Gene-environment interactions with CD14 C-260T and their relationship to total serum IgE levels in adults

BACKGROUND: Both endotoxin exposure and a single nucleotide polymorphism in one of its receptors, CD14 C-260T, have been separately associated with total serum IgE levels. Furred pets might also influence IgE levels through their effects on endotoxin levels. However, how these factors interact to influence total IgE levels is not well known, especially in adults. OBJECTIVE: We sought to investigate the interactive relationship between endotoxin levels, pet exposure, and CD14 C-260T genotype on total serum IgE levels in adults. METHODS: Mothers enrolled in an ongoing cohort study were genotyped for the CD14 C-260T polymorphism. Exposure to pets was assessed by using questionnaires and dust allergen levels collected in the home. Endotoxin exposure was estimated by using dust collected from mothers' bedroom floors. The primary outcome measure was total serum IgE level. RESULTS: CD14 C-260T genotype was assessed in 517 (85.2%) of the 607 women enrolled in the study. The CD14 C-260T genotype was significantly associated with total IgE levels; however, this relationship appeared to be modified by the level of endotoxin exposure. Similar interactions between CD14 C-260T and pet exposure were not seen, regardless of the measure of pet exposure used. CONCLUSIONS: The CD14 C-260T genotype and endotoxin exposure together appear to influence total serum IgE levels in adults. The absence of a similar gene-environment interaction for pet exposure suggests separate mechanisms of action. CLINICAL IMPLICATIONS: A common polymorphism in the endotoxin receptor, CD14 C-260T, and dust endotoxin levels in the home might interact to influence total serum IgE levels into adulthood.     

Gene-environment interactions between CD14 C-260T and endotoxin exposure on Foxp3+ and Foxp3- CD4+ lymphocyte numbers and total serum IgE levels in early childhood.

BACKGROUND: Innate immune system stimuli, such as endotoxin, seem to affect allergy risk. Previously, we described gene-environment interactions between the endotoxin receptor polymorphism C-260T of the CD14 gene and endotoxin exposure on total serum IgE level; however, the mechanism of this interaction is not known. OBJECTIVE: To examine whether this gene-environment interaction affects early CD4(+)Foxp3(-) or CD4(+)Foxp3(+) lymphocyte numbers. METHODS: Participating children were part of a birth cohort in the Detroit metropolitan area. Participants were genotyped for the CD14 C-260T polymorphism. Endotoxin exposure was estimated from dust measured in the home when children were 6 months old. Intracellular Foxp3 protein expression, a regulatory T-cell marker, was used to characterize CD4(+) lymphocytes in blood samples collected at the age of 12 months; total serum IgE level was also measured at this time. Because race/ethnicity may confound or modify genetic associations, all analyses were stratified by race/ethnicity. RESULTS: We observed a significant gene-environment interaction between CD14 C-260T genotype and endotoxin exposure on CD4(+) lymphocyte numbers, particularly CD4(+)Foxp3(-) lymphocytes. Stratified analyses suggest effect modification by race/ ethnicity on CD4(+)Foxp3(+) lymphocyte numbers, with a significant interaction in African American children but not in white children. The interaction between CD14 C-260T genotype and endotoxin exposure on total IgE levels was opposite that observed for CD4(+) lymphocyte numbers, suggesting reciprocal relationships. CONCLUSIONS: A gene-environment interaction between endotoxin and CD14 C-260T genotype on IgE levels may be the result of an upstream, opposing effect on CD4(+)Foxp3(+) and CD4(+)Foxp3(-) lymphocyte numbers. Race/ethnicity may affect which of these cell populations is affected by this gene-environment interaction.     

Seasonal variations of serum IgE levels in normal children

The importance of season as a variable in total IgE production in normal children is demonstrated. Recent history of allergen exposure as well as respiratory infection, both of which are seasonally determined, should be considered in evaluating serum IgE values.     

Reduced levels of soluble CD14 in atopic children

BACKGROUND: A reduced microbial stimulation has been reported as a reason for the increasing prevalence of atopic diseases in industrialized countries. Antigen-presenting cells (APC), responding to microbial signals by pattern recognition receptors such as CD14, have an important role in the development of the Th1/Th2 balance. OBJECTIVE: We hypothesized that atopic children have a lower expression of CD14 on monocytes and lower soluble CD14 levels (sCD14). METHODS: Seventy-six children were followed prospectively from birth and signs of atopic disease were evaluated. The expression of CD14 on monocytes was analysed with flow cytometry at 0, 3, 6, 12 and 18 months. Circulating levels of sCD14 were analysed by ELISA and total IgE was analysed by fluoroenzymo immunoassay at these ages, and in a subgroup, followed up at 7 years. RESULTS: Levels of sCD14 were reduced at 7 years both in children with a current or a cumulative history of atopy compared to non-atopic children with P=0.002 and 0.001, respectively. Sensitized children with atopic symptoms had lower sCD14 at 3 and 18 months and at 7 years of age than non-atopic non-sensitized children with P=0.023, 0.039 and 0.008, respectively. CONCLUSION: The lower levels of sCD14 observed in atopic children may be a consequence of an atopic family heredity and/or atopic disease, but it may also reflect a reduced capacity to respond to microbial signals.     

Asthma and serum IgE levels in children in a desert country

The frequency of asthma admissions to the paediatric outpatient clinic in a teaching hospital in Kuwait was found to increase from 8.8 to 14.9% of all admissions during a 3-year period. Seasonal variation of admissions was consistent, with peak incidences during the cold and humid months. The incidence of asthma was remarkably well correlated to low temperature and high frequency of upper respiratory infections but not to pollen seasons or occurrence of dust storms. In agreement with the clinical impression that atopic allergy is frequent in Kuwait, high levels of IgE were found in different groups of individuals. In umbilical cord serum, elevated IgE levels in blood donors and in children with asthma or other diseases were clearly higher than those found in corresponding groups in Western countries. Possible factors contributing to the generally increased IgE levels may be endemic diseases, like viral hepatitis and brucellosis.     

CD14 expression in the first 24h of sepsis: effect of -260C>T CD14 SNP

Sepsis is defined as systemic inflammation caused by infection. The membrane bound CD14 (mCD14) or the soluble form (sCD14) play a crucial role facing Gram-negative and Gram-positive sepsis since they are pattern recognition receptors of the innate immune response enabling cells to produce inflammatory cytokines against bacterial infections. A -260C>T single nucleotide polymorphism (SNP) was detected in the promoter modulating the CD14 gene expression. We hypothesized that the CD14 expression depends of the genetic inheritance of -260C>T CD14 SNP and it is modulated by sepsis condition. We investigated human CD14 expression on early sepsis diagnosis (in vivo) and after LPS stimulation (in vitro), and determined the -260C>T CD14 SNP. We found that TT homozygotes showed higher mCD14 density (p = 0.0207), but not different sCD14 levels when compared to the CT+CC genotypes. Monocyte mCD14 density and sCD14 serum levels in our sample of early 14 septic patients were significantly higher than normal 30 controls (p<0.0001). Our results suggest that the -260TT CD14 genotype is associated with higher monocyte mCD14, but not sCD14 expression, and that in the first 24 h after sepsis diagnosis, both monocyte mCD14 density and sCD14 levels are elevated, similarly to what is observed in vitro upon challenge with LPS.     

Eotaxin polymorphisms and serum total IgE levels in children with asthma

BACKGROUND: Eotaxin (chemokine, CC motif, ligand; CCL11) is a potent eosinophil chemoattractant strongly implicated in the pathobiology of asthma. Genetic variation at the CCL11 locus has been correlated with serum total IgE, blood eosinophil counts, and circulating eotaxin protein levels in several case-control asthma studies. Family-based association studies of CCL11 genetic variants have not been reported to date. OBJECTIVE: To evaluate 9 common CCL11 single nucleotide polymorphisms (SNPs) in nuclear families ascertained through patients with asthma participating in the Childhood Asthma Management Program study. METHODS: Single nucleotide polymorphism genotyping was performed by using minisequencing and probe hybridization platforms. Family-based association analysis for asthma and 4 asthma-related intermediate quantitative phenotypes was performed by using FBAT. RESULTS: One SNP, -384A>G, was associated with asthma among African American families (P = .01). CCL11 SNPs and haplotypes were not associated with asthma among white or Hispanic families. Two low-frequency alleles in strong pairwise linkage disequilibrium, -426C and IVS2+199A, were associated with lower serum total IgE levels (P = .0006 and P = .009, respectively) in white families, whereas 2 more common variants, -576C and g.4438C, were associated with higher IgE levels in African American families (P = .01-.04). Haplotype analysis in the white cohort provided additional evidence of association with serum total IgE, implicating 2 haplotypes. No single SNP or haplotype associations were observed with blood eosinophil levels, FEV(1), or airway responsiveness. CONCLUSION: These findings provide further evidence that genetic variation at the CCL11 locus is an important determinant of serum total IgE levels among patients with asthma.     

Increased levels of serum IgE in children of mothers with systemic lupus erythematosus

Various allergic diseases have been described in patients with systemic lupus erythematosus (SLE). In the present study, we evaluated the prevalence of allergic disease and serum IgE levels in 36 children of 26 mothers with SLE. None of the subjects had any rheumatic symptoms. There was at least one type of allergic disease in 28 (78%) of the 36 children of mothers with SLE, as compared with 30% in Japanese control children ( P <0.01). The prevalence of atopic dermatitis and bronchial asthma was higher in children of mothers with SLE (64% and 28%) than in controls (19% and 9%) ( P <0.01, respectively). Fourteen of the 36 subjects (39%) had higher levels of serum IgE than those of normal range for age-matched healthy Japanese children with no atopic family disease in the immediate family history, and these children had atopic disease. Among the 14 children with high serum-IgE levels, seven had neither immediate nor remote family history of atopic disease, while the others had an immediate family history of atopic disease. We think that genetic factors may influence the presence of allergic disease in children of mothers with SLE, and that the increased serum IgE levels in children of SLE mothers with no allergic family history may be a part of subclinical immunologic abnormalities related to SLE.     

Association of CD14 promoter polymorphisms and soluble CD14 levels in mite allergen sensitization of children in Taiwan

CD14 is responsible for environmental lipopolysaccharide recognition and is a positional candidate gene for allergy. We hypothesized that genetic polymorphisms in the promoter region of the CD14 gene may be associated with Dermatophagoides pteronysinnus (Der p) allergen sensitization in children. Three single nucleotide polymorphisms (SNPs) of the CD14 promoter region, C(–159)T, A(–1,145)G, and G(–1,359)T were genotyped, and analyzed in 240 randomized case–control school-age children in Taiwan. Serum concentrations of IgE and soluble CD14 (sCD14) were also assayed. We found a significant inverse correlation of sCD14 and total serum IgE levels in our study population. Moreover, sCD14 binds Der p allergen in vitro in a dose-dependent manner. The distribution of three SNPs genotypes was similar in asthmatic children and the control group. However, there was a significant difference in the distribution of genotype CD14 G(–1,359)T, but not C(–159)T, between mite-sensitive and non-sensitive children. Haplotype analysis showed strong linkage disequilibrium among these three SNPs in the CD14 promoter region. Carriers of the CD14–159C/–1,145A/–1,359T haplotype had the highest IgE and lowest sCD14 levels as compared to other haplotypes. Our results support the hypothesis that CD14 gene variants may play an important role in influencing allergen sensitization of children in Taiwan.     

Increased soluble CD14 serum levels and altered CD14 expression of peripheral blood monocytes in HIV-infected patients.

Serum levels of soluble CD14 were elevated in HIV-infected asymptomatic patients or those with lymphadenopathy (CDC II/III) 2.9 +/- 0.8 mg/l compared with normal controls with 2.2 +/- 0.47 mg/l, P < 0.001. A further rise was seen in patients with ARC (CDC IVA) 3.8 +/- 1.1 mg/l, P < 0.01 and patients with AIDS (CDC IVB-D) 5.7 +/- 2.5 mg/l, P < 0.01. Although absolute numbers of CD14+ cells decrease in the AIDS group, the percentage of CD14+ monocytes did not change. In contrast, levels of soluble T cell antigens sCD4 and sCD8, which are higher in HIV-infected patients compared with normal subjects, showed no increase with disease progression. Serum levels of sCD14 were correlated positively with beta 2-microglobulin levels (rs = 0.63, P < 0.0001). Whereas the percentage of CD14+ monocytes did not change, an increase in monocytic CD14 expression in HIV-infected patients was observed (P < 0.01). The percentage of a monocyte subset expressing both CD14 and CD16 increased from 6% in normal healthy persons to 13% in HIV-infected patients (P < 0.001), and did not vary between the HIV patient groups. Incubation of cultured peripheral blood monocytes with azidothymidine had no effect on either normal or LPS-induced or IL-4-inhibited sCD14 release in vitro. Therefore, an effect of AZT on sCD14 serum values in vivo is considered to be unlikely. Our data further provide evidence that monocytes/macrophages are engaged in HIV infection.     

Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study

BACKGROUND: Both a functional promoter polymorphism in the gene encoding CD14 (C-260T) and exposure to endotoxin are believed to play key roles in modulating the immune response and expression of atopic disease. OBJECTIVE: We aimed to evaluate the role of the CD14 C-260T polymorphism in a population of African descent and to test for interaction between this genotype and house dust endotoxin (HDE) exposure on atopic phenotypes. METHODS: Asthmatic probands and their families were recruited as part of the Barbados Asthma Genetics Study. The C-260T polymorphism and two additional CD14 promoter markers (G-1461T, C-1721T) were genotyped. Endotoxin was measured in house dust samples. RESULTS: Using a Family-Based Association Test, the C-260T allele appeared to be protective against asthma ( z = -2.444; P = .015) and asthma severity ( z = -2.615; P = .009) under a recessive model. No significant associations were observed for the G-1461T and C-1721T markers both individually and in haplotypes. In a case-control analysis, the CD14 TT genotype was found to reduce risk of asthma compared with the CD14 CC/CT genotypes (odds ratio [OR], 0.26; 95% CI, 0.14-0.49) and was associated with lower asthma severity scores ( P < .002). The TT genotype might protect against asthma for individuals with low HDE (OR, 0.09; 95% CI, 0.03-0.24), but may be a risk factor for individuals with high HDE (OR, 11.66; 95% CI, 1.03-131.7), suggesting a gene-environment interaction. CONCLUSION: These data suggest that the CD14-260 polymorphism may play a role in controlling risk to atopic disease and underscore the importance of incorporating key environmental exposures into studies of genetic risk factors.     

A promoter polymorphism in the CD14 gene is associated with elevated levels of soluble CD14 but not with IgE or atopic diseases

BACKGROUND: A polymorphism in the promoter region of the CD14 gene, C-159T, has been shown to be associated with increased levels of soluble CD14 (sCD14) and decreased serum immunoglobulin E (IgE) and the expression of a more severe atopic phenotype in previous studies. METHODS: To test if these associations are consistently found in different populations and different age groups, we genotyped 2048 children of different age groups as well as 888 adults from different regions of Germany for the CD14 C-159T polymorphism. RESULTS: While an association between this promoter polymorphism and levels of sCD14 could be confirmed in our study population (CC: 1017 ng/ml vs TT: 1370 ng/ml, P = 0.03), no association between CD14 C-159T genotypes and IgE levels or the prevalence of atopic diseases was seen. CONCLUSIONS: The lack of association between CD14 genotypes and IgE as well as atopic outcomes in this large German study population seems to indicate that CD14 genotypes may not directly be involved in the development of allergies during childhood.     

TLR4/Asp299Gly, CD14/C-260T, plasma levels of the soluble receptor CD14 and the risk of coronary heart disease: The PRIME Study

TLR4 and CD14 are two components of the LPS receptor complex, which are considered to play a key role in the pathogenesis of atherosclerosis. TLR4/Asp299Gly and CD14/C-260T polymorphisms are thought to modulate the activity of this complex. The aim of the study was to examine the association between the TLR4/Asp299Gly and CD14/C-260T polymorphisms, plasma levels of the soluble receptor CD14 (sCD14), and the incidence of coronary heart disease (CHD) in a prospective cohort (the PRIME Study) of 9758 healthy men aged 50-59 years recruited in France and Northern Ireland. A nested case-control design was used, comparing the 249 participants who developed a CHD event during the 5-year follow-up with 492 population- and age-matched control subjects. The two polymorphisms were genotyped and baseline plasma concentrations of sCD14 were measured. None of the two polymorphisms, or sCD14 levels, either considered alone or in combination, were associated with the risk of CHD. The CD14/C-260T allele was associated with increased plasma concentrations of soluble thrombomodulin and vascular cell adhesion molecule-1 and, to a lesser extent, sCD14. No relationship was observed between the TLR4 polymorphism and, any of the inflammatory and endothelial markers measured. The TLR4/Asp299Gly and CD14/C-260T polymorphisms and plasma sCD14 concentrations do not appear as significant predictors of the risk of CHD in healthy individuals.     

IgE levels in the sera of asthmatic children

The serum IgE concentrations of children with varying grades of asthma were determined. The mean serum IgE level in each grade corresponded with the severity of asthma in that grade, there being a significantly increased mean serum IgE level in children in the most severely affected grades. Several individuals with pronounced asthma had anomalously low serum IgE levels and conversely a few subjects with no, or minimal clinical evidence of asthma had disproportionately high levels of IgE. An immunopathological interpretation of these findings is discussed.