Bower Abbey L, Lang Dean H, Vogler George P, Vandenbergh David J, Blizard David A, Stout Joseph T, McClearn Gerald E, Sharkey Neil A
The Biomechanics Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802-5702, USA.
J Bone Miner Res. 2006 Aug;21(8):1267-75. doi: 10.1359/jbmr.060501.
A sample of 693 mice was used to identify regions of the mouse genome associated with trabecular bone architecture as measured using microCT. QTLs for bone in the proximal tibial metaphysis were identified on several chromosomes indicating regions containing genes that regulate properties of trabecular bone.
Age-related osteoporosis is a condition of major concern because of the morbidity and mortality associated with osteoporotic fractures in humans. Osteoporosis is characterized by reduced bone density, strength, and altered trabecular architecture, all of which are quantitative traits resulting from the actions of many genes working in concert with each other and the environment over the lifespan. microCT gives accurate measures of trabecular bone architecture providing phenotypic data related to bone volume and trabecular morphology. The primary objective of this research was to identify chromosomal regions called quantitative trait loci (QTLs) that contain genes influencing trabecular architecture as measured by microCT.
The study used crosses between C57BL/6J (B6) and DBA/2J (D2) as progenitor strains of a second filial (F2) generation (n = 141 males and 148 females) and 23 BXD recombinant inbred (RI) strains (n approximately 9 of each sex per strain). The proximal tibial metaphyses of the 200-day-old mice were analyzed by microCT to assess phenotypic traits characterizing trabecular bone, including bone volume fraction, trabecular connectivity, and quantitative measures of trabecular orientation and anisotropy. Heritabilities were calculated and QTLs were identified using composite interval mapping.
A number of phenotypes were found to be highly heritable. Heritability values for measured phenotypes using RI strains ranged from 0.15 for degree of anisotropy in females to 0.51 for connectivity density in females and total volume in males. Significant and confirmed QTLs, with LOD scores 4.3 in the F2 cohort and 1.5 in the corresponding RI cohort were found on chromosomes 1 (43 cM), 5 (44 cM), 6 (20 cM), and 8 (49 cM). Other QTLs with LOD scores ranging from 2.8 to 6.9 in the F2 analyses were found on chromosomes 1, 5, 6, 8, 9, and 12. QTLs were identified using data sets comprised of both male and female quantitative traits, suggesting similar genetic action in both sexes, whereas others seemed to be associated exclusively with one sex or the other, suggesting the possibility of sex-dependent effects.
Identification of the genes underlying these QTLs may lead to improvements in recognizing individuals most at risk for developing osteoporosis and in the design of new therapeutic interventions.
使用693只小鼠样本，以确定小鼠基因组中与小梁骨结构相关的区域，小梁骨结构通过显微CT进行测量。在几条染色体上鉴定出了胫骨近端干骺端骨的数量性状基因座（QTL），表明这些区域含有调节小梁骨特性的基因。
与年龄相关的骨质疏松症是一个主要关注的问题，因为人类骨质疏松性骨折会导致发病和死亡。骨质疏松症的特征是骨密度降低、强度下降以及小梁结构改变，所有这些都是数量性状，是许多基因在整个生命周期中相互协同作用以及与环境共同作用的结果。显微CT能准确测量小梁骨结构，提供与骨体积和小梁形态相关的表型数据。本研究的主要目的是确定被称为数量性状基因座（QTL）的染色体区域，这些区域包含影响通过显微CT测量的小梁结构的基因。
该研究使用C57BL/6J（B6）和DBA/2J（D2）之间的杂交作为第二代杂交（F2）代（n = 141只雄性和148只雌性）的亲本品系，以及23个BXD重组近交（RI）品系（每个品系每种性别约9只）。对200日龄小鼠的胫骨近端干骺端进行显微CT分析，以评估表征小梁骨的表型特征，包括骨体积分数、小梁连通性以及小梁方向和各向异性的定量测量。计算遗传力，并使用复合区间作图法鉴定QTL。
发现许多表型具有高度遗传性。使用RI品系测量的表型的遗传力值范围从雌性各向异性程度的0.15到雌性连通性密度和雄性总体积的0.51。在染色体1（43 cM）、5（44 cM）、6（20 cM）和8（49 cM）上发现了显著且得到确认的QTL，在F2队列中的LOD分数为4.3，在相应的RI队列中为1.5。在F2分析中，LOD分数范围从2.8到6.9的其他QTL在染色体1、5、6、8、9和12上被发现。使用由雄性和雌性数量性状组成的数据集鉴定QTL，这表明两性中存在相似的遗传作用，而其他一些似乎仅与一种性别相关，这表明存在性别依赖性效应的可能性。
鉴定这些QTL背后的基因可能有助于改进对最易患骨质疏松症个体的识别，并有助于设计新的治疗干预措施。
