart rate recovery and T-wave alternans are independent predictors of cardiovascular mortality. We tested whether these parameters contain supplementary prognostic information., Methods: A total of 3609 consecutive patients (2157 men) referred for a routine, clinically indicated bicycle exercise test were enrolled in the Finnish Cardiovascular Study (FINCAVAS). Exercise capacity was measured in metabolic equivalents, heart rate recovery as the decrease in heart rate from maximum to one minute post-exercise, and T-wave alternans by time-domain Modified Moving Average method., Results: During 57-month median follow-up (interquartile range 35-78 months), 96 patients died of cardiovascular causes (primary endpoint) and 233 from any cause. All three parameters were independent predictors of cardiovascular mortality when analysed as continuous variables. Adding metabolic equivalents (p < 0.001), heart rate recovery (p = 0.002) or T-wave alternans (p = 0.01) to the linear model improved its predictive power for cardiovascular mortality. The combination of low exercise capacity (<6 metabolic equivalents), reduced heart rate recovery (≤12 beats/min) and elevated T-wave alternans (≥60 μV) yielded the highest hazard ratio for cardiovascular mortality of 16.5 (95% confidence interval 4.0-67.7, p < 0.001). Harrell's C index was 0.719 (confidence interval 0.665-0.772) for cardiovascular mortality with previously defined cutpoints (<8 units for metabolic equivalents, ≤18 beats/min for heart rate recovery and ≥60 μV for T-wave alternans)., Conclusion: The prognostic capacity of the clinical exercise test is enhanced by combined analysis of exercise capacity, heart rate recovery and T-wave alternans., (© The European Society of Cardiology 2014.)

Published
2015
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