Human Genetics

, Volume 112, Issue 1, pp 62–70

Common variations in noncoding regions of the human natriuretic peptide receptor A gene have quantitative effects

  • Joshua W. Knowles
  • Laurie M. Erickson
  • Vanessa K. Guy
  • Carlie S. Sigel
  • Jennifer C. Wilder
  • Nobuyo Maeda
Original Investigation

DOI: 10.1007/s00439-002-0834-z

Cite this article as:
Knowles, J.W., Erickson, L.M., Guy, V.K. et al. Hum Genet (2003) 112: 62. doi:10.1007/s00439-002-0834-z

Abstract.

Genetic susceptibility to common conditions, such as essential hypertension and cardiac hypertrophy, is probably determined by various combinations of small quantitative changes in the expression of many genes. NPR1, coding for natriuretic peptide receptor A (NPRA), is a potential candidate, because NPRA mediates natriuretic, diuretic, and vasorelaxing actions of the nariuretic peptides, and because genetically determined quantitative changes in the expression of this gene affect blood pressure and heart weight in a dose-dependent manner in mice. To determine whether there are common quantitative variants in human NPR1, we have sequenced the entire human NPR1 gene and identified 10 polymorphic sites in its non-coding sequence by using DNA from 34 unrelated human individuals. Five of the sites are single nucleotide polymorphisms; the remaining five are length polymorphisms, including a highly variable complex dinucleotide repeat in intron 19. There are three common haplotypes 5' to this dinucleotide repeat and three 3' to it, but the 5' haplotypes and 3' haplotypes appear to be randomly associated. Transient expression analysis in cultured cells of reporter plasmids with the proximal promoter sequences of NPR1 and its 3' untranslated regions showed that these polymorphisms have functional effects. We conclude that common NPR1 alleles can alter expression of the gene as much as two-fold and could therefore significantly affect genetic risks for essential hypertension and cardiac hypertrophy in humans.

Copyright information

© Springer-Verlag 2002

Authors and Affiliations

  • Joshua W. Knowles
    • 1
  • Laurie M. Erickson
    • 1
  • Vanessa K. Guy
    • 1
  • Carlie S. Sigel
    • 1
  • Jennifer C. Wilder
    • 1
  • Nobuyo Maeda
    • 1
  1. 1.Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599–7525, USA
  2. 2.Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599–7525, USA
  3. 3.Present address: Fujisawa Research Institute of America, 1801 Maple Avenue, Evanston, Illinois, USA