Lazáry Aron, Kósa János P, Tóbiás Bálint, Lazáry Judit, Balla Bernadett, Bácsi Krisztián, Takács István, Nagy Zsolt, Mezo Tibor, Speer Gábor, Lakatos Péter
1st Department of Internal Medicine, Semmelweis University, Koranyi S. u. 2/a., Budapest H-1083, Hungary.
Eur J Endocrinol. 2008 Aug;159(2):187-96. doi: 10.1530/EJE-08-0021. Epub 2008 May 9.
Osteoporosis (OP) is a multifactorial disease with high heritability but its exact genetic background is still poorly understood. We examined the effect of 24 single nucleotide polymorphisms (SNPs) located in five genes--alkaline phosphatase, matrix metalloproteinase-2, tissue inhibitor of metalloproteases-2 (TIMP2), fibroblast growth factor receptor-1 (FGFR1), and fatty acid-binding protein-3 (FABP3)--previously not associated with OP.
We performed a genotype-phenotype association study at a university hospital.
A total of 360 Hungarian postmenopausal women were involved in the study. Bone mineral density (BMD) was determined at spine, hip, and distal radius. Genomic DNA was extracted from venous blood samples and a high-throughput genotyping method based on single-based primer extension was applied for allelic discrimination. Robust statistical tools were utilized for multiplex data analysis.
SNP rs6996321 in FGFR1 was significantly related to spine BMD (P=0.002) and rs10914367 in FABP3 was associated with hip BMD (P=0.028). Non-vertebral fracture risk was significantly increased in carriers of 'A' allele of rs9900972 in TIMP2 (odds ratio=2.06, P=0.0187). We could also identify validated gene-gene interactions significantly affecting BMD and fracture risk.
We identified two previously unreported SNPs in FGFR1 and FABP3 associated with BMD and a third SNP in TIMP2 related to risk for non-vertebral osteoporotic fractures. This is the first report about the association between these allelic variants and the phenotypes of postmenopausal OP. Further studies need to clarify the role of these genes and their polymorphisms in the process of bone loss.
骨质疏松症（OP）是一种具有高遗传性的多因素疾病，但其确切的遗传背景仍知之甚少。我们研究了位于五个基因——碱性磷酸酶、基质金属蛋白酶 - 2、金属蛋白酶组织抑制剂 - 2（TIMP2）、成纤维细胞生长因子受体 - 1（FGFR1）和脂肪酸结合蛋白 - 3（FABP3）——中的24个单核苷酸多态性（SNP）的影响，这些基因此前未被发现与OP相关。
我们在一家大学医院进行了一项基因型 - 表型关联研究。
共有360名匈牙利绝经后女性参与了该研究。在脊柱、髋部和桡骨远端测定骨密度（BMD）。从静脉血样本中提取基因组DNA，并应用基于单碱基引物延伸的高通量基因分型方法进行等位基因鉴别。使用稳健的统计工具进行多重数据分析。
FGFR1中的SNP rs6996321与脊柱骨密度显著相关（P = 0.002），FABP3中的rs10914367与髋部骨密度相关（P = 0.028）。TIMP2中rs9900972的“A”等位基因携带者的非椎体骨折风险显著增加（优势比 = 2.06，P = 0.0187）。我们还发现了经证实的基因 - 基因相互作用，其显著影响骨密度和骨折风险。
我们在FGFR1和FABP3中鉴定出两个先前未报道的与骨密度相关的SNP，以及TIMP2中一个与非椎体骨质疏松性骨折风险相关的第三个SNP。这是关于这些等位基因变体与绝经后OP表型之间关联的首次报道。进一步的研究需要阐明这些基因及其多态性在骨质流失过程中的作用。
