ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: PLoS Genet. 2019 Dec 16;15(12):e1008530.

In brief: This genome-wide association study in a cohort of healthy infants shows that, already during the first two years of life, genetic variation in the genes encoding Vitamin D binding protein and Vitamin D 25-hydroxylase correlate with serum 25(OH)D levels and responses to vitamin D supplementation.

Commentary: Previous studies have shown that several genetic factors influence vitamin D status. However, no genome-wide association studies (GWAS) have evaluated the role of such genetic factors in infants and young children. This study by Kämpe et al. applied a GWAS approach in a cohort of 975 healthy Finnish infants, recruited to a randomized intervention study to evaluate the effects of 10 µg vs 30 µg supplemental vitamin D from age 2 weeks to 2 years (1). The original trial results showed that the higher vitamin D supplemental dose did not provide additional benefits for bone strength or susceptibility to infections (1). Here, the authors evaluated how genetic variation in these infants influences serum 25(OH)D concentrations, responses to vitamin D supplements, and skeletal outcomes. The GWAS identified two strong association signals involving the genes GC (Vitamin D binding protein) and CYP2R1 (Vitamin D 25-hydroxylase). Based on 25(OH)D measurements in umbilical cord and 24 months samples, the authors were able to assess genetic variation in relation to vitamin D supplementation responses. The GC locus was associated with the magnitude of 25(OH)D change during intervention. The original intervention study (1) found no differences in bone parameters at 24 months, as measured by peripheral quantitative computed tomography (pQCT), between the two vitamin D intervention groups. However, this study showed that haplotypes at the GC locus and the CYP2R1 locus showed strong associations with pQCT parameters, suggesting that low 25(OH)D does causally negatively impact on bone in 24-month-old children.

Both identified genes – GC and CYP2R1 – have previously been associated with serum 25(OH)D levels in several GWAS reports in older cohorts but this study is the first to confirm that genetic variation in these genes influences vitamin D metabolism and even responses to supplementation already in infancy. The cohort was genetically homogeneous (ethnic Finns), which may have enabled identification of these strong associations despite the relatively small cohort size. Further, the participants were also relatively homogeneous regarding their baseline vitamin D status as most were vitamin D sufficient already at onset of vitamin D supplementation. It remains to be evaluated whether these genetic findings can be replicated in larger and genetically and biochemically more heterogeneous cohorts of infants. The findings suggest that infants with certain risk haplotypes may benefit from higher vitamin D supplemental doses, and in contrast, others may be at increased risk of unnecessary high serum 25(OH)D levels with increased supplemental doses. Future follow-up of this cohort will hopefully elucidate whether GC and CYP2R1 genotypes predict longer-term health outcomes.

Reference:

1. Rosendahl, J., et al., Effect of Higher vs Standard Dosage of Vitamin D3 Supplementation on Bone Strength and Infection in Healthy Infants: A Randomized Clinical Trial. JAMA Pediatr, 2018;172(7):646–654.