Functional Polymorphism in theSuppressor of Cytokine Signaling 1Gene Associated with Adult Asthma

Abstract

Suppressor of cytokine signaling (SOCS) 1 is an essential physiologic regulator of the IFN-gamma signaling that is crucial to lead appropriate immune responses, and impaired IFN-gamma production is considered a hallmark of atopic diseases. Recent study has shown that SOCS1 is also crucial in attenuating type 1 IFN signaling and in limiting the host response to viral infection. Clinical and experimental evidence suggest an important role for respiratory viral infections in the development of asthma. To assess genetic functional variants of SOCS1 related to susceptibility and clinical phenotypes in adult asthma in a Japanese population, we conducted association and haplotype analyses of 462 subjects with adult asthma and 639 control subjects. After screening for polymorphisms, we identified a total of 13 variants and characterized the linkage disequilibrium (LD) mapping of the gene. Three variants were selected for genotyping with regard to the LD pattern, and we found a significant association between an SOCS1 promoter polymorphism -1478CA > del and adult asthma (P = 0.0063). The three-locus haplotype of SOCS1 using these three polymorphisms also showed a positive association with a haplotype T-C-del (-5388T, -3969C, and -1478 del; P = 0.0097). Furthermore, reporter gene analysis revealed that related promoter variant -1478 del enhanced the transcriptional level of SOCS1 in human lung epithelial cells, and induced higher levels of protein expression of SOCS1 and lower phosphorylation of STAT1 stimulated with IFN-beta. These findings suggest that the SOCS1 gene might be involved in the development of adult asthma through functional genetic polymorphism.

The SOCS-1 -1478CA/del Polymorphism is not Associated with Colorectal Cancer or Age at Onset in Turkish Subjects

“…For the purpose of this study, we selected this well-defined single nucleotide polymorphism as it has been previously shown to have functional consequences (Harada et al, 2007). Based on the observed prevalence of the minor del allele, our study had 80% power to detect a relative risk of 1.67 with a significance level (alpha) of 0.05 (two-tailed) between CC cases and controls.…”

“…The procedure for detecting the SOCS-1 -1478CA>del polymorphism was based on PCR amplification (forward primer: 5'-TGTCGTCCAGCTGCACCTC-3'; reverse primer: 5'-ACCACAGGCTTCAGAGGAAC-3'), restriction cleavage with DdeI (New England Biolabs, Ipswich, MA, USA) and separation of the DNA fragments by 3% agarose gel electrophoresis [figure1], as previously described (Harada et al, 2007). For quality control, genotyping analyses were done blind with respect to case/control status, and a random 25% of the samples were repeated.…”

“…In particular, evidence suggests that SOCS-1 acts as a critical regulator of the IFN-γ (Piganis et al, 2011) and IL-4 (Losman et al, 1999) signaling pathways, which are both involved in the pathogenesis of CC (Landi et al, 2007;Slattery et al, 2011). A functional SOCS-1 promoter polymorphism (-1478CA>del) has been shown to increase SOCS-1 transcription in vitro (Harada et al, 2007). Notably, a high tumor-specific expression of SOCS1 has recently suggested a direct tumor-promoting function of SOCS1 (Zhang et al, 2012).…”

Replication of genetic association studies in asthma and related phenotypes

“…The details of these subjects have been described elsewhere. 10,12,14 For childhood controls and the investigation of total and specific IgE levels, we recruited children attending an elementary school in Chiba City, Japan. The clinical characteristics of this population as well as inclusion and exclusion criteria have been described previously.…”

“…12 The re-evaluation of these associations is conditioned by the limitations of the original reports in which childhood asthma included subjects with nonatopic asthma and those who were o4 years of age. The adult asthma cases also included nonatopic asthma in some of these reports.…”