Abstract
Vitamin D is important for normal skeletal homeostasis, especially in growing children. There are no previous genome-wide association (GWA) studies exploring genetic factors that influence vitamin D metabolism in early childhood. We performed a GWA study on serum 25-hydroxyvitamin D (25(OH)D) and response to supplementation in 761 healthy term-born Finnish 24-month-old children, who participated in a randomized clinical trial comparing effects of 10 μg and 30 μg of daily vitamin D supplementation from age 2 weeks to 24 months. Using the Illumina Infinium Global Screening Array, which has been optimized for imputation, a total of 686085 markers were genotyped across the genome. Serum 25(OH)D was measured at the end of the intervention at 24 months of age. Skeletal parameters reflecting bone strength were determined at the distal tibia at 24 months using peripheral quantitative computed tomography (pQCT) (data available for 648 children). For 25(OH)D, two strong GWA signals were identified, localizing to GC (Vitamin D binding protein) and CYP2R1 (Vitamin D 25-hydroxylase) genes. The GWA locus comprising the GC gene also associated with response to supplementation. Further evidence for the importance of these two genes was obtained by comparing association signals to gene expression data from the Genotype-Tissue Expression project and performing colocalization analyses. Through the identification of haplotypes associated with low or high 25(OH)D concentrations we used a Mendelian randomization approach to show that haplotypes associating with low 25(OH)D were also associated with low pQCT parameters in the 24-month-old children. In this first GWA study on 25(OH)D in this age group we show that already at the age of 24 months genetic variation influences 25(OH)D concentrations and determines response to supplementation, with genome-wide significant associations with GC and CYP2R1. Also, the dual association between haplotypes, 25(OH)D and pQCT parameters gives support for vertical pleiotropy mediated by 25(OH)D.
Highlights
Vitamin D is a fat-soluble prohormone essential for calcium and phosphate homeostasis, and believed to be important for many other cellular processes in the human body
We show that genetic variation in the genes coding for Vitamin D binding protein (GC) and Vitamin D 25-hydroxylase (CYP2R1) are important determinants for serum 25-hydroxyvitamin D concentration in 2-year-old children
All participants in this study were originally included in the Vitamin D intervention (VIDI) study, a randomized clinical trial investigating whether 30 μg compared with 10 μg of daily vitamin D3 supplementation, given from age 2 weeks to 24 months, would be beneficial for Finnish infants [12]
Summary
Vitamin D is a fat-soluble prohormone essential for calcium and phosphate homeostasis, and believed to be important for many other cellular processes in the human body. Vitamin D deficiency has been associated with various diseases and outcomes, including skeletal disorders, infections, autoimmunity and all-cause mortality [1, 2]. In large systematic reviews and randomized trials, the effects of vitamin D on human health have been varying and associations to health outcomes hard to replicate [3,4,5]. The best understood consequences of vitamin D deficiency are rickets in children and osteomalacia in adults, two disorders characterized by poor mineralization of the bone matrix [6, 7]. Vitamin D food fortification and supplementation have been implemented to improve vitamin D status in these countries, including Finland [10, 11]
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