Haplotypes in the CYP2R1 gene are associated with levels of 25(OH)D and bone mineral density, but not with other markers of bone metabolism (MrOS Sweden).

Sakamuri V Reddy,Anne Björk,Östen Ljunggren,Magnus Karlsson,Claes Ohlsson,Hans Mallmin,Andreas Kindmark,Dan Mellström,Gunnar Johansson

doi:10.1371/journal.pone.0209268

Sakamuri V Reddy, Anne Björk + Show 7 more

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https://doi.org/10.1371/journal.pone.0209268

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Abstract

ObjectivePolymorphisms in the CYP2R1 gene encoding Vitamin D 25-hydroxylase have been reported to correlate with circulating levels of 25-OH vitamin D3 (25(OH)D). It is unknown whether these variations also affect overall bone metabolism. In order to elucidate the overall associations of polymorphisms in the CYP2R1, we studied haplotype tagging single nucleotide polymorphisms (SNPs) in the gene and serum levels of 25(OH)D, calcium, phosphate, parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23), as well as bone mineral density (BMD).MethodsBaseline data on serum parameters and BMD from MrOS Sweden, a prospective population-based cohort study of elderly men (mean age 75 years, range 69–81), were analyzed. Genotyping was performed for eight SNPs covering the CYP2R1 gene in 2868 men with available samples of DNA. Subjects were followed up concerning incidence of fracture during five years.ResultsThere was a significant genetic association with circulating levels of 25(OH)D (4.6–18.5% difference in mean values between SNP alleles), but there were no correlations with levels of calcium, phosphate, PTH or FGF23 for any genetic variant. No differences were found in fracture incidence between the variants. There was an inverse relationship between lower BMD and concomitant higher 25(OH)D for three of the haplotypes (p < 0.005).ConclusionsCommon variants in the CYP2R1 gene encoding Vitamin D 25-hydroxylase correlate with levels of circulating 25(OH)D but do not otherwise associate with measures of calcium and phosphate homeostasis. Presence of the specific haplotypes may be an indicator of risk for low 25(OH)D levels, and may in addition be correlated to bone mineral density.

Highlights

The increasing incidence of osteoporosis-related fractures with increasing age is a major health problem, leading to suffering and increased mortality, as well as economic problems for both the individual and society [1, 2]
There was a significant genetic association with circulating levels of 25(OH)D (4.6–18.5% difference in mean values between single nucleotide polymorphisms (SNPs) alleles), but there were no correlations with levels of calcium, phosphate, Parathyroid hormone (PTH) or fibroblast growth factor 23 (FGF23) for any genetic variant
Common variants in the CYP2R1 gene encoding Vitamin D 25-hydroxylase correlate with levels of circulating 25(OH)D but do not otherwise associate with measures of calcium and phosphate homeostasis

Summary

Introduction

The increasing incidence of osteoporosis-related fractures with increasing age is a major health problem, leading to suffering and increased mortality, as well as economic problems for both the individual and society [1, 2]. Osteoporosis is characterised by low bone mineral density (BMD), and bone micro architectural deterioration. Both environmental and hereditary factors have been shown be important and to interact, for BMD as well as for fractures [3,4,5]. By stimulating the conversion of 25(OH)D into the active form 1,25-dihydroxyvitamin D3, PTH causes an enhanced absorption of calcium in the intestine. Another important phosphate regulating factor participating in bone and mineral metabolism is the fibroblast growth factor 23 (FGF23) which in turn is regulated by levels of phosphate and 1,25-dihydroxyvitamin D3 [8, 9]. Vitamin D deficiency can lead to musculoskeletal diseases such as rickets and osteomalacia, but vitamin D supplementation may prevent extra skeletal diseases such as respiratory tract infections, asthma exacerbations, pregnancy complications and premature deaths. [10]

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