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

Immunoglobulin E (IgE) has a major role in the pathogenesis of allergic dis orders 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 stu dy, the segregation analysis was extended by the addition of 108 probands a nd their families, ascertained in the same manner. A mixed recessive model (i.e., major recessive gene and residual genetic effect) was the best-fitti ng and most-parsimonious one-locus model of the segregation analysis. A mix ed two-major-gem model (i.e., two major genes and residual genetic effect) fit the data significantly better than did the mixed recessive one-major-ge ne model. The second gene modified the effect of the first recessive gene. Individuals with the genotype aaBB (homozygous high-risk allele at the firs t gene and homozygous low-risk allele at the second locus) had normal IgE l evels (mean 23 IU/ml), and only individuals with genotypes aaBb and aabb ha d high IgE levels (mean 282 IU/ml). A genomewide screening was performed us ing 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 previou sly 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 gen es, plus residual genetic effects, regulate total serum IgE levels.