CD14, a key candidate gene associated with a specific immune response to cockroach.

BACKGROUND: Sensitization to cockroach allergen is one of the strongest predictors of asthma morbidity, especially among African Americans. OBJECTIVE: Our aims were to determine the genomic basis of cockroach sensitization and the specific response to cockroach antigen. METHODS: We investigated the Th1/Th2 cytokine profile of co-cultured plasmacytoid dendritic cells (pDCs) and CD4+ T cells and the 'transcript signature' of the immune response to cockroach antigen using high-throughput expression profiling of co-cultured cells. RESULTS: We observed significantly elevated levels of IL-13, IL-10, and TNF-alpha, but undetectable levels of IL-12p70 and IFN-alpha, when cultures were exposed to crude cockroach antigen. A significant difference was observed for IL-13 between cockroach-allergic and non-allergic individuals (P=0.039). Microarray analyses demonstrated a greater response at 48 h compared with 4 h, with 50 genes being uniquely expressed in cockroach antigen-treated cells, including CD14, S100A8, CCL8, and IFI44L. The increased CD14 expression was further observed in purified pDCs, human monocytic THP-1 cells, and the supernatant of co-cultured pDCs and CD4+ T cells on exposure to cockroach extract. Furthermore, the most differential expression of CD14 between cockroach allergy and non-cockroach allergy was only observed among individuals with the CC 'high-risk' genotype of the CD14-260C/T. Ingenuity Pathways Analysis analyses suggested the IFN signalling as the most significant canonical pathway. CONCLUSION: Our results suggest that these differentially expressed genes, particularly CD14, and genes in the IFN signalling pathway may be important candidates for further investigation of their role in the immune response to cockroach allergen.

TSLP polymorphisms are associated with asthma in a sex-specific fashion.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in thymic stromal lymphopoietin (TSLP) have been associated with IgE (in girls) and asthma (in general). We sought to determine whether TSLP SNPs are associated with asthma in a sex-specific fashion. METHODS: We conducted regular and sex-stratified analyses of association between SNPs in TSLP and asthma in families of children with asthma in Costa Rica. Significant findings were replicated in whites and African-American participants in the Childhood Asthma Management Program, in African-Americans in the Genomic Research on Asthma in the African Diaspora study, in whites and Hispanics in the Children's Health Study, and in whites in the Framingham Heart Study (FHS). MAIN RESULTS: Two SNPs in TSLP (rs1837253 and rs2289276) were significantly associated with a reduced risk of asthma in combined analyses of all cohorts (P values of 2 × 10(-5) and 1 × 10(-5) , respectively). In a sex-stratified analysis, the T allele of rs1837253 was significantly associated with a reduced risk of asthma in males only (P = 3 × 10(-6) ). Alternately, the T allele of rs2289276 was significantly associated with a reduced risk of asthma in females only (P = 2 × 10(-4) ). Findings for rs2289276 were consistent in all cohorts except the FHS. CONCLUSIONS: TSLP variants are associated with asthma in a sex-specific fashion.

Leptin receptor polymorphisms and lung function decline in COPD.

Only a fraction of all smokers develop chronic obstructive pulmonary disease (COPD), suggesting a large role for genetic susceptibility. The leptin receptor (LEPR) is present in human lung tissue and may play a role in COPD pathogenesis. The present study examined the association between genetic variants in the LEPR gene and lung function decline in COPD. In total, 429 European Americans were randomly selected from the National Heart Lung and Blood Institute Lung Health Study. 36 single nucleotide polymorphisms (SNPs) in LEPR were genotyped using the Illumina GoldenGate platform (Broad Institute, Cambridge, MA, USA). Mean annual decline in forced expiratory volume in 1 s % predicted over the 5-yr period was calculated using linear regression. Linear regression models were also used to adjust for potential confounders. In addition, in vivo expression of the receptor gene was assessed with immunohistochemistry on lungs from smoke-exposed inbred mice. We identified significant associations (p<0.05) between lung function decline and 21 SNPs. Haplotype analyses confirmed several of these associations seen with individual markers. Immunohistochemistry results in inbred mice strains support a potential role of LEPR in COPD pathogenesis. We identified genetic variants in the LEPR gene significantly associated with lung function decline in a population of smokers with COPD. Our results support a role for LEPR as a novel candidate gene for COPD.

Association of G-protein-coupled receptor 154 with asthma and total IgE in a population of the Caribbean coast of Colombia.

BACKGROUND: G protein-coupled receptor 154 was described as an asthma susceptibility gene by positional cloning. It has been subsequently associated with asthma and other inflammatory diseases in several populations with different ethnic origin. Replication of associations adds reliability to these findings. OBJECTIVE: To analyze the association of G protein-coupled receptor 154 with asthma and total and mite-specific IgE levels in a population of the Caribbean Coast of Colombia. METHODS: We genotyped seven single nucleotide proteins (SNPs) in GPR154 in 475 asthmatics, 394 controls and 116 families from Cartagena, Colombia using either SnaPshot or TaqMan. Total and specific IgE against Blomia tropicalis and Dermatophagoides pteronyssinus were determined by ELISA. Hardy-Weinberg equilibrium was assessed and case-control and family-based analyses were performed to evaluate the association between the SNPs and their haplotypes and asthma and IgE. Association analyses in the case-control dataset were corrected by population stratification using 52 ancestry informative markers. RESULTS: Allelic distribution was similar to that described in other populations. Two SNPs were associated with the same direction of the effect in both datasets. Allele A of Hopo546333 was protective for asthma (case-control OR: 0.42; 95% CI: 0.17-0.99, P=0.042; P=0.043; families Z score=-2,236; P=0.025). Similarly, allele C of rs740347 conferred low risk for asthma (OR: 0.44; 95% CI: 0.28-0.70, P=0.00017; Pc=0.00037) and total IgE (OR: 0.29; 95% CI: 0.09-0.88, P=0.015; Pc=0.030) in the case-control study and families (Z score=-3.207, P=0.0013; Z score=-3.182, P=0.0014, respectively). Haplotype CCAGGT was associated with total IgE (OR: 1.76; 95% CI: 1.14-2.71, P=0.006, Pc=0.007) in the case-controls group and CGCGGT with both phenotypes (P=0.044 and P=0.032, respectively) in families. Neither SNPs nor haplotypes were associated with levels of mite-specific IgE. CONCLUSIONS: Our findings in a sample of asthmatics from Colombia suggest a relevant role of G protein-coupled receptor 154 in the pathogenesis of asthma and allergy.