Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 33, Pages 14034-14039Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0904084106
Keywords
association study; osmoregulation; sodium; transient receptor potential; cell volume regulation
Categories
Funding
- National Institutes of Health [R21AG029968, 30AG08017, P30 AG008017, P50 AT00066]
- American Heart Association
- Department of Veterans Affairs
- Spanish Ministry of Science and Innovation [SAF2006-13893-C02-02, SAF2006-04973, red HERACLES FIS RD06/0009]
- Marato de TV3 [061331, 080430]
- Generalitat de Catalunya
- Department of Veterans Affairs (OBAS)
- Oregon Clinical and Translational Research Institute (OCTR)
- National Center for Research Resources (NCRR) [UL1 RR024140]
- component of the National Institutes of Health (NIH)
- NIH Roadmap for Medical Research
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
- National Institute on Aging (NIA)
- National Center for Research Resources (NCRR)
- National Institutes of Health Roadmap for Medical Research [UL1 RR024140, U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01-AG027810]
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Disorders of water balance are among the most common and morbid of the electrolyte disturbances, and are reflected clinically as abnormalities in the serum sodium concentration. The transient receptor potential vanilloid 4 (TRPV4) channel is postulated to comprise an element of the central tonicity-sensing mechanism in the mammalian hypothalamus, and is activated by hypotonic stress in vitro. A nonsynonymous polymorphism in the TRPV4 gene gives rise to a Pro-to-Ser substitution at residue 19. We show that this polymorphism is significantly associated with serum sodium concentration and with hyponatremia (serum sodium concentration <= 135 mEq/L) in 2 non-Hispanic Caucasian male populations; in addition, mean serum sodium concentration is lower among subjects with the TRPV4(P19S) allele relative to the wild-type allele. Subjects with the minor allele were 2.4-6.4 times as likely to exhibit hyponatremia as subjects without the minor allele (after inclusion of key covariates). Consistent with these observations, a human TRPV4 channel mutated to incorporate the TRPV4(P19S) polymorphism showed diminished response to hypotonic stress (relative to the wild-type channel) and to the osmotransducing lipid epoxyeicosatrienoic acid in heterologous expression studies. These data suggest that this polymorphism affects TRPV4 function in vivo and likely influences systemic water balance on a population-wide basis.
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