Sex-stratified linkage analysis identifies a female-specific locus for IgE to cockroach in Costa Ricans

Abstract

Rationale: The basis for gender influences on allergen-specific IgEs is unclear.

Objectives: To perform regular and sex-stratified genomewide linkage analyses of IgE to each of three allergens (Ascaris lumbricoides, Blatella germanica [German cockroach]), and Dermatophagoides pteronyssinus [dust mite]) and to conduct an association study of a candidate gene in a linked genomic region.

Methods: Genomewide linkage analyses of allergen-specific IgEs were conducted in 653 members of eight large families of Costa Rican children with asthma. An analysis of the association between single-nucleotide polymorphisms in thymic stromal lymphopoietin (TSLP) and IgE measurements was conducted in 417 parent-child trios in Costa Rica. Significant results were replicated in 470 families of white children in the Childhood Asthma Management Program (CAMP).

Measurements and main results: Among all subjects, there was suggestive evidence of linkage (LOD >/= 2.72) to IgE to Ascaris (on chromosome 7q) and IgE to dust mite (on chromosomes 7p and 12q). In a sex-stratified analysis, there was significant evidence of linkage to IgE to cockroach on chromosome 5q23 (peak LOD, 4.14 at 127 cM) in female subjects. TSLP is located within the 1.5 LOD-unit support interval for this linkage peak and has female-specific effects on lung disease in mice. In a sex-stratified analysis, the T allele of single-nucleotide polymorphism rs2289276 in TSLP was associated with reductions in IgE to cockroach (in Costa Rican girls) and total IgE (in girls in Costa Rica and in CAMP; P value for sex-by-genotype interaction, <0.01 in both studies).

Conclusions: Consistent with findings in murine models, a variant in TSLP may have female-specific effects on allergic phenotypes.

Figure 1.

Results of genomewide multipoint linkage analysis for allergen-specific IgE levels in eight pedigrees of Costa Rican children with asthma. In each figure, results are presented for all subjects and after stratification by sex. Blue lines and red lines denote suggestive (LOD ⩾ 1.90) and significant (LOD ⩾ 3.3) LOD scores, as suggested by Lander and Kruglyak (44). Measurements for each of the three allergen-specific IgE levels were transformed to a log₁₀ scale. Models for all subjects were adjusted for sex. (A) Ascaris serum IgE. For Ascaris-specific IgE, results are for linkage after the inclusion of nine additional markers on chromosome 7. (B) Cockroach serum IgE. (C) Dust mite serum IgE. (A, B) Blue lines, all individuals; red lines, females only; green lines, males only.