Major genes regulating total serum immunoglobulin E levels in families with asthma

Abstract

Immunoglobulin E (IgE) has a major role in the pathogenesis of allergic disorders and asthma. Previous data from 92 families, each identified through a proband with asthma, showed evidence for two major genes regulating total serum IgE levels. One of these genes mapped to 5q31-33. In the current study, the segregation analysis was extended by the addition of 108 probands and their families, ascertained in the same manner. A mixed recessive model (i.e., major recessive gene and residual genetic effect) was the best-fitting and most-parsimonious one-locus model of the segregation analysis. A mixed two-major-gene model (i.e., two major genes and residual genetic effect) fit the data significantly better than did the mixed recessive one-major-gene model. The second gene modified the effect of the first recessive gene. Individuals with the genotype aaBB (homozygous high-risk allele at the first gene and homozygous low-risk allele at the second locus) had normal IgE levels (mean 23 IU/ml), and only individuals with genotypes aaBb and aabb had high IgE levels (mean 282 IU/ml). A genomewide screening was performed using variance-component analysis. Significant evidence for linkage was found for a novel locus at 7q, with a multipoint LOD score of 3. 36 (P=.00004). A LOD score of 3.65 (P=.00002) was obtained after genotyping additional markers in this region. Evidence for linkage was also found for two previously reported regions, 5q and 12q, with LOD scores of 2.73 (P=.0002) and 2.46 (P=.0004), respectively. These results suggest that several major genes, plus residual genetic effects, regulate total serum IgE levels.

Figures

Figure 1

Relationship between total serum IgE levels and BHR, in the offspring of 200 asthmatic parents

Figure 2

Distributions of adjusted log10(IgE) in 200 Dutch families. Vertical bars represent the distribution of the observed adjusted log10(IgE). The two curves represent the distributions of the three genotypes under the best-fitting mixed recessive model.

Figure 3

Distributions of adjusted log10(IgE) in 200 Dutch families. Vertical bars represent the distribution of the observed adjusted log10(IgE). The four curves represent the distributions of the nine genotypes under the best-fitting mixed two-major-gene model.

Figure 4

Genomewide screen for major genes regulating adjusted log10(IgE) levels in 200 Dutch families, using variance-component analysis. Three hundred forty-four evenly spaced autosomal markers were genotyped. Vertical dotted lines divide genomes into 22 chromosomes.

Figure 5

Multipoint linkage analysis of log10(IgE) on chromosome 7, using variance-component approach