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Analysis of a missense variant of the human N-formyl peptide receptor that is associated with agonist-independent β-arrestin association and indices of inflammation

The Pharmacogenomics Journal volume 7, pages 190–199 (2007)Cite this article

Abstract

Formyl-Met-Leu-Phe (fMLP) is a potent chemoattractant molecule released from both bacteria and damaged mitochondria that activates fMLP receptors (FPR) leading to neutrophil chemotaxis, degranulation and superoxide production. A common missense single nucleotide polymorphism in the human FPR1 gene at nucleotide c.32C>T results in the amino-acid substitution, p.I11T, in the FPR1 extracellular amino-terminus. The minor (c.32T) allele frequencies were 0.25, 0.27, 0.25, 0.15 and 0.14 in healthy Caucasian, African, East Indian, Chinese and Native Canadian individuals, respectively. In subjects homozygous for the p.T11 allele, we find elevated serum concentrations of C-reactive protein, increased absolute counts of blood leukocytes and neutrophils, and erythrocyte sedimentation rates. When expressed in HEK 293 and RBL-2H3 cells a substantial proportion of FPR1 p.I11T variant is retained intracellularly and agonist-independent internalization of the FPR1 p.I11T variant, but not the wild-type FPR1, is constitutively associated with β-arrestin2-GFP in vesicles. Moreover, basal N-acetyl-D-glucosaminidase release is increased in primary neutrophils isolated from subjects either heterozygous or homozygous for the FPR1 p.T11 allele. Taken together, the data suggest an increased receptor activity and phenotypic expression of increased inflammatory indices in subjects with the p.T11 allele.

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Abbreviations

CRP:

C reactive protein

ESR:

erythrocyte sedimentation rate

fMLP:

formyl-Met-Leu-Phe

FPR1:

formyl peptide receptor

GFP:

green fluorescent protein

GPCR:

G protein-coupled receptor

HEK 293:

human embryonic kidney cells

PMA:

phorbol myristate acetate⁁RBL-2H3⁁rat basophilic leukemia cells

SNP:

single nucleotide polymorphism

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Acknowledgements

SSGF and RAH hold Canada Research Chairs and are Career Investigators of the Heart and Stroke Foundation of Ontario. This work was supported by HSFO Grants T-4987 and T-5933 to SSGF, HSFO Grant T-4772 to RAH and CIHR Grant MOP 43959 to RDF.

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Authors and Affiliations

  1. Cell Biology Research Group, The University of Western Ontario, London, ON, Canada

    M Bhattacharya, F M Ribeiro, R D Feldman & S S G Ferguson

  2. Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, The University of Western Ontario, London, ON, Canada

    J Wang & R A Hegele

  3. Department of Physiology & Pharmacology, The University of Western Ontario, London, ON, Canada

    S J Dixon, R D Feldman & S S G Ferguson

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  1. M Bhattacharya
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Correspondence to S S G Ferguson.

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Bhattacharya, M., Wang, J., Ribeiro, F. et al. Analysis of a missense variant of the human N-formyl peptide receptor that is associated with agonist-independent β-arrestin association and indices of inflammation. Pharmacogenomics J 7, 190–199 (2007). https://doi.org/10.1038/sj.tpj.6500416

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