Low Vitamin D Levels Not Associated With Risk of Atopy

Single-nucleotide polymorphisms (SNPs) strongly associated with low vitamin D (25OHD) levels did not confer an increased risk of asthma, atopic dermatitis, or elevated immunoglobulin E (IgE), according to study results published in PLoS Medicine.¹

J. Brent Richards, MD, MSc, associate professor at McGill University in Montreal, Canada, spoke with Pulmonology Advisor on the significance of the research. “Our study provides a better estimate of the association between low vitamin D levels and the risk of atopy compared with observational studies and small short-term prevention [randomized controlled trials (RCTs)],” said Dr Richards. “Mendelian randomization greatly limits confounding and is free of reverse causation with the added benefit of providing a lifelong assessment of exposure to low vitamin D levels with sample sizes larger than can practically be done with RCTs.” 

Vitamin D may influence atopy susceptibility through immunoregulatory properties,² and with insufficiency affecting 42% of Americans,³ prevention of atopy with vitamin D supplementation would be a major public health victory.

Numerous epidemiologic studies and RCTs have identified an association between low vitamin D levels and asthma, atopic dermatitis, and elevated IgE.¹ A meta-analysis⁴ of observational studies showed higher serum levels of 25OHD were associated with a reduced risk of asthma exacerbations. A 2015 meta-analysis² revealed that both vitamin D deficiency and insufficiency may increase the risk of asthma exacerbations. Additionally, a 2016 Cochrane⁵ review of RCTs found that vitamin D administration reduced the risk of asthma exacerbations.

However, controversy exists on the role of vitamin D in atopy.^1,6 A 2015 meta-analysis of RCTs found no significant effect on the risk for asthma exacerbations or lung function with vitamin D supplementation.⁶ Another meta-analysis found higher serum levels of 25OHD showed little evidence of an association with asthma incidence, prevalence, or severity.⁴ Furthermore, clinical practice guidelines have not incorporated vitamin D supplementation into the treatment recommendations for atopic disease.¹

Given the controversy, the researchers employed a Mendelian randomized design utilizing SNPs known to be associated with 25OHD levels to test the influence of the SNPs on asthma, atopic dermatitis, and total serum IgE levels. Data were taken from the largest genome-wide association study (GWAS) meta-analyses to date: the asthma GABRIEL consortium combined with the UK Biobank, and the EAGLE eczema consortium. 

The SNPs were taken from the SUNLIGHT consortium, which identified 4 genome-wide vitamin D-associated SNPs: rs2282679 in GC (involved in vitamin D transport), rs12785878 near DHCR7 (involved in vitamin D synthesis), rs10741657 near CYP2R1 (involved in vitamin D hepatic hydroxylation), and rs6013897 in CYP24A1 (involved in vitamin D catabolism).

Effect estimates of each SNP on 25OHD levels were obtained using data from the Canadian Multicenter Osteoporosis Study because the effects were not given in the SUNLIGHT Consortium due to variations in measurement of vitamin D among the study cohorts.

To validate the SNPs included in the study, the researchers tested for: a strong association with 25OHD, an absence of association with known confounders of the 25OHD-outcome association, and the absence of pleiotropy (when the SNP influences the atopic outcome through mechanisms independent of vitamin D). No bias through linkage disequilibrium was found.

Results showed that none of the four 25OHD-lowering SNPs were associated with asthma, atopic dermatitis, or elevated IgE levels (P ≥.2). The authors concluded by stating, “These results persisted in sensitivity analyses assessing population stratification and pleiotropy and vitamin D synthesis and metabolism pathways.”

Study Limitations

• Residual bias is possible, as the exact function of the studied SNPs is unknown.
• Findings do not exclude an association between studied outcomes and 1,25-dihydoxyvitamin D.
• The study was underpowered to detect odds ratios smaller than 1.33 for childhood asthma.
• The population studied was of white, European ancestry, and results may not be generalizable to other groups.

References

1. Manousaki D, Paternoster L, Standl M, et al. Vitamin D levels and susceptibility to asthma, elevated immunoglobulin E levels, and atopic dermatitis: a Mendelian randomization study [published online May 9, 2017]. PLoS Med. doi:10.1371/journal.pmed.1002294
2. Man L, Zhang Z, Zhang M, et al. Association between vitamin D deficiency and insufficiency and the risk of childhood asthma: evidence from a meta-analysis. Int J Clin Exp Med. 2015;8(4):5699-5706.
3. Forrest KYZ, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res. 2011;31(1):48-54.
4. Cassim R, Russell MA, Lodge CJ, Lowe AJ, Koplin JJ, Dharmage SC. The role of circulating 25 hydroxyvitamin D in asthma: a systematic review. Allergy. 2015;70(4):339-354.
5. Martineau AR, Cates CJ, Urashima M, et al. Vitamin D for the management of asthma [published online September 5, 2016]. Cochrane Database Syst Rev. doi:10.1002/14651858.CD011511.pub2
6. Luo J1, Liu D, Liu CT. Can vitamin D supplementation in addition to asthma controllers improve clinical outcomes in patients with asthma?: a meta-analysis. Medicine (Baltimore). 2015;94(50):e2185.