A SOCS-1 promoter variant is associated with total serum IgE levels

• Published in: The Journal of immunology (1950) Vol. 187; no. 5; pp. 2794 - 2802
• Main Authors: Mostecki, Justin, Cassel, Suzanne L, Klimecki, Walter T, Stern, Debra A, Knisz, Judit, Iwashita, Sachiyo, Graves, Penelope, Miller, Rachel L, van Peer, Maartje, Halonen, Marilyn, Martinez, Fernando D, Vercelli, Donata, Rothman, Paul B
• Format: Journal Article
• Language: English
• Published: United States 01.09.2011
• Subjects: Animals; Base Sequence; Child; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation - genetics; Genome-Wide Association Study; Genotype; Humans; Immunoglobulin E - biosynthesis; Immunoglobulin E - blood; Immunoglobulin E - genetics; Linkage Disequilibrium; Mice; Mice, Knockout; Molecular Sequence Data; Polymorphism, Single Nucleotide; Promoter Regions, Genetic - genetics; Reverse Transcriptase Polymerase Chain Reaction; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Transfection
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0902569

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.