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Two polymorphisms in the Cx40 promoter are associated with hypertension and left ventricular hypertrophy

Kjestine Schmidt1,2, Frank J Kaiser2,3, Jeanette Erdmann2,4

  • 1a Institut für Physiologie, Universität zu Lübeck , Lübeck , Germany .

Clinical and Experimental Hypertension (New York, N.Y. : 1993)
|May 21, 2015
PubMed

Insights

A specific genetic variation in the GJA5 gene, the -44G>A single nucleotide polymorphism (SNP), is linked to hypertension and left ventricular hypertrophy (LVH) in men. This finding may implicate connexin40 in cardiovascular risk.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Hypertension Research

Background:

  • Connexin40 (a gap junction protein) deficiency in mice causes hypertension and cardiac hypertrophy by increasing renin production.
  • The GJA5 gene encodes connexin40, with transcripts including exon1A and exon2.
  • This study investigated GJA5 polymorphisms and their association with hypertension and left ventricular hypertrophy (LVH) in a human cohort.

Purpose of the Study:

  • To identify polymorphisms in the human GJA5 gene.
  • To determine the association of GJA5 polymorphisms with hypertension and LVH.
  • To explore the functional impact of identified polymorphisms on gene expression.

Main Methods:

  • Selected a cohort (n=1677) based on a GJA5 intron SNP (rs791295).
  • Sequenced the GJA5 coding region and upstream promoter of transcript 1A in 178 probands.
  • Performed reporter gene assays in HeLa and human endothelial cells to assess promoter activity.

Main Results:

  • No coding region alterations found; functional connexin40 expression was presumed in all probands.
  • Two linked SNPs (rs35594137 -44G>A and rs11552588 +71A>G) were found at increased frequency upstream of transcript 1A.
  • The rare genotype of these SNPs was significantly associated with hypertension and LVH, particularly in men.
  • Identified SNPs did not alter promoter activity in reporter gene assays.

Conclusions:

  • The -44G>A SNP upstream of connexin40 transcript 1A is suggested as a risk factor for hypertension in men.
  • The precise mechanisms linking this SNP to hypertension remain unclear.
  • Animal studies suggest renin-producing cells may play a role in the observed hypertension.
Abstract

Keywords:
Cx40 transcript 1Aconnexin40 gene (GJA5)hypertensionpolymorphismsrenin-producing cells

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