title: Genetic variations in GPSM3 associated with protection from rheumatoid arthritis affect its transcript abundance.
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.
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Gall
authors.affiliation: Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: A
authors.initials: A
authors.lastname: Wilson
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Schroer
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Gross
authors.affiliation: Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: P
authors.initials: P
authors.lastname: Stoilov
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA.|Department of Behavioral Medicine and Psychiatry, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: V
authors.initials: V
authors.lastname: Setola
authors.affiliation: Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Watkins
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Siderovski
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; C487218:GPSM3 protein, human; D020730:Guanine Nucleotide Dissociation Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering
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