Section of Endocrinology, Department of Medicine, Rikshospitalet University Hospital, Oslo, Norway.
J Bone Miner Res. 2011 Aug;26(8):1793-801. doi: 10.1002/jbmr.396.
Genome-wide gene expressions in bone biopsies from patients with postmenopausal osteoporosis and healthy controls were profiled, to identify osteoporosis candidate genes. All osteoporotic patients (n = 27) in an unbiased cohort of Norwegian women presented with bone mineral density (BMD) T-scores of less than -2.5 SD and one or more confirmed low-energy fracture(s). A validation group (n = 18) had clinical and laboratory parameters intermediate to the control (n = 39) and osteoporosis groups. RNA from iliac crest bone biopsies were analyzed by Affymetrix microarrays and real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Differentially expressed genes in osteoporosis versus control groups were identified using the Bayesian ANOVA for microarrays (BAMarray) method, whereas the R-package Limma (Linear Models for Microarray Data) was used to determine whether these transcripts were explained by disease, age, body mass index (BMI), or combinations thereof. Laboratory tests showed normal ranges for the cohort. A total of 609 transcripts were differentially expressed in osteoporotic patients relative to controls; 256 transcripts were confirmed for disease when controlling for age or BMI. Most of the osteoporosis susceptibility genes (80%) also were confirmed to be regulated in the same direction in the validation group. Furthermore, 217 of 256 transcripts were correlated with BMD (adjusted for age and BMI) at various skeletal sites (|r| > 0.2, p < .05). Among the most distinctly expressed genes were Wnt antagonists DKK1 and SOST, the transcription factor SOX4, and the bone matrix proteins MMP13 and MEPE, all reduced in osteoporosis versus control groups. Our results identify potential osteoporosis susceptibility candidate genes adjusted for confounding factors (ie, age and BMI) with or without a significant correlation with BMD.
对绝经后骨质疏松症患者和健康对照者的骨活检进行全基因组基因表达谱分析，以鉴定骨质疏松候选基因。在挪威女性的无偏倚队列中，所有骨质疏松症患者（n = 27）的骨密度（BMD）T 评分均低于-2.5 SD，且有一个或多个经证实的低能量骨折。验证组（n = 18）的临床和实验室参数处于对照组（n = 39）和骨质疏松组之间。通过 Affymetrix 微阵列和实时逆转录聚合酶链反应（RT-PCR）分析髂嵴骨活检的 RNA。使用贝叶斯方差分析（BAMarray）方法鉴定骨质疏松症与对照组之间差异表达的基因，而使用 R 包 Limma（用于微阵列数据的线性模型）确定这些转录物是否由疾病、年龄、体重指数（BMI）或其组合解释。实验室测试显示队列的正常范围。与对照组相比，骨质疏松症患者中共有 609 个转录物差异表达；当控制年龄或 BMI 时，有 256 个转录物与疾病相关。大多数骨质疏松症易感基因（80%）也在验证组中以相同的方向被证实受到调控。此外，256 个转录物中有 217 个与各种骨骼部位的 BMD（调整年龄和 BMI）相关（|r| > 0.2，p <.05）。表达最明显的基因包括 Wnt 拮抗剂 DKK1 和 SOST、转录因子 SOX4 以及骨基质蛋白 MMP13 和 MEPE，这些基因在骨质疏松症患者中均低于对照组。我们的研究结果确定了潜在的骨质疏松症易感候选基因，这些基因可调整混杂因素（即年龄和 BMI），并与 BMD 具有或不具有显著相关性。
