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 - 03/02/12
, Augusto A. Litonjua, MD a, c, d, Kelan G. Tantisira, MD a, c, d, Jessica Lasky-Su, ScD a, c, Shamil R. Sunyaev, PhD c, Barbara J. Klanderman, PhD a, c, Juan C. Celedón, MD, DrPH a, e, Lydiana Avila, MD f, Manuel E. Soto-Quiros, MD, PhD f, Scott T. Weiss, MD a, c, d
Corresponding author: Rose Du, MD, PhD, Department of Neurosurgery, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115.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.
Le texte complet de cet article est disponible en PDF.Key words : Gene-environment interaction, genome-wide association study, vitamin D, asthma exacerbation
Abbreviations used : CAMP, CRTAM, OR, PLCL1, SNP, TTS
Plan
| Supported by National Institutes of Health (NIH) grants R21HL089842 and R01HL092197. We acknowledge the Childhood Asthma Management Program (CAMP) investigators and research team, supported by the National Heart, Lung, and Blood Institute (NHLBI), for collection of CAMP Genetic Ancillary Study data. All work on data collected from the CAMP Genetic Ancillary Study was conducted at the Channing Laboratory of the Brigham and Women’s Hospital under appropriate CAMP policies and human subjects’ protections. The CAMP Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, P01 HL083069, R01 HL086601, and T32 HL07427 from the NHLBI/NIH. |
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| Disclosure of potential conflict of interest: A. A. Litonjua, K. G. Tantisira, S. R. Sunyaev, B. J. Klanderman, and M. E. Soto-Quiros receive research support from the National Institutes of Health. J. C. Celedón is on the advisory board for Genentech, receives research support from the NIH, and receives royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 129 - N° 2
P. 368 - février 2012 Retour au numéro
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