Maternal 17q21 genotype influences prenatal vitamin D effects on offspring asthma/recurrent wheeze

Abstract

Background: Prenatal vitamin D3 supplementation has been linked to reduced risk of early-life asthma/recurrent wheeze. This protective effect appears to be influenced by variations in the 17q21 functional single nucleotide polymorphism rs12936231 of the child, which regulates the expression of ORMDL3 (ORM1-like 3) and for which the high-risk CC genotype is associated with early-onset asthma. However, this does not fully explain the differential effects of supplementation. We investigated the influence of maternal rs12936231 genotype variation on the protective effect of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze.

Methods: We determined the rs12936231 genotype of mother-child pairs from two randomised controlled trials: the Vitamin D Antenatal Asthma Reduction Trial (VDAART, n=613) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010, n=563), to examine the effect of maternal genotype variation on offspring asthma/recurrent wheeze at age 0-3 years between groups who received high-dose prenatal vitamin D3 supplementation versus placebo.

Results: Offspring of mothers with the low-risk GG or GC genotype who received high-dose vitamin D3 supplementation had a significantly reduced risk of asthma/recurrent wheeze when compared with the placebo group (hazard ratio (HR) 0.54, 95% CI 0.37-0.77; p<0.001 for VDAART and HR 0.56, 95% CI 0.35-0.92; p=0.021 for COPSAC2010), whereas no difference was observed among the offspring of mothers with the high-risk CC genotype (HR 1.05, 95% CI 0.61-1.84; p=0.853 for VDAART and HR 1.11, 95% CI 0.54-2.28; p=0.785 for COPSAC2010).

Conclusion: Maternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze.

Trial registration: ClinicalTrials.gov NCT00920621 NCT00856947.

Conflict of interest statement

Conflict of interest: H.M. Knihtilä has nothing to disclose. Conflict of interest: R.S. Kelly has nothing to disclose. Conflict of interest: N. Brustad has nothing to disclose. Conflict of interest: M. Huang has nothing to disclose. Conflict of interest: P. Kachroo has nothing to disclose. Conflict of interest: B.L. Chawes has nothing to disclose. Conflict of interest: J. Stokholm has nothing to disclose. Conflict of interest: K. Bønnelykke has nothing to disclose. Conflict of interest: C-E.T. Pedersen has nothing to disclose. Conflict of interest: H. Bisgaard has nothing to disclose. Conflict of interest: A.A. Litonjua reports author royalties from UpToDate, Inc., outside the submitted work. Conflict of interest: J.A. Lasky-Su has nothing to disclose. Conflict of interest: S.T. Weiss has nothing to disclose.

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Figures

Figure 1.

Kaplan-Meier survival curves for the effect of high-dose prenatal vitamin D3 supplementation on the development of asthma/recurrent wheeze at age 0–3 years stratified by maternal 17q21 functional SNP rs12936231 genotype in the VDAART and COPSAC2010 trials. *P<0.05 in the Cox proportional hazard regression model.

Figure 2.

Kaplan-Meier survival curves for the effect of high-dose prenatal vitamin D3 supplementation on the development of asthma/recurrent wheeze at age 0–3 years stratified by mother and child 17q21 functional SNP rs12936231 genotype combinations in the VDAART and COPSAC2010 trials. G is considered as the dominant low-risk allele and C as the recessive high-risk allele. *P=0.005 in the Cox proportional hazard regression model.