Published ahead of print on January 31, 2008, doi:10.1164/rccm.200711-1697OC Am. J. Respir. Crit. Care Med., Volume 177, Number 8, April 2008, 830-836 A more recent version of this article appeared on April 15, 2008
Submitted on November 16, 2007 Sex-stratified Linkage Analysis Identifies a Locus for IgE to Cockroach in Female Costa RicansGary M Hunninghake1,1 Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA, 2 Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA, 3 Division of Pediatric Pulmonology, Hospital Nacional de Ninos, San Jose, Costa Rica, 4 Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA, 5 Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA, 6 Ontario Institute for Cancer Research, Ottawa, ON, Canada, 7 Department of Psychiatry, University of California at Los Angeles, Los Angeles, CA, USA, 8 Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Center for Genomic Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA * To whom correspondence should be addressed. E-mail: juan.celedon{at}channing.harvard.edu.
Rationale: The basis for gender influences on allergen-specific IgEs is unclear. Objectives: To perform regular and sex-stratified genome-wide 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: Genome-wide linkage analyses of allergen-specific IgEs were conducted in 653 members of eight large families of Costa Rican children with asthma. An analysis of association between SNPs in thymic stromal lymphopoietin (TSLP) and IgE measurements was then 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). 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 females. 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 SNP 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 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. Key words: Immunoglobulin E, Linkage, Thymic Stromal Lymphopoietin, Single Nucleotide Polymorphisms
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