绝经后妇女MTHFR基因多态性位点联合作用与骨质疏松易感性的相关性分析

目的研究5,10亚甲基四氢叶酸还原酶(methylene tetrahydrofolate reductase,MTHFR)的2个多态性位点rs1801131 A1298C和rs1801133 C677T的联合作用与苏州地区绝经后妇女骨质疏松遗传易感性的相关性。方法对从苏州市城区随机抽取的261例45~70岁绝经后妇女进行流行病学调查、基础资料测量及桡骨远端骨密度测定,利用荧光定量PCR技术(TaqMan)进行基因分型。应用SAS 9.1.3统计软件进行统计分析,PHASE 2.0软件进行单倍型分析,应用广义多因子降维法(GMDR软件,version 0.7)检测位点-位点、位点-环境之间的联合作用。结果调整年龄、体质量指数(BMI)、腰臀比(WHR)及产次后,MTHFR基因rs1801133(C→T)的位点变异与骨质疏松的发生成正关联。与野生型rs1801133 CC基因型相比,突变纯合型rs1801133 TT及CT/TT型可以显著增加骨质疏松的发生风险[调整OR=2.63,2.37;95%CI=(1.20~5.77),(1.16~4.87)]。经1000次置换检验(Permutation test)方法校正后,该位点的基因型频率分布在病例组与对照组间仍存在统计学差异。单倍型分析结果显示,与最常见的单倍型CC相比,含突变等位基因rs1801131 A的单倍型AC可以显著降低绝经后妇女骨质疏松的患病风险[调整OR=0.60;95%CI=(0.39~0.90)]。广义多因子降维法结果显示,模型A1 A2(rs1801131,rs1801133)为最佳模型(交叉验证一致性10/10,P=0.0107)。结论 MTHFR基因rs1801133位点多态性与苏州地区绝经后妇女骨质疏松的发病风险存在明显关联;rs1801131位点可能与rs1801133位点产生联合作用,共同影响绝经后妇女骨质疏松的发生风险。

Relationship between MTHFR gene polymorphisms and osteoporosis in postmenopausal women

Objective To investigate the relationship between MTHFR gene（rs1801131 A1298 C and rs1801133C677T） polymorphisms and osteoporosis in the postmenopausal women of Suzhou urban area. Methods A population-based case-control study was conducted, including 261 postmenopausal women aged from 45 to 70 years enrolled throughrandomized cluster sampling in the community of Suzhou city. Epidemiology questionnaires were performed to gain the dataof healthy status. Bone mineral density and basic information were measured. The polymorphisms of MTHFR genes were de-tected using the polymerase chain reaction-restriction fragment length polymorphism（ PCR-RFLP） by TaqMan real-timePCR. Results After adjustment for age, BMI, WHR and parity times, the variants of rs1801133（C→T）was positivelyassociated with risk of osteoporosis. Compared with the wild-type homozygote, the variant genotypes of rs1801133 TT andCT/ TT were associated with higher risk to osteoporosis respectively [adjusted ORs（95%CI）= 2. 63（1. 20-5. 77）, 2. 37（1. 16-4. 87）]. Haplotype analysis of two SNPs indicated that haplotype AC, with variant allele A of rs1801131, could re-duce the risk for osteoporosis compared with haplotype CC [ ORs（ 95%CI）= 0 . 60（ 0. 39-0. 90）]. Model A1 A2（rs1801131, rs1801133） was the best model（CV Consistency= 10/ 10,P= 0. 0107） with GMDR method. Conclusions The MTHFR rs1801133 polymorphism may contribute to the susceptibility of osteoporosis in postmenopausal women. Thejoint-action of rs1801131 A1298 C and rs1801133 C677 T mayinfluence the risk of postmenopausal osteoporosis.