Mitchell Jonathan A, Chesi Alessandra, Elci Okan, McCormack Shana E, Kalkwarf Heidi J, Lappe Joan M, Gilsanz Vicente, Oberfield Sharon E, Shepherd John A, Kelly Andrea, Zemel Babette S, Grant Struan F A
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
J Bone Miner Res. 2015 Sep;30(9):1676-83. doi: 10.1002/jbmr.2508. Epub 2015 May 26.
We aimed to determine if adult bone mineral density (BMD) susceptibility loci were associated with pediatric bone mass and density, and if sex and pubertal stage influenced any association. We analyzed prospective areal BMD (aBMD) and bone mineral content (BMC) data from the Bone Mineral Density in Childhood Study (n = 603, European ancestry, 54% female). Linear mixed models were used to assess if 77 single-nucleotide polymorphisms (SNPs) near known adult BMD susceptibility loci interacted with sex and pubertal stage to influence the aBMD/BMC; adjusting for age, BMI, physical activity, and dietary calcium. The strongest main association was observed between an SNP near C7orf58 and distal radius aBMD. However, this association had a significant sex • SNP interaction, revealing a significant association only in females (b = -0.32, p = 1.8 × 10(-6)). Furthermore, the C12orf23 locus had significant interactions with both sex and pubertal stage, revealing associations in females during Tanner stage I for total hip aBMD (b = 0.24, p = 0.001) and femoral neck aBMD (b = 0.27, p = 3.0 × 10(-5)). In contrast, the sex • SNP interactions for loci near LRP5 and WNT16 uncovered associations that were only in males for total body less head BMC (b = 0.22, p = 4.4 × 10(-4)) and distal radius aBMD (b = 0.27, p = 0.001), respectively. Furthermore, the LRP5 locus interacted with both sex and pubertal stage, demonstrating associations that were exclusively in males during Tanner V for total hip aBMD (b = 0.29, p = 0.003). In total, significant sex • SNP interactions were found at 15 loci; pubertal stage • SNP interactions at 23 loci and 19 loci interacted with both sex and pubertal stage. In conclusion, variants originally associated with adult BMD influence bone mass in children of European ancestry, highlighting the fact that many of these loci operate early in life. However, the direction and magnitude of associations for a large number of SNPs only became evident when accounting for sex and maturation.
我们旨在确定成人骨矿物质密度（BMD）易感基因座是否与儿童骨量和骨密度相关，以及性别和青春期阶段是否会影响这种关联。我们分析了来自儿童骨矿物质密度研究（n = 603，欧洲血统，54%为女性）的前瞻性面积骨密度（aBMD）和骨矿物质含量（BMC）数据。使用线性混合模型来评估已知成人BMD易感基因座附近的77个单核苷酸多态性（SNP）是否与性别和青春期阶段相互作用，从而影响aBMD/BMC；同时对年龄、体重指数、身体活动和膳食钙进行了校正。在C7orf58附近的一个SNP与桡骨远端aBMD之间观察到最强的主要关联。然而，这种关联存在显著的性别•SNP相互作用，仅在女性中显示出显著关联（b = -0.32，p = 1.8×10⁻⁶）。此外，C12orf23基因座与性别和青春期阶段均存在显著相互作用，在坦纳I期女性的全髋aBMD（b = 0.24，p = 0.001）和股骨颈aBMD（b = 0.27，p = 3.0×10⁻⁵）中显示出关联。相比之下，LRP5和WNT16附近基因座的性别•SNP相互作用分别在男性的全身除头部BMC（b = 0.22，p = 4.4×10⁻⁴）和桡骨远端aBMD（b = 0.27，p = 0.001）中发现了关联。此外，LRP5基因座与性别和青春期阶段均相互作用，在坦纳V期男性的全髋aBMD中显示出仅在男性中的关联（b = 0.29，p = 0.003）。总共在15个基因座发现了显著的性别•SNP相互作用；在23个基因座发现了青春期阶段•SNP相互作用，19个基因座与性别和青春期阶段均相互作用。总之，最初与成人BMD相关的变异会影响欧洲血统儿童的骨量，突出了许多这些基因座在生命早期起作用的事实。然而，只有在考虑性别和成熟度时，大量SNP关联的方向和程度才变得明显。
