title: A SOCS-1 promoter variant is associated with total serum IgE levels.
abstract: SOCS-1 is a critical regulator of multiple signaling pathways, including those activated by cytokines that regulate Ig H chain class switching to IgE. Analysis of mice with mutations in the SOCS-1 gene demonstrated that IgE levels increase with loss of SOCS-1 alleles. This suggested that overall SOCS-1 acts as an inhibitor of IgE expression in vivo. A genetic association study was performed in 474 children enrolled in the Tucson Children's Respiratory Study to determine if genetic variation in the SOCS-1 locus correlates with altered levels of IgE. Carriers of the C-allele for a novel, 3' genomic single nucleotide polymorphism (SNP) in the SOCS-1 gene (SOCS1+1125G > C; rs33932899) were found to have significantly lower levels of serum IgE compared with those of homozygotes for the G-allele. Analysis demonstrated that the SOCS1+1125G > C SNP was in complete linkage disequilibrium with an SNP at position SOCS1-820G > T (rs33977706) of the SOCS-1 promoter. Carriers of the T-allele at the SOCS1-820G > T were also found to be associated with the decreased IgE. The promoter SNP increased transcriptional activity of the SOCS-1 promoter in reporter assays and human B cells. Consistent with this observation, the presence of this polymorphism within the promoter abolished binding of yin yang-1, which is identified as a negative regulator of SOCS-1 transcriptional activity. These data suggest that genetic variation in the SOCS-1 promoter may affect IgE production.
authors.affiliation: Department of Microbiology, Columbia University, New York, NY 10032, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Mostecki
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Cassel
authors.forename: Walter T
authors.initials: WT
authors.lastname: Klimecki
authors.forename: Debra A
authors.initials: DA
authors.lastname: Stern
authors.forename: Judit
authors.initials: J
authors.lastname: Knisz
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Iwashita
authors.forename: Penelope
authors.initials: P
authors.lastname: Graves
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Miller
authors.forename: Maartje
authors.initials: M
authors.lastname: van Peer
authors.forename: Marilyn
authors.initials: M
authors.lastname: Halonen
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Martinez
authors.forename: Donata
authors.initials: D
authors.lastname: Vercelli
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rothman
mesh_terms: D000818:Animals; D001483:Base Sequence; D002648:Child; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D015810:Linkage Disequilibrium; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*; D014162:Transfection
chemical_list: C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007073:Immunoglobulin E