Genetic variation in GC and CYP2R1 affects 25-hydroxy-vitamin D concentration and skeletal parameters

Vitamin D (vit D) is a fat-soluble prohormone essential for calcium and phosphate homeostasis. Vit D is also critical for many other cellular processes in the human body. Vit D deficiency is associated with various diseases and outcomes, including skeletal disorders, infections, autoimmunity, mental health, and ‘mortality from all causes’. The best understood consequences of vit D deficiency are rickets in children and osteomalacia in adults — two disorders characterized by poor mineralization of bone matrix. Especially for a child’s growing skeleton childhood, sufficient absorption of calcium and phosphate, mediated principally by “active vit D” (which is 1a,25-dihydroxy-vit D, the metabolite that is by far the mose potent ligand for the vit D receptor, VDR) is important. Because vit D synthesis in skin from 7-dehydrocholesterol requires sunlight exposure, children living in northern latitudes have greater risk for vit D deficiency. Vit D food-fortification and supplementation improves vit D status in these countries, including Finland [here we go again, picking on THIS poor little country 😉].

Authors [see attached article] postulated that individual genetic factors might be very important in maintaining sufficiently healthy levels of vit D, and that these genetic properties, and their downstream effects, may be easier to identify in Finnish children whose sunlight exposure is low. Combined with a randomized vit D intervention study — comparing effects of 10 μg vs 30 μg of daily vit D supplementation — from age 2 weeks to 24 months, authors carried out a genome-wide association study (GWAS). This study focused on serum 25-hydroxy vit D [25(OH)D] concentrations at the 24-mo time-point — to search for genetic variations that would be important determinants for 25(OH)D levels in 761 24-mo-old healthy Finnish children. [The 25(OH)D concentration at age 24 months was chosen as ‘the outcome variable’, although 25(OH)D had also been assessed at birth (umbilical cord) and at 12 mo.]

Hence, these GEITP pages are continuing with their gene-environment interactions theme: “the environment” includes “high vs low doses” daily vit D supplementation in young Finnish children (up to age 24 mo) who are exposed only to weak sunshine; “the genes” include those which respond most profoundly to this environmental signal.

At age 24 mo, mother’s 25(OH)D levels are less likely to have an effect; feeding patterns are more constant after the decreased influence of breast feeding. Authors adjusted all association models for “the intervention group” because of its strong effect on 25(OH)D at the 24-mo time point — but having two “intervention groups” — also enabled the authors to assess genetic variation, relative to the supplementation response. Authors also explored how genetic variation — associated with either higher, or lower, 25(OH)D levels — affected skeletal parameters, as measured with peripheral quantitative computed tomography (pQCT).

For 25(OH)D, two strong GWAS signals were identified — localizing to the GC gene (encoding GC vit-D binding protein) and the CYP2R1 gene (encoding vit D 25-hydroxylase) gene. The GWAS also showed that the GC gene was associated with the 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 (GTEx) Project and by performing co-localization analyses. Through the identification of haplotypes (i.e. a DNA segment or group of genes, on one chromosome of the chromosome pair, within any organism that was inherited together from a single parent) associated with low or high 25(OH)D levels, authors used a Mendelian Randomization (MR) approach (method of using measured variation — in genes of known function — to examine causal effect(s) of a modifiable exposure on disease in observational studies) to show that haplotypes associated with low 25(OH)D were also correlated with low pQCT parameters in the 24-mo-old children. In this first GWAS on 25(OH)D levels in this age group, authors therefore have shown that — already at the age of 24 mo — differences in genetic susceptibility influence 25(OH)D concentrations, and these differences determine the response to supplementation, which reflect functions of GC and CYP2R1 gene expression. Also, the associations among haplotypes, 25(OH)D, and pQCT parameters — lend support for vertical pleiotropy [pleiotropy implies that one single-nucleotide variant (SNV) shows significant associations with multiple traits, across many GWAS; a key feature of vertical pleiotropy is that two traits — that are biologically related — should remain related, regardless of which specific gene or variant is causing the effect] mediated by 25(OH)D. 😊


PLoS Genet Dec 2019; 15: e1008530

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