Jin Huilin, Stewart Tracy L, Hof Rob Van't, Reid David M, Aspden Richard M, Ralston Stuart
Rheumatic Disease Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Edinburgh, UK.
J Bone Miner Res. 2009 Mar;24(3):448-54. doi: 10.1359/jbmr.081111.
Three polymorphisms have been identified in the 5' regulatory region of the COL1A1 gene at positions -1997 (rs1107946), -1663 (rs2412298), and +1245G/T (rs1800012), which combine to form haplotypes that have been associated with BMD in several populations. These polymorphisms and haplotypes have not thus far been studied in relation to biomechanical properties of bone or fracture risk. Genotypes and haplotypes of the COL1A1 gene were related to the biomechanical properties of bone ex vivo in samples of bone tissue obtained from the femoral head of 98 consecutive patients undergoing surgery for low-trauma hip fractures. Genotype and haplotype frequencies in the hip fracture cases were compared with 3418 population-based controls recruited from the same region. All three polymorphisms were associated with material density of the bone core, yield strength, and toughness. The association between -1663InsdelT and +1245G/T alleles, yield strength, and toughness remained significant after adjusting for material density of the core and other confounding factors. A haplotype comprising the unfavorable allele at all three polymorphic sites (-1997T/-1663delT/+1245T) was also associated with yield strength, modulus, and toughness after adjusting for confounding factors. This haplotype was carried by 19/94 (20.2%) patients with hip fracture compared with only 2/3399 (0.06%) female controls drawn from the general population (p < 0.0001). In contrast, there was no significant difference between cases and controls in genotype distribution for the individual polymorphisms. This study shows that common genetic variants in the 5' regulatory region of COL1A1 are associated with biomechanical properties of bone and reduced bone quality by mechanisms independent of their effects on BMD. The biomechanically unfavorable allele at each polymorphic site defines a haplotype that is extremely rare in the general population but that is approximately 400-fold enriched in hip fracture patients. This haplotype may have clinical value as a genetic marker for susceptibility to hip fracture, and further studies to investigate this possibility would be of interest.
在COL1A1基因的5'调控区已鉴定出三个多态性位点，分别位于-1997（rs1107946）、-1663（rs2412298）和+1245G/T（rs1800012），它们组合形成的单倍型已在多个群体中与骨密度相关。迄今为止，尚未对这些多态性和单倍型与骨的生物力学特性或骨折风险进行研究。在98例因低创伤性髋部骨折接受手术的连续患者的股骨头骨组织样本中，研究了COL1A1基因的基因型和单倍型与离体骨生物力学特性的关系。将髋部骨折病例的基因型和单倍型频率与从同一地区招募的3418名基于人群的对照进行比较。所有三个多态性均与骨芯的材料密度、屈服强度和韧性相关。在调整骨芯材料密度和其他混杂因素后，-1663InsdelT和+1245G/T等位基因、屈服强度和韧性之间的关联仍然显著。在调整混杂因素后，一个在所有三个多态性位点均包含不利等位基因的单倍型（-1997T/-1663delT/+1245T）也与屈服强度、模量和韧性相关。94例髋部骨折患者中有19例（20.2%）携带此单倍型，而从一般人群中抽取的女性对照中只有2例（0.06%）携带（p<0.0001）。相比之下，单个多态性的基因型分布在病例和对照之间没有显著差异。本研究表明，COL1A1基因5'调控区的常见遗传变异与骨的生物力学特性相关，并通过独立于其对骨密度影响的机制降低骨质量。每个多态性位点的生物力学不利等位基因定义了一个在一般人群中极为罕见但在髋部骨折患者中富集约400倍的单倍型。该单倍型可能作为髋部骨折易感性的遗传标志物具有临床价值，进一步研究以探讨这种可能性将是有意义的。
