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Human Molecular Genetics Advance Access originally published online on December 1, 2006
Human Molecular Genetics 2007 16(3):243-253; doi:10.1093/hmg/ddl447
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Sex-specific linkage to total serum immunoglobulin E in families of children with asthma in Costa Rica

Benjamin A. Raby1,2,3, Manuel E. Soto-Quiros4, Lydiana Avila4, Stephen L. Lake1,3, Amy Murphy1,3, Catherine Liang1, Eduardo Fournier4, Mitzi Spesny4, Jody S. Sylvia1, Andrei Verner5, Thomas J. Hudson5, Barbara J. Klanderman1, Nelson B. Freimer6, Edwin K. Silverman1,3 and Juan C. Celedón1,2,3,*

1 Channing Laboratory and Respiratory Disorders Program, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA, 2 Division of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA, 3 Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA, 4 Division of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica, and, 5 Genome Québec Innovation Centre, McGill University, Montreal, Canada, 6 Department of Psychiatry, University of California at Los Angeles, Los Angeles, California

* To whom correspondence should be addressed. Tel: +1 6175250964; Fax: +1 6175250958; Email: juan.celedon{at}channing.harvard.edu

Received September 28, 2006; Accepted November 23, 2006

Serum total immunoglobulin E (IgE) is a critical intermediate phenotype of allergic diseases. Although total IgE exhibits sexual dimorphism in humans (with males demonstrating higher IgE than females), the molecular basis of this difference is unknown. A genome-wide scan of 380 short-tandem repeat (STR) markers was performed in eight extended pedigrees of asthmatic children (n=655) from the Central Valley of Costa Rica. Genome-wide linkage analysis of total IgE was performed by variance component models. Among all subjects, only one genomic region (chromosome 7p15) showed modest evidence of linkage to total IgE (LOD=1.60). In contrast, a sex-stratified analysis revealed distinct genetic architectures of total IgE in males and females and identified significant linkage to total IgE on a novel male-specific locus on chromosome 20p12 (LOD=3.63 at 36 cM). Genotyping of additional STRs on chromosome 20 resulted in improved evidence for linkage (LOD=3.75 at 33 cM) and a 1.5 LOD-unit support interval for the linkage peak between 26 and 38 cM. Three polymorphisms in two genes on chromosome 20p12 (JAG1 and ANKRD5) were then found to be associated with total IgE in 420 nuclear families of Costa Rican children with asthma. Two of these polymorphisms (in JAG1) were significantly associated with total IgE in families of boys (n=264) but not in families of girls (n=156) with asthma. JAG1 is a hematopoetic cell growth factor that may regulate normal B-cell development. This is the first demonstration of a possible genetic basis for differences in total IgE between sexes.


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