J Allergy Clin Immunol. 2012 Feb;129(2):368-73, 373.e1-5. doi: 10.1016/j.jaci.2011.09.034. Epub 2011 Nov 1.

Genome-wide association study reveals class I MHC-restricted T cell-associated molecule gene (CRTAM) variants interact with vitamin D levels to affect asthma exacerbations.

Du R, Litonjua AA, Tantisira KG, Lasky-Su J, Sunyaev SR, Klanderman BJ, Celedón JC, Avila L, Soto-Quiros ME, Weiss ST.

Source

Channing Laboratory, Brigham and Women's Hospital, Boston, Mass 02115, USA. rdu@partners.org

Abstract

BACKGROUND:

It has recently been shown that vitamin D deficiency can increase asthma development and severity and that variations in vitamin D receptor genes are associated with asthma susceptibility.

OBJECTIVE:

We sought to find genetic factors that might interact with vitamin D levels to affect the risk of asthma exacerbation.

METHODS:

We conducted a genome-wide study of gene-vitamin D interaction on asthma exacerbations using population-based and family-based approaches on 403 subjects and trios from the Childhood Asthma Management Program. Twenty-three polymorphisms with significant interactions were studied in a replication analysis in 584 children from a Costa Rican cohort.

RESULTS:

We identified 3 common variants in the class I MHC-restricted T cell-associated molecule gene (CRTAM) that were associated with an increased rate of asthma exacerbations based on the presence of a low circulating vitamin D level. These results were replicated in a second independent population (unadjusted combined interaction, P = .00028-.00097; combined odds ratio, 3.28-5.38). One variant, rs2272094, is a nonsynonymous coding polymorphism of CRTAM. Functional studies on cell lines confirmed the interaction of vitamin D and rs2272094 on CRTAM expression. CRTAM is highly expressed in activated human CD8(+) and natural killer T cells, both of which have been implicated in asthmatic patients.

CONCLUSION:

The findings highlight an important gene-environment interaction that elucidates the role of vitamin D and CD8(+) and natural killer T cells in asthma exacerbation in a genome-wide gene-environment interaction study that has been replicated in an independent population. The results suggest the potential importance of maintaining adequate vitamin D levels in subsets of high-risk asthmatic patients.