Mechanisms of asthma and allergic inflammation
Major quantitative trait locus for eosinophil count is located on chromosome 2q

https://doi.org/10.1016/j.jaci.2004.05.060Get rights and content

Background

Eosinophils are granulocytic white blood cells implicated in asthma and atopic disease. The degree of eosinophilia in the blood of patients with asthma correlates with the severity of asthmatic symptoms. Quantitative trait loci (QTL) linkage analysis of eosinophil count may be a more powerful strategy of mapping genes involved in asthma than linkage analysis using affected relative pairs.

Objective

To identify QTLs responsible for variation in eosinophil count in adolescent twins.

Methods

We measured eosinophil count longitudinally in 738 pairs of twins at 12, 14, and 16 years of age. We typed 757 highly polymorphic microsatellite markers at an average spacing of ∼5 centimorgans across the genome. We then used multipoint variance components linkage analysis to test for linkage between marker loci and eosinophil concentrations at each age across the genome.

Results

We found highly significant linkage on chromosome 2q33 in 12-year-old twins (logarithm of the odds = 4.6; P = .000002) and suggestive evidence of linkage in the same region in 14-year-olds (logarithm of the odds = 1.0; P = .016). We also found suggestive evidence of linkage at other areas of the genome, including regions on chromosomes 2, 3, 4, 8, 9, 11, 12, 17, 20, and 22.

Conclusion

A QTL for eosinophil count is present on chromosome 2q33. This QTL might represent a gene involved in asthma pathophysiology.

Section snippets

Methods

Twins were recruited as part of an ongoing study concerned with the development of melanocytic naevi (moles), the clinical protocol of which has been described in detail elsewhere.16., 17., 18. Twins were enlisted by contacting the principals of primary schools in the greater Brisbane area, by media appeals, and by word of mouth. It is estimated that approximately 50% of the eligible birth cohort was recruited into the study and was typical of the population with respect to eosinophil

Results

The results of the univariate variance components tests for linkage are displayed in Fig 1. Each plot displays LOD scores for all 3 ages so that it is possible to compare the consistency of results across measurement occasions. The strongest evidence of linkage occurred at age 12 years on chromosome 2q (LOD = 4.70; P = .000002). There was also a smaller peak in the same location at age 14 years (LOD = 1.0; P = .016), but not at age 16 years, at which there were far fewer twins tested and hence less

Discussion

The most promising result from this study is the large linkage peak on chromosome 2q33 for eosinophil count in 12-year-old twins. Several studies have reported suggestive linkages to asthma31 and asthma-related phenotypes in the 2q33 region, including circulating IgE,13 bronchial hyperresponsiveness,14 and reaction to a skin prick test.31 Several candidate genes are present within this region, including genes involved in T-cell signaling (CD28 and CTLA-4) and apoptosis (caspase 8).

A major

References (35)

  • F.D. Martinez et al.

    Linkage of circulating eosinophils to markers on chromosome 5q

    Am J Respir Crit Care Med

    (1998)
  • L.J. Palmer et al.

    Linkage of chromosome 5q and 11q gene markers to asthma-associated quantitative traits in Australian children

    Am J Respir Crit Care Med

    (1998)
  • D.S. Postma et al.

    Genetic susceptibility to asthma—bronchial hyperresponsiveness coinherited with a major gene for atopy

    N Engl J Med

    (1995)
  • S. Marquet et al.

    Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33

    Nat Genet

    (1996)
  • S. Marquet et al.

    Full results of the genome-wide scan which localises a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33

    Eur J Hum Genet

    (1999)
  • S.E. Daniels et al.

    A genome-wide search for quantitative trait loci underlying asthma

    Nature

    (1996)
  • M.H. Dizier et al.

    Genome screen for asthma and related phenotypes in the French EGEA study

    Am J Respir Crit Care Med

    (2000)
  • Cited by (0)

    Funding source: collection of phenotypes and DNA samples was supported by grants from the Queensland Cancer Fund, the Australian National Health and Medical Research Council (950998, 981339, and 241944) and the US National Cancer Institute (CA88363) to Dr Nick Hayward. The genome scans were supported by the Australian National Health and Medical Research Council's Program in Medical Genomics and funding from the Center for Inherited Disease Research (Director, Dr Jerry Roberts) at Johns Hopkins University to Dr Jeff Trent.

    View full text