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Genome-wide linkage analysis of chromogranin b expression in the ceph pedigrees: Implications for exocytotic sympathochromaffin secretion in humans

Academic Article
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Overview

authors

  • Greenwood, T. A.
  • Cadman, P. E.
  • Stridsberg, M.
  • Nguyen, S.
  • Taupenot, L.
  • Schork, Nicholas
  • O'Connor, D. T.

publication date

  • June 2004

journal

  • Physiological Genomics  Journal

abstract

  • Chromogranin B (CgB), a major member of the chromogranin/secretogranin family of catecholamine storage vesicle secretory proteins, plays both intracellular (vesiculogenic) and extracellular (prohormone) roles in the neuroendocrine system, and its biosynthesis and release are under the control of efferent sympathetic nerve traffic ("stimulus-transcription coupling"). To explore the role of heredity in control of CgB, we conducted a genome-wide linkage analysis of CgB release in 12 extended CEPH (Centre d'Etude du Polymorphisme Humain) pedigrees. Region-specific radioimmunoassays were used to measure five CgB fragments in plasma: CgB1-16, CgB312-331, CgB439-451, CgB568-577, and CgB647-657. Substantial heritability, as measured by h2r, was observed for three of the fragment concentrations, CgB312-331, CgB439-451, and CgB568-577, which yielded h2r estimates ranging from 0.378 (P = 0.002) to 0.910 (P < 0.0000001). Variance-component genome-wide linkage analysis with 654 microsatellite markers at 5 cM spacing identified a major quantitative trait locus for CgB312-331 on chromosome 11q24-q25 with a maximum multipoint LOD score of 5.84. Significant allelic associations between markers in the region and CgB levels were also observed. Although the 2-LOD confidence interval for linkage did not include the CgB locus itself, known trans-activators of the CgB gene promoter, or prohormone cleaving proteases, examination of positional candidate loci within this region yielded novel and plausible physiological candidates for further exploration. Allelic variation in this region may thus influence effects of sympathetic outflow on target organs in humans.

subject areas

  • Alleles
  • Animals
  • Barium
  • Catecholamines
  • Chromogranin B
  • Chromogranins
  • Chromosomes, Human, Pair 11
  • Chromosomes, Human, Pair 20
  • Cohort Studies
  • Exocytosis
  • Genetic Variation
  • Humans
  • Lod Score
  • Microsatellite Repeats
  • PC12 Cells
  • Parents
  • Pedigree
  • Peptide Fragments
  • Potassium Channel Blockers
  • Potassium Channels
  • Protein Structure, Tertiary
  • Quantitative Trait Loci
  • Rats
  • Siblings
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Research

keywords

  • CHGB
  • catecholamine
  • chromaffin
  • chromogranin B
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Identity

International Standard Serial Number (ISSN)

  • 1094-8341

Digital Object Identifier (DOI)

  • 10.1152/physiolgenomics.00104.2003

PubMed ID

  • 15138309
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Additional Document Info

start page

  • 119

end page

  • 127

volume

  • 18

issue

  • 1

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