OBJECTIVE: The capability of the protein NEDD4L to reduce renal tubular expression of epithelial Na+ channel (ENaC) is influenced by a functional rs4149601 G→A NEDD4L polymorphism. As diuretics and β-blockers inhibit renal sodium reabsorption and renin release, respectively, we hypothesized that the β-blocker or diuretic-induced blood pressure reduction and prevention of cardiovascular disease would be greater in patients with the highest ENaC expression (rs4149601 G-allele), whereas there would be no such genetically mediated differences in treatment efficacy among patients treated with the vasodilator diltiazem. METHODS: We related rs4149601 status to 6-month blood pressure reduction and risk of cardiovascular events in 5152 hypertensive patients (DBP ≥ 100 mmHg) from the Nordic Diltiazem Study (NORDIL) randomized to either β-blocker and/or diuretic-based treatment or diltiazem-based treatment. RESULTS: In patients on β-blocker or diuretic monotherapy, carriers of the G-allele had greater SBP reduction (19.5 ± 16.8 vs. 15.0 ± 19.3 mmHg, P < 0.001) and DBP reduction (15.4 ± 8.3vs. 14.1 ± 8.4 mmHg, P = 0.02) and during 4.5 years of follow-up among patients randomized to β-blockers and/or diuretics, carriers of the G-allele had greater protection from cardiovascular events [relative risk (RR) = 0.52, 95% confidence interval (CI) = 0.36-0.74, P < 0.001] as compared to AA homozygotes. Within the diltiazem group, there was no difference in blood pressure reduction or risk of cardiovascular events according to genotype. CONCLUSION: The functional NEDD4L rs4149601 polymorphism influences the efficacy of β-blocker and/or diuretic-based antihypertensive treatment both in terms of blood pressure reduction and cardiovascular disease protection, whereas diltiazem-based antihypertensive treatment efficacy is not influenced by this NEDD4L polymorphism.
RCT Entities:
OBJECTIVE: The capability of the protein NEDD4L to reduce renal tubular expression of epithelial Na+ channel (ENaC) is influenced by a functional rs4149601 G→A NEDD4L polymorphism. As diuretics and β-blockers inhibit renal sodium reabsorption and renin release, respectively, we hypothesized that the β-blocker or diuretic-induced blood pressure reduction and prevention of cardiovascular disease would be greater in patients with the highest ENaC expression (rs4149601 G-allele), whereas there would be no such genetically mediated differences in treatment efficacy among patients treated with the vasodilator diltiazem. METHODS: We related rs4149601 status to 6-month blood pressure reduction and risk of cardiovascular events in 5152 hypertensivepatients (DBP ≥ 100 mmHg) from the Nordic Diltiazem Study (NORDIL) randomized to either β-blocker and/or diuretic-based treatment or diltiazem-based treatment. RESULTS: In patients on β-blocker or diuretic monotherapy, carriers of the G-allele had greater SBP reduction (19.5 ± 16.8 vs. 15.0 ± 19.3 mmHg, P < 0.001) and DBP reduction (15.4 ± 8.3vs. 14.1 ± 8.4 mmHg, P = 0.02) and during 4.5 years of follow-up among patients randomized to β-blockers and/or diuretics, carriers of the G-allele had greater protection from cardiovascular events [relative risk (RR) = 0.52, 95% confidence interval (CI) = 0.36-0.74, P < 0.001] as compared to AA homozygotes. Within the diltiazem group, there was no difference in blood pressure reduction or risk of cardiovascular events according to genotype. CONCLUSION: The functional NEDD4Lrs4149601 polymorphism influences the efficacy of β-blocker and/or diuretic-based antihypertensive treatment both in terms of blood pressure reduction and cardiovascular disease protection, whereas diltiazem-based antihypertensive treatment efficacy is not influenced by this NEDD4L polymorphism.
Authors: Yun Ju Sung; Lisa de Las Fuentes; Thomas W Winkler; Daniel I Chasman; Amy R Bentley; Aldi T Kraja; Ioanna Ntalla; Helen R Warren; Xiuqing Guo; Karen Schwander; Alisa K Manning; Michael R Brown; Hugues Aschard; Mary F Feitosa; Nora Franceschini; Yingchang Lu; Ching-Yu Cheng; Xueling Sim; Dina Vojinovic; Jonathan Marten; Solomon K Musani; Tuomas O Kilpeläinen; Melissa A Richard; Stella Aslibekyan; Traci M Bartz; Rajkumar Dorajoo; Changwei Li; Yongmei Liu; Tuomo Rankinen; Albert Vernon Smith; Salman M Tajuddin; Bamidele O Tayo; Wei Zhao; Yanhua Zhou; Nana Matoba; Tamar Sofer; Maris Alver; Marzyeh Amini; Mathilde Boissel; Jin Fang Chai; Xu Chen; Jasmin Divers; Ilaria Gandin; Chuan Gao; Franco Giulianini; Anuj Goel; Sarah E Harris; Fernando P Hartwig; Meian He; Andrea R V R Horimoto; Fang-Chi Hsu; Anne U Jackson; Candace M Kammerer; Anuradhani Kasturiratne; Pirjo Komulainen; Brigitte Kühnel; Karin Leander; Wen-Jane Lee; Keng-Hung Lin; Jian'an Luan; Leo-Pekka Lyytikäinen; Colin A McKenzie; Christopher P Nelson; Raymond Noordam; Robert A Scott; Wayne H H Sheu; Alena Stančáková; Fumihiko Takeuchi; Peter J van der Most; Tibor V Varga; Robert J Waken; Heming Wang; Yajuan Wang; Erin B Ware; Stefan Weiss; Wanqing Wen; Lisa R Yanek; Weihua Zhang; Jing Hua Zhao; Saima Afaq; Tamuno Alfred; Najaf Amin; Dan E Arking; Tin Aung; R Graham Barr; Lawrence F Bielak; Eric Boerwinkle; Erwin P Bottinger; Peter S Braund; Jennifer A Brody; Ulrich Broeckel; Brian Cade; Archie Campbell; Mickaël Canouil; Aravinda Chakravarti; Massimiliano Cocca; Francis S Collins; John M Connell; Renée de Mutsert; H Janaka de Silva; Marcus Dörr; Qing Duan; Charles B Eaton; Georg Ehret; Evangelos Evangelou; Jessica D Faul; Nita G Forouhi; Oscar H Franco; Yechiel Friedlander; He Gao; Bruna Gigante; C Charles Gu; Preeti Gupta; Saskia P Hagenaars; Tamara B Harris; Jiang He; Sami Heikkinen; Chew-Kiat Heng; Albert Hofman; Barbara V Howard; Steven C Hunt; Marguerite R Irvin; Yucheng Jia; Tomohiro Katsuya; Joel Kaufman; Nicola D Kerrison; Chiea Chuen Khor; Woon-Puay Koh; Heikki A Koistinen; Charles B Kooperberg; Jose E Krieger; Michiaki Kubo; Zoltan Kutalik; Johanna Kuusisto; Timo A Lakka; Carl D Langefeld; Claudia Langenberg; Lenore J Launer; Joseph H Lee; Benjamin Lehne; Daniel Levy; Cora E Lewis; Yize Li; Sing Hui Lim; Ching-Ti Liu; Jianjun Liu; Jingmin Liu; Yeheng Liu; Marie Loh; Kurt K Lohman; Tin Louie; Reedik Mägi; Koichi Matsuda; Thomas Meitinger; Andres Metspalu; Lili Milani; Yukihide Momozawa; Thomas H Mosley; Mike A Nalls; Ubaydah Nasri; Jeff R O'Connell; Adesola Ogunniyi; Walter R Palmas; Nicholette D Palmer; James S Pankow; Nancy L Pedersen; Annette Peters; Patricia A Peyser; Ozren Polasek; David Porteous; Olli T Raitakari; Frida Renström; Treva K Rice; Paul M Ridker; Antonietta Robino; Jennifer G Robinson; Lynda M Rose; Igor Rudan; Charumathi Sabanayagam; Babatunde L Salako; Kevin Sandow; Carsten O Schmidt; Pamela J Schreiner; William R Scott; Peter Sever; Mario Sims; Colleen M Sitlani; Blair H Smith; Jennifer A Smith; Harold Snieder; John M Starr; Konstantin Strauch; Hua Tang; Kent D Taylor; Yik Ying Teo; Yih Chung Tham; André G Uitterlinden; Melanie Waldenberger; Lihua Wang; Ya Xing Wang; Wen Bin Wei; Gregory Wilson; Mary K Wojczynski; Yong-Bing Xiang; Jie Yao; Jian-Min Yuan; Alan B Zonderman; Diane M Becker; Michael Boehnke; Donald W Bowden; John C Chambers; Yii-Der Ida Chen; David R Weir; Ulf de Faire; Ian J Deary; Tõnu Esko; Martin Farrall; Terrence Forrester; Barry I Freedman; Philippe Froguel; Paolo Gasparini; Christian Gieger; Bernardo Lessa Horta; Yi-Jen Hung; Jost Bruno Jonas; Norihiro Kato; Jaspal S Kooner; Markku Laakso; Terho Lehtimäki; Kae-Woei Liang; Patrik K E Magnusson; Albertine J Oldehinkel; Alexandre C Pereira; Thomas Perls; Rainer Rauramaa; Susan Redline; Rainer Rettig; Nilesh J Samani; James Scott; Xiao-Ou Shu; Pim van der Harst; Lynne E Wagenknecht; Nicholas J Wareham; Hugh Watkins; Ananda R Wickremasinghe; Tangchun Wu; Yoichiro Kamatani; Cathy C Laurie; Claude Bouchard; Richard S Cooper; Michele K Evans; Vilmundur Gudnason; James Hixson; Sharon L R Kardia; Stephen B Kritchevsky; Bruce M Psaty; Rob M van Dam; Donna K Arnett; Dennis O Mook-Kanamori; Myriam Fornage; Ervin R Fox; Caroline Hayward; Cornelia M van Duijn; E Shyong Tai; Tien Yin Wong; Ruth J F Loos; Alex P Reiner; Charles N Rotimi; Laura J Bierut; Xiaofeng Zhu; L Adrienne Cupples; Michael A Province; Jerome I Rotter; Paul W Franks; Kenneth Rice; Paul Elliott; Mark J Caulfield; W James Gauderman; Patricia B Munroe; Dabeeru C Rao; Alanna C Morrison Journal: Hum Mol Genet Date: 2019-08-01 Impact factor: 6.150
Authors: J A Johnson; L H Cavallari; A L Beitelshees; J P Lewis; A R Shuldiner; D M Roden Journal: Clin Pharmacol Ther Date: 2011-09-14 Impact factor: 6.875
Authors: Caitrin W McDonough; Sarah E Burbage; Julio D Duarte; Yan Gong; Taimour Y Langaee; Stephen T Turner; John G Gums; Arlene B Chapman; Kent R Bailey; Amber L Beitelshees; Eric Boerwinkle; Carl J Pepine; Rhonda M Cooper-DeHoff; Julie A Johnson Journal: J Hypertens Date: 2013-04 Impact factor: 4.844