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 singlenucleotide 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.

Sex-specific effect of IL9 polymorphisms on lung function and polysensitization

“…A male-specific linkage, as in this study, was found with a measure of lung function (FEV 1 /FCV, FVC being the forced vital capacity) in the Hutterites at a position 15 cM telomeric from our linkage peak, whereas a female-specific linkage was reported with specific IgE to cockroach in Costa Ricans at a position 24 cM centromeric from our peak. 6 These results suggest that there may be several genes with sex-specific effects in the 5q31 region. Both 5q31 and 11q23 regions have been previously reported to be linked and associated with several asthma phenotypes in a non sex-specific manner.…”

“…4 Among the many genome-wide (GW) linkage scans published to date, only two scans conducted in isolated populations (the Hutterites and a genetic isolate from Costa Rica), have searched for sex-specific genetic factors. 1,[6][7][8] In the Huterrites, sex-specific linkages were found for immunoglobulin E (IgE) levels, lymphocyte counts and measures of lung function. 1,7 In Costa Rican families sex-specific linkages and associations were reported for total IgE and specific IgE to cockroach.…”

“…1,7 In Costa Rican families sex-specific linkages and associations were reported for total IgE and specific IgE to cockroach. 6,8 Although taking into account factors such as sex that modify gene expression may lead to the detection of new genetic factors; multivariate linkage analysis of complex traits can also increase power to detect genes with small effects. 9 This is of particular relevance for asthma-related phenotypes for which a given chromosomal region is often linked to several phenotypes, suggesting the presence of genes with pleiotropic effects.…”

Association of STAT6 and ADAM33 single nucleotide polymorphisms with asthma bronchiale and IgE level and its possible epigenetic background

“…maternal behaviour and diet could influence epigenetic programming of the fetus 53 . The gender related difference in distribution of total IgE levels would probably be attributed to other loci than STAT6 as suggested by some reports 50,[55][56][57] . Although the observed s1 parental origin related to the difference in total IgE levels according to gender is interesting, the size of subgroups (patients were subsequently divided according to their gender) is relatively small and the observed results must be evaluated to rule out an influence of small numbers.…”

Genetics and Asthma Disease Susceptibility in the US Latino Population

“…A locus on 5q23 was associated with cockroach-specific IgE in Costa Rican children in a genome-wide linkage analysis when it was analyzed with sex-stratified linkage analysis. 76 The TSLP gene was identified in this region, and the proposal was made that a variant in TSLP may have female-specific effects on allergic phenotypes. Further replication studies are needed to confirm this association in additional populations, but the biological importance of TSLP makes the study provocative.…”