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Genetic variations in GPSM3 associated with protection from rheumatoid arthritis affect its transcript abundance

Genes & Immunity volume 17, pages 139–147 (2016)Cite this article

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Abstract

G protein signaling modulator 3 (GPSM3) is a regulator of G protein-coupled receptor signaling, with expression restricted to leukocytes and lymphoid organs. Previous genome-wide association studies have highlighted single-nucleotide polymorphisms (SNPs; rs204989 and rs204991) in a region upstream of the GPSM3 transcription start site as being inversely correlated to the prevalence of rheumatoid arthritis (RA)—this association is supported by the protection afforded to Gpsm3-deficient mice in models of inflammatory arthritis. Here, we assessed the functional consequences of these polymorphisms. We collected biospecimens from 50 volunteers with RA diagnoses, 50 RA-free volunteers matched to the aforementioned group and 100 unmatched healthy young volunteers. We genotyped these individuals for GPSM3 (rs204989, rs204991), CCL21 (rs2812378) and HLA gene region (rs6457620) polymorphisms, and found no significant differences in minor allele frequencies between the RA and disease-free cohorts. However, we identified that individuals homozygous for SNPs rs204989 and rs204991 had decreased GPSM3 transcript abundance relative to individuals homozygous for the major allele. In vitro promoter activity studies suggest that SNP rs204989 is the primary cause of this decrease in transcript levels. Knockdown of GPSM3 in THP-1 cells, a human monocytic cell line, was found to disrupt ex vivo migration to the chemokine MCP-1.

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Acknowledgements

This work was supported in part by the National Institutes of Health under Award Number U54GM104942. BJG and DPS thank Dr Teresa Tarrant (UNC-Chapel Hill TARC) for helpful discussions on this topic.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA

    B J Gall, A B Schroer, J D Gross, V Setola & D P Siderovski

  2. Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV, USA

    A Wilson & C M Watkins

  3. Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV, USA

    P Stoilov

  4. Department of Behavioral Medicine and Psychiatry, West Virginia University School of Medicine, Morgantown, WV, USA

    V Setola

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  1. B J Gall
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Correspondence to D P Siderovski.

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Gall, B., Wilson, A., Schroer, A. et al. Genetic variations in GPSM3 associated with protection from rheumatoid arthritis affect its transcript abundance. Genes Immun 17, 139–147 (2016). https://doi.org/10.1038/gene.2016.3

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