Genetic variation in GC and CYP2R1 affects 25-hydroxyvitamin D concentration and skeletal parameters: A genome-wide association study in 24-month-old Finnish children.,PLOS Genetics

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Genetic variation in GC and CYP2R1 affects 25-hydroxyvitamin D concentration and skeletal parameters: A genome-wide association study in 24-month-old Finnish children.
PLOS Genetics ( IF 4.0 ) Pub Date : 2019-12-16 , DOI: 10.1371/journal.pgen.1008530
Anders Kämpe _{1,

2,

3} , Maria Enlund-Cerullo _{4,

5,

6} , Saara Valkama _{4,

6} , Elisa Holmlund-Suila _{4,

6} , Jenni Rosendahl _{4,

6} , Helena Hauta-Alus _{4,

6} , Minna Pekkinen _{4,

5,

6} , Sture Andersson ₄ , Outi Mäkitie _{1,

2,

4,

5,

6}

Affiliation

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.

中文翻译：

GC和CYP2R1的遗传变异影响25-羟基维生素D浓度和骨骼参数：一项针对24个月大的芬兰儿童的全基因组关联研究。

维生素D对于正常的骨骼动态平衡非常重要，尤其是对于成长中的儿童。以前没有全基因组关联（GWA）研究来探索影响儿童早期维生素D代谢的遗传因素。我们对761名健康的足月出生的芬兰24个月大儿童进行了一项针对血清25-羟基维生素D（25（OH）D）和对补充的反应的GWA研究，他们参加了一项随机临床试验，比较了10μg和30μg的作用从2周龄到24个月，每天补充微克维生素D。使用针对插补进行了优化的Illumina Infinium全球筛选阵列，在整个基因组中对总共686085个标记进行了基因分型。干预结束时在24个月大时测量血清25（OH）D。使用外围定量计算机断层扫描（pQCT）（可用于648名儿童的数据）在24个月时测定胫骨远端的反映骨强度的骨骼参数。对于25（OH）D，鉴定出两个强GWA信号，定位于GC（维生素D结合蛋白）和CYP2R1（维生素D 25-羟化酶）基因。包含GC基因的GWA基因座也与对补充的反应有关。通过将关联信号与来自基因型组织表达项目的基因表达数据进行比较并进行共定位分析，获得了这两个基因重要性的进一步证据。通过鉴定与低或高25（OH）D浓度相关的单倍型，我们使用孟德尔随机方法显示与低25（OH）D相关的单倍型在24个月大的儿童中也与低pQCT参数相关。在该年龄组中首次对25（OH）D进行的GWA研究中，我们表明，在24个月大的时候，遗传变异已经影响25（OH）D的浓度并确定了对补充的反应，并且与GC和CYP2R1在全基因组范围内具有显着关联。同样，单倍型，25（OH）D和pQCT参数之间的双重关联为25（OH）D介导的垂直多向性提供了支持。在该年龄组中首次对25（OH）D进行的GWA研究中，我们表明，在24个月大的时候，遗传变异已经影响25（OH）D的浓度并确定了对补充的反应，并且与GC和CYP2R1在全基因组范围内具有显着关联。同样，单倍型，25（OH）D和pQCT参数之间的双重关联为25（OH）D介导的垂直多向性提供了支持。在该年龄组中首次对25（OH）D进行的GWA研究中，我们表明，在24个月大的时候，遗传变异已经影响25（OH）D的浓度并确定了对补充的反应，并且与GC和CYP2R1在全基因组范围内具有显着关联。同样，单倍型，25（OH）D和pQCT参数之间的双重关联为25（OH）D介导的垂直多向性提供了支持。

更新日期：2019-12-17

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