Correspondence Genetic variation in NEDD4L, salt sensitivity, and hypertension: human NEDD4L rs4149601 G allele generates evolutionary new isoform I with C2 domain

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Tomoaki Ishigami, Naomi Araki, Shintaro Minegishi, Masanari Umemura, and Satoshi Umemura

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e carefully read the recent articles in the Journal of Hypertension by Dahlberg et al. [1] and the editorial comment on the manuscript by Graham and Padmanabhan [2]. Dahlberg et al. performed a population-based cohort study with 27 564 participants in Sweden and reported that the NEDD4L salt sensitivityassociated genotype is associated with higher blood pressure, which may translate into increased risks for cardiovascular disease (CVD)-related morbidity and mortality. The role of NEDD4L genotype in their study was clarified successfully using a hypothesis-driven approach, which might be a potent alternative strategy to genome-wide association studies (GWAS) for hypertension. However, a detailed understanding of the structures of genes and single-nucleotide polymorphisms (SNPs) is needed to avoid data misinterpretation and incorrect conclusions. As we reported previously, products of the NEDD4L gene showed molecular diversity in both humans and rodents [3,4]. Products derived from the human NEDD4L gene were particularly complex because the G allele of rs4149601 generated an evolutionary new isoform with a C2 domain, referred to as ‘ isoform I’ [3]. On the contrary, the A allele of rs4149601 failed to be spliced appropriately, resulting in a stop codon in exon 2 [3]. In addition to ‘isoform I’, we would like to stress the existence of a common NEDD4L gene product called ‘isoform II’, possessing an evolutionary conserved C2 domain [3]. In summary, individuals with GG genotype of rs4149601 would have three different isoforms, two with a C2 domain and one with no C2 domain [5], and individuals with AA genotype of rs4149601 would have two different isoforms, one with and one without a C2 domain. The NEDD4L genotype is thus very complicated, but a correct understanding of its genetic characteristics is expected to facilitate interpretation of the results of the present study.

ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.

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is associated with cardiovascular disease and cardiovascular death. J Hypertens 2014; 32:294–299. Graham L, Padmanabhan S. Nedd4l in essential hypertension. J Hypertens 2014; 32:230–232. Dunn DM, Ishigami T, Pankow J, von Niederhausern A, Alder J, Hunt SC, et al. Common variant of human nedd4l activates a cryptic splice site to form a frameshifted transcript. J Hum Genet 2002; 47:665– 676. Umemura M, Ishigami T, Tamura K, Sakai M, Miyagi Y, Nagahama K, et al. Transcriptional diversity and expression of nedd4l gene in distal nephron. Biochem Biophys Res Commun 2006; 339:1129–1137. Araki N, Umemura M, Miyagi Y, Yabana M, Miki Y, Tamura K, et al. Expression, transcription, and possible antagonistic interaction of the human nedd4l gene variant: implications for essential hypertension. Hypertension 2008; 51:773–777.

Journal of Hypertension 2014, 32:1905–1912 Department of Medical Science and Cardio-renal Medicine, Yokohama City University Graduate School of Medicine, Yokohama-city, Kanagawa, Japan Correspondence to Tomoaki Ishigami, PhD, MD, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan. E-mail: [email protected] J Hypertens 32:1905–1912 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000293

Reply Jonas Dahlberg a,b and Olle Melander a,b

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hank you for your interest in our article ‘Genetic variation in NEDD4L, an epithelial sodium channel regulator, is associated with cardiovascular disease and cardiovascular death [1].’ As you point out [2], the studied gene variance was selected for study in nearly 30 000 individuals in relation to cardiovascular disease and death for two reasons: previous literature, including our own results, showing that the gene variance studied has been previously associated with salt sensitivity, response to diuretic therapy and higher blood pressure [3–5], and previous studies showing that the rs4149601 variant affects splicing and thus structure and potentially also function. We are grateful that you emphasize that the molecular consequences of the rs4149601 are more complex than we summarize in our introduction and discussion, and believe that this underlines very clearly the need to follow up, from a mechanistic molecular point of view, why this genetic variance is associated with significantly increased risk of cardiovascular disease and mortality in the general population.

ACKNOWLEDGEMENTS REFERENCES 1. Dahlberg J, Sjogren M, Hedblad B, Engstrom G, Melander O. Genetic variation in nedd4l, an epithelial sodium channel regulator,

Journal of Hypertension

Conflicts of interest There are no conflicts of interest. www.jhypertension.com

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Correspondence

REFERENCES 1. Dahlberg J, Sjogren M, Hedblad B, Engstrom G, Melander O. Genetic variation in nedd4l, an epithelial sodium channel regulator, is associated with cardiovascular disease and cardiovascular death. J Hypertens 2014; 32:294–299. 2. Ishigami T, Araki N, Minegishi S, Umemura M, Umemura S. Genetic variation in NEDD4L, salt sensitivity, and hypertension: human NEDD4L rs4149601 G allele generates evolutionary new isoform I with C2 domain. J Hypertens 2014; 32:1905. 3. Dahlberg J, Nilsson LO, von Wowern F, Melander O. Polymorphism in nedd4l is associated with increased salt sensitivity, reduced levels of p-renin and increased levels of nt-proanp. PloS One 2007; 2:e432. 4. Svensson-Farbom P, Wahlstrand B, Almgren P, Dahlberg J, Fava C, Kjeldsen S, et al. A functional variant of the nedd4l gene is associated with beneficial treatment response with beta-blockers and diuretics in hypertensive patients. J Hypertens 2011; 29:388–395. 5. Fava C, von Wowern F, Berglund G, Carlson J, Hedblad B, Rosberg L, et al. 24-h ambulatory blood pressure is linked to chromosome 18q21-22 and genetic variation of nedd4l associates with cross-sectional and longitudinal blood pressure in swedes. Kidney Int 2006; 70:562–569. Journal of Hypertension 2014, 32:1905–1912 a

Department of Clinical Sciences in Malmo¨, Lund University and bDepartment of Internal Medicine, Ska˚ne University Hospital, Malmo¨, Sweden Correspondence to Jonas Dahlberg, Ingrid Marie Nilssons gata 42, 20502, Malmo¨, Sweden. E-mail: [email protected]

J Hypertens 32:1905–1912 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000294

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