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Association of Vitamin D Receptor Gene Polymorphisms with Childhood and Adult Asthma

Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Harvard Partners Center for Genomics and Genetics, Brigham and Women's Hospital; Division of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center; Harvard Medical School; and Harvard School of Public Health, Boston, Massachusetts; and GSF-National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany

Correspondence and requests for reprints should be addressed to Benjamin Raby, M.D.C.M., M.P.H., Channing Laboratory, Brigham and Women's Hospital, Boston, MA 02115. E-mail: benjamin.raby{at}channing.harvard.edu

Vitamin D receptor (VDR) polymorphisms have been associated with several immune-related diseases, and VDR and vitamin D itself modulate T cell differentiation. VDR maps to chromosome 12q, near a region commonly linked to asthma. We evaluated VDR as part of a 12q positional candidate survey, and in response to observations of VDR polymorphism associations with asthma and atopy in a founder population of Quebec. Twenty-eight loci in 7 positional candidates (7 in VDR) were genotyped in 582 families. Whereas other candidates demonstrated no association, the VDR ApaI polymorphism demonstrated significant transmission distortion, with undertransmission of the C allele in a ratio of 4:5 (p = 0.01). This association was most prominent in girls, in whom distortion was more marked (p = 0.009). Sex-specific associations between multiple VDR polymorphisms and immunoglobulin E levels were also observed (p = 0.006–0.01). Asthma associations were replicated in a second cohort (517 females with asthma and 519 matched control subjects): 4 of 6 VDR variants demonstrated significant association (p = 0.02–0.04). The direction of association in this second cohort was opposite to the effects seen in the trios, but similar to findings in the Quebec study. These results suggest that VDR influences asthma and allergy susceptibility in a complex manner.

Key Words: association studies • asthma • genetics • replication • VDR

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