McLean Robert R, Karasik David, Selhub Jacob, Tucker Katherine L, Ordovas Jose M, Russo Giuseppina T, Cupples L Adrienne, Jacques Paul F, Kiel Douglas P
Research and Training Institute, Hebrew Rehabilitation Center for Aged, Boston, Massachusetts 01702, USA.
J Bone Miner Res. 2004 Mar;19(3):410-8. doi: 10.1359/JBMR.0301261. Epub 2003 Dec 22.
A study of a polymorphism in the MTHFR gene, plasma folate, and bone phenotypes in 1632 individuals revealed that the genotype effect on BMD and quantitative ultrasound was dependent on the level of folate. Our findings support the hypothesis that the association between an MTHFR polymorphism and bone phenotypes depends on folate status.
Genome-wide screens using quantitative ultrasound (QUS) and BMD phenotypes have shown suggestive linkage on chromosome 1pter-1p36.3, a region containing the methylenetetrahydrofolate reductase (MTHFR) gene. Individuals homozygous (TT) for the MTHFR C677T polymorphism who have low plasma folate concentrations exhibit elevated plasma homocysteine (tHcy) concentrations that may compromise bone quality. We hypothesized that folate status might modify an association between the C677T polymorphism and bone, possibly by influencing homocysteine concentrations.
QUS (broadband ultrasound attenuation [BUA], speed of sound, and quantitative ultrasound index) of the heel and BMD of the hip and spine were measured in 1632 male and female members of the Framingham Offspring Study (1996-2001). Participants were assessed for plasma folate concentration and genotyped for the MTHFR C677T polymorphism. TT participants were compared with individuals in the CC + CT group using analysis of covariance.
Adjusted mean QUS and BMD measures did not differ between C677T groups. Although all participants with plasma folate concentrations > or =4 ng/ml had approximately 2% higher QUS and BMD than those with folate <4 ng/ml, the association disappeared after controlling for tHcy. Suggestive interactions between folate status and the C677T group (CC + CT versus TT) were found for hip BMD (p < or = 0.05) and BUA (p = 0.11). Compared with CC + CT participants, TT individuals had lower mean BUA (p = 0.06) and Ward's area BMD (p = 0.08) within the folate <4 ng/ml group and significantly higher hip BMD (p < or = 0.05) within the folate > or =4 ng/ml group. For both folate groups, TT participants had higher age-adjusted mean plasma tHcy versus CC + CT participants. Controlling for tHcy in these models did not affect the statistical significance of the interaction effects.
Our findings support the hypothesis that the association between the C677T MTHFR polymorphism and bone phenotypes depends on folate status. The mechanism mediating the association, however, remains unclear, but may be partially caused by homocysteine effects on bone.
对1632名个体的亚甲基四氢叶酸还原酶（MTHFR）基因多态性、血浆叶酸和骨表型进行的一项研究表明，基因型对骨密度（BMD）和定量超声的影响取决于叶酸水平。我们的研究结果支持这样一种假设，即MTHFR多态性与骨表型之间的关联取决于叶酸状态。
使用定量超声（QUS）和BMD表型进行的全基因组筛查显示，在1号染色体短臂末端至1p36.3区域存在提示性连锁，该区域包含亚甲基四氢叶酸还原酶（MTHFR）基因。血浆叶酸浓度低的MTHFR C677T多态性纯合子（TT）个体表现出血浆同型半胱氨酸（tHcy）浓度升高，这可能会损害骨质。我们假设叶酸状态可能会改变C677T多态性与骨骼之间的关联，可能是通过影响同型半胱氨酸浓度来实现的。
在弗雷明汉后代研究（1996 - 2001年）的1632名男性和女性成员中，测量了足跟的QUS（宽带超声衰减[BUA]、声速和定量超声指数）以及髋部和脊柱的BMD。对参与者的血浆叶酸浓度进行评估，并对MTHFR C677T多态性进行基因分型。使用协方差分析将TT参与者与CC + CT组的个体进行比较。
C677T组之间调整后的平均QUS和BMD测量值没有差异。尽管所有血浆叶酸浓度≥4 ng/ml的参与者的QUS和BMD比叶酸<4 ng/ml的参与者高约2%，但在控制tHcy后这种关联消失了。在髋部BMD（p≤0.05）和BUA（p = 0.11）方面，发现叶酸状态与C677T组（CC + CT与TT）之间存在提示性相互作用。与CC + CT参与者相比，在叶酸<4 ng/ml组中，TT个体的平均BUA较低（p = 0.06），沃德氏区BMD较低（p = 0.08）；在叶酸≥4 ng/ml组中，TT个体的髋部BMD显著较高（p≤0.05）。对于两个叶酸组，TT参与者的年龄调整后平均血浆tHcy均高于CC + CT参与者。在这些模型中控制tHcy并不影响相互作用效应的统计学显著性。
我们的研究结果支持这样一种假设，即C677T MTHFR多态性与骨表型之间的关联取决于叶酸状态。然而，介导这种关联的机制仍不清楚，但可能部分是由同型半胱氨酸对骨骼的影响所致。
