骨质疏松致病候选基因研究进展 2

大部分骨量，在以后常常不能再恢复。一旦骨质疏松合并骨折发生，就无足够有效的药物可以使骨质疏松的骨骼恢复原来的骨质量。因此，预防性治疗是处理骨质疏松性骨折的最可靠方式。骨质疏松候选基因研究的一个潜在应用是评估骨质疏松性骨折的危险性。如果能分离鉴定出预测低骨密度和骨质疏松性骨折的基因多态性，那么就以此作为筛选工具，鉴定高危人群以及作出是否有必要进行药物干涉，使患者在骨折前就能进行有效的预防性治疗。研究已显示食物中钙和维生素D的补充引起的骨量增多的反应部分依赖于维生素D受体基因多态性，不同的VDR基因型对维生素D和钙的反应不同。可以肯定多态性标记在候选基因的应用，能提供给患者适当的治疗方法的信息，以决定哪类患者最适用于哪种治疗方案，并检测各种药物治疗的有效性。目前，骨质疏松候选基因尚不能成熟的应用于骨质疏松的诊断，尚需在不同种族中大规模样本研究后，才能应用于临床。

　　三、展望

　　虽然对候选基因多态性是否是决定骨量和骨质疏松性骨折危险性方面最重要的因素，仍有争议，但基因在骨质疏松病因中的决定作用是毋庸质疑的。目前发现参与调控的基因有67个之多,但哪些基因起主要作用以及基因之间怎样相互作用尚不清楚。更难理解的是为什么这些等位基因有时存在，有时不存在，有时甚至是相反的结果。所以研究必须在大样本，或者是高骨量的年轻人，按照统一的标准，多中心协作进行。同时，骨质疏松是一个受遗传、饮食、吸烟、酒精摄入和运动等因素影响的复杂疾病，决定了研究遗传基因和环境因素之间相互作用会更加重要。进一步的研究会确定骨质疏松的直接病因；找出敏感的基因标记，预测骨质疏松的骨折危险性；寻找新的基因克隆分子，开发药物防止骨丢失和逆转骨质疏松。只有解决了这些问题才能找到有效的线索，将骨质疏松的基因预防和治疗带入一个全新的领域。

　　参考文献

　　［1］Ross pD.Ossteoporosis,frequency,consequences and risk factors. Arch Intern Med,1996,156:1399-1411.

　　［2］Ferrari SL,Rizzoli R,Slosman DO,et al.Do dietary calcium and age explain the controversy surrounding the relationship between bone mineral density and vitamin D receptor gene polymophisms? J Bone Miner Res,1998,13:363-370．

　　［3］Ferrari S,Rizzoli R,Manen D,et al.Vitamin D receptor gene start codon polymorphisms (FokⅠ) and bone mineral density: interaction with age, dietary calcium, and 3′-end region polymorphisms.J Bone Miner Res,1998,13:925-930．

　　［4］Araih,Miyamoto KI,Takitani Y,et al.A vitamin D receptor gene polymorphism in the translation initiation codon: effect on prote in activity and relation to bone mineral density in Japanese women.J Bone Miner Res,1997,12:915-921．

　　［5］Zhao J,Zhou X,Meng X,et al.Polymorphism of vitamin D receptor gene and its association with bone mineral density and ostecalcin in Chinese.Chin Med j,1997,110:366-371．

　　［6］Cooper GS,Umbach DM.Are Vitamin D receptor polymorphisms associated with bone mineral density? a meta-analysis.J Bone Miner Res 1996,11:1841-1849．

　　［7］Willing MC,Torner JC,Burns TL,et al.Determinants of bone mineral density in postmenopausal white iowas.Biol Sci Med Sci,1997,52:M337-342．

　　［8］Smith EP,Boyd J,Frank GR,et al.Estrogen resistance caused by a mutation in the estrogen receptor gene in a man.N Engl J Med,1995,331:1056-1061．

　　［9］Kobayashi S,Inoue T,Hosoi T,et al.Association of bone mineral density with polymorphism of the estrogen receptor gene.J Bone Miner Res,1996,11:306-311．

　　［10］Tsukamoto K,Inoue S,Hosoi T,et al.Isolation and radiation hybrid mapping of dinucleotide repeat polymerphism at the human estrogen receptor-beta locus.J hum Genet,1998,43:73-74．

　　［11］Willing MC,Sower M,Aron D, et al.Bone mineral density and its change in white women: estrogen and vitamin D receptor genotypes and their interaction.J bone Miner Res,1998,13:695-705．

　　［12］Gennari L,Becherini L,Masi L,et al.Vitamin D and receptor allelic variants in Italian postmenopausal women: evidence of mutiple gene contribution to bone mineral density.J Clin Endocrinol Metab,1998,83:939-944．

　　［13］Murray RE,Mcguigan F,Grant SF,et al.Polymorphisms of the Interlenkin-6 gene are associated with bone mineral density.Bone,1997,21:89-92．

　　［14］Dietz FR，Mathews KD.Update on genetic bases of disorders with orthopaedic manifestations.J Bone Joint Surg(Am),1996,78:1583-1595．

　　［15］Spotila LD,Coligen A,Sereda L,et al.Mutaation anallysis of code sequense for type Ⅰ procollege in individuals with low bone dendity.J Bone Miner res,1994,9:923-932.

　　［16］Grant SFA,Reid SM,Blake G,et al.Reduced bone density and osteoporisis associated with a polymorphic Sp Ⅰ site in the collagen type Ⅰ alpha Ⅰ gene.Nature Genetics,1996,14:203-205．

　　［17］Uitterlinden AG,Durqer H,Huang A,et al.Relations of alleles of the collagen type Ⅰ alpha 1gene to bone density and the risk of osteoporotic fractures in postmenopausal women.N Engl J Med,1998,338:1016-1021．

　　［18］Reed BY,Zerwekh JE,Sakhaee,et al.Serum IGF-Ⅰ is low and correlated with osteoblastic surface in idiopathic osteoporosis.J Bone Miner res,1995,10:1218-1224.

　　［19］Zhang R,Supowit SC,Klein GC,et al.Rat t