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

doi:10.1016/j.jaci.2006.07.007

Journal of Allergy and Clinical Immunology

Volume 118, Issue 4, October 2006, Pages 851-857

https://doi.org/10.1016/j.jaci.2006.07.007 Get rights and content

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.

Section snippets

Study population

This study was approved by the Institutional Review Board at Henry Ford Health System and was compliant with its Health Insurance Portability and Accountability Act policy. Expectant mothers receiving prenatal care from a large, integrated health care delivery system in metropolitan Detroit, Michigan, were invited to participate in WHEALS. To be eligible, pregnant women in their second and third trimesters had to be at least 21 years of age, live in a geographically defined area of urban and

Results

Recruitment for this longitudinal cohort study began in August 2003 and was ongoing at the time of these analyses. The population used in this study comprised mothers with due dates beginning September 1, 2003, and with 1 month of postnatal follow-up data as of July 19, 2005. During this time period, 1112 women were identified as eligible and were invited to participate. Of these 1112 women, 505 (45.4%) refused participation, and 607 (54.6%) enrolled. At the time of this study, 517 (85.2%)

Discussion

In this study we observed a significant relationship between CD14 C-260T genotype and total serum IgE levels. Although other studies have found individuals with the CC genotype to have higher total serum IgE levels12, 13, 22 when compared with CT and TT individuals, this study suggests that the magnitude and possibly the direction of this relationship is predicated on the level of endotoxin exposure. For example, at lower levels of endotoxin exposure, the CC genotype appeared to be associated

References (43)

L. Portengen et al.
Endotoxin exposure and atopic sensitization in adult pig farmers
J Allergy Clin Immunol
(2005)
M.K. Tulic et al.
Role of toll-like receptor 4 in protection by bacterial lipopolysaccharide in the nasal mucosa of atopic children but not adults
Lancet
(2004)
J. da Silva Correia et al.
Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. transfer from CD14 to TLR4 and MD-2
J Biol Chem
(2001)
D.A. Meyers et al.
Evidence for a locus regulating total serum IgE levels mapping to chromosome 5
Genomics
(1994)
J.E. Gereda et al.
Metropolitan home living conditions associated with indoor endotoxin levels
J Allergy Clin Immunol
(2001)
A.A. Litonjua et al.
Polymorphisms in the 5′ region of the CD14 gene are associated with eczema in young children
J Allergy Clin Immunol
(2005)
W. Eder et al.
Opposite effects of CD14/−260 on serum IgE levels in children raised in different environments
J Allergy Clin Immunol
(2005)
C. Ober et al.
A second-generation genomewide screen for asthma-susceptibility alleles in a founder population
Am J Hum Genet
(2000)
J.E. Gern et al.
Effects of dog ownership and genotype on immune development and atopy in infancy
J Allergy Clin Immunol
(2004)
J.A. Platts-Mills et al.
Airborne endotoxin in homes with domestic animals: implications for cat-specific tolerance
J Allergy Clin Immunol
(2005)

D.G. Marsh et al.

Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations

Science

(1994)

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Supported by grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (AI61774, AI50681, AI51598, AI50594), and by the Fund for Henry Ford Hospital.

Disclosure of potential conflict of interest: L. K. Williams has received grant support from the National Institute of Allergy and Infections Diseases (NIAID); the National Heart, Lung, and Blood Institute; and the National Institute of Diabetes and Digestive and Kidney Diseases. D. R. Ownby has received grant support from the NIAID. The rest of the authors have declared that they have no conflict of interest.

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Mechanisms of asthma and allergic inflammationGene-environment interactions with CD14 C-260T and their relationship to total serum IgE levels in adults

Background

Objective

Methods

Results

Conclusions

Clinical implications

Section snippets

Study population

Results

Discussion

J Allergy Clin Immunol

Lancet

J Biol Chem

Genomics

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Am J Hum Genet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Immunity

J Biol Chem

J Allergy Clin Immunol

J Am Coll Cardiol

House dust endotoxin and allergic sensitization in children

Am J Respir Crit Care Med

Environmental exposure to endotoxin and its relation to asthma in school-age children

N Engl J Med

Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations

Science

Mechanisms of asthma and allergic inflammation
Gene-environment interactions with CD14 C-260T and their relationship to total serum IgE levels in adults