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Olle Melander

Principal investigator

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24-hour Ambulatory Blood Pressure is Linked to Chromosome 18q21-22 and Genetic Variation of NEDD4L Associates with Cross-Sectional and Longitudinal Blood Pressure in Swedes.

Author

  • Cristiano Fava
  • Fredrik Wowern
  • Göran Berglund
  • Jonas Carlson
  • Bo Hedblad
  • Lena Nilsson
  • Philippe Burri
  • Peter Almgren
  • Olle Melander

Summary, in English

Numerous linkage studies have indicated chromosome 18q21–22 as a locus of importance for blood pressure regulation. This locus harbors the neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloride-sensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single nucleotide polymorphism markers located within the NEDD4L gene) on chromosome 18 between 70–104 cM and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found for 24 h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P=0.0014). In a large population sample (n=4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by alternative splicing leads to varying expression of a functionally crucial C2 domain, was associated with diastolic blood pressure (DBP) (P=0.03) and DBP progression over time (P=0.04). A genotype combination of the rs4149601 and an intronic NEDD4L marker (rs2288774) was associated with systolic blood pressure (SBP) (P=0.01), DBP (P=0.04), and progression of both SBP (P=0.03) and DBP (P=0.05) over time. A quantitative transmission disequilibrium test in the family material of the rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure, possibly as a consequence of altered NEDD4L interaction with ENaC.

Department/s

  • Genomics, Diabetes and Endocrinology
  • Cardiovascular Research - Hypertension
  • Internal Medicine - Epidemiology
  • Cardiology
  • Cardiovascular Research - Epidemiology
  • Diabetes - Islet Patophysiology
  • Department of Clinical Sciences, Malmö

Publishing year

2006

Language

English

Pages

562-569

Publication/Series

Kidney International

Volume

70

Issue

3

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Urology and Nephrology

Keywords

  • blood pressure
  • linkage
  • NEDD4L
  • genetics

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology
  • Cardiovascular Research - Hypertension
  • Internal Medicine - Epidemiology
  • Cardiovascular Research - Epidemiology
  • Diabetes - Islet Patophysiology

ISBN/ISSN/Other

  • ISSN: 1523-1755