Polymorphisms in the 5 ' region of the CD14 gene are associated with eczema in young children

Harvard University, Cambridge, Massachusetts, United States
Journal of Allergy and Clinical Immunology (Impact Factor: 11.48). 06/2005; 115(5):1056-62. DOI: 10.1016/j.jaci.2005.02.006
Source: PubMed


Variants in the CD14 gene (CD14) are hypothesized to be associated with atopic disorders. However, most studies have only investigated one polymorphism in this gene.
We sought to study the association of 5 single nucleotide polymorphisms (SNPs) in the 5' flanking region of CD14 with eczema and serum IgE levels in young children.
We genotyped 5 SNPs in an approximately 6.5-kb region in the 5' region of CD14 in 344 2-year-old white children from 2 birth cohorts in the northeastern United States. We examined the relation of both single SNPs and haplotypes in CD14 with the atopic outcomes.
Two SNPs were significantly associated with eczema. In dominant models adjusted for potential confounders, SNP rs2569193 was associated with significantly decreased risk for eczema (odds ratio [OR] for CT/TT vs CC, 0.5; 95% CI, 0.3-0.8), whereas SNP rs2569190 (also reported as the C-159T) was associated with significantly increased risk for eczema (OR for CT/TT vs CC, 2.3; 95% CI, 1.4-3.8). The CT/TT genotypes of SNP rs2569190 also had higher geometric means of serum IgE than the CC genotype (24.6 vs 15 IU/mL, P = .025). Haplotype analyses provided results similar to those of the single SNP analyses.
Our results contradict previous reports that have found a protective effect of the T allele of SNP rs2569190 (C-159T) against atopic disorders. Nevertheless, these results confirm the importance of polymorphisms in CD14 in the development of atopy, and future studies of this gene region will need to account for linkage disequilibrium and environmental exposures unique to the study population.

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    • "The Boston Home Allergens and Asthma and the Connecticut Childhood Asthma Study cohorts were similar with respect to their geographic ascertainment area, recruitment scheme, data collection time frames, and data collection methods. In a similar manner to previous work, the two cohorts were combined for this analysis [15,17]. No evidence of population stratification was detected in the combined cohort (p-value = 0.90). "
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    ABSTRACT: Polymorphisms in the endotoxin-mediated TLR4 pathway genes have been associated with asthma and atopy. We aimed to examine how genetic polymorphisms in innate immunity pathways interact with endotoxin to influence asthma risk in children. In a previous analysis of 372 children from the Boston Home Allergens and the Connecticut Childhood Asthma studies, 7 SNPs in 6 genes (CARD15, TGFB1, LY96, ACAA1, DEFB1 and IFNG) involved in innate immune pathways were associated with asthma, and 5 SNPs in 3 genes (CD80, STAT4, IRAK2) were associated with eczema. We tested these SNPs for interaction with early life endotoxin exposure (n = 291), in models for asthma and eczema by age 6. We found a significant interaction between endotoxin and a SNP (rs156265) in ACAA1 (p = 0.0013 for interaction). Increased endotoxin exposure (by quartile) showed protective effects for asthma in individuals with at least one copy of the minor allele (OR = 0.39 per quartile increase in endotoxin, 95% CI 0.15 to 1.01). Endotoxin exposure did not reduce the risk of asthma in children homozygous for the major allele. Our findings suggest that protective effects of endotoxin exposure on asthma may vary depending upon the presence or absence of a polymorphism in ACAA1.
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    • "Wang et al. (21) 2005 Chinese The T allele was associated with elevated IgE when the T allele was part of a haplotype containing a D5S2011 E allele. Litonjua et al. (14) 2005 Caucasian in America Infants with CC/CT genotypes had significantly increase risk for eczema and elevated total IgE. Kedda et al. (41) 2005 Caucasian in Australia There was a weak association (P = 0.084) with the T allele that was associated with atopy. "
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    ABSTRACT: This review considers the data from studies analysing associations between the CD14C-159T single nucleotide polymorphism (SNP) and asthmatic phenotypes and discusses the variability of the conclusions. By searching PubMed and EMBASE for articles on CD14C-159T -related population or family-based association studies, 47 were identified up till September 2007. Collectively, the studies reviewed herein consistently showed population differences in frequencies of the alleles of the SNP, with African descent having the highest C allele frequencies, followed by Caucasians and Asians. The T allele of the SNP was associated with increased sCD14 in some studies but not in others. Inconsistently, the C allele, or even occasionally the T allele, was associated with atopic phenotypes in a population subgroup. There are several explanations for these inconsistencies, including lack of power, linkage disequilibrium, gene-gene interactions, population admixture and gene-environment interactions. If the SNP was associated with functional changes to the coded protein and thus modulating susceptibility to allergic disease, its effect may be modest and dependent on other co-existent, ethnicity-specific, genetic or environmental risk factors.
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    • "A polymorphism in the TLR2 gene was associated with a severe AD phenotype [8]. Additionally, variations in the CD14 gene, encoding part of the cell membrane receptor for LPS, as well as in the CARD15 gene, encoding an intracellular LPS receptor, have shown associations with AD [27,28]. Thus, genes in the downstream pathway of TLR signalling also constitute reasonable candidate genes for this frequent skin disease. "
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    ABSTRACT: Atopic dermatitis (AD) is a common inflammatory skin disorder, affecting up to 15% of children in industrialized countries. Toll-interacting protein (TOLLIP) is an inhibitory adaptor protein within the toll-like receptor (TLR) pathway, a part of the innate immune system that recognizes structurally conserved molecular patterns of microbial pathogens, leading to an inflammatory immune response. In order to detect a possible role of TOLLIP variation in the pathogenesis of AD, we screened the entire coding sequence of the TOLLIP gene by SSCP in 50 AD patients. We identified an amino acid exchange in exon 6 (Ala222Ser) and a synonymous variation in exon 4 (Pro139Pro). Subsequently, these two variations and four additional non-coding polymorphisms (-526 C/G, two polymorphisms in intron 1 and one in the 3'UTR) were genotyped in 317 AD patients and 224 healthy controls. The -526G allele showed borderline association with AD in our cohort (p = 0.012; significance level after correction for multiple testing 0.0102). Haplotype analysis did not yield additional information. Evaluation of mRNA expression by quantitative real-time polymerase chain reaction in six probands with the CC and six with the GG genotype at the -526 C/G locus did not reveal significant differences between genotypes. Variation in the TOLLIP gene may play a role in the pathogenesis of AD. Yet, replication studies in other cohorts and populations are warranted to confirm these association results.
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