Association of the methylenetetrahydrofolate reductase C677T polymorphism and fracture risk in Chinese postmenopausal women

Abstract

Osteoporotic fractures are a leading cause of disability and, indirectly, of death in the elderly population. Previous studies have shown that homocysteine level and the C677T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) may be involved in the development of osteoporosis and its related fracture in European populations. The aim of this study was to verify the association of this polymorphism with bone mineral density (BMD) and fractures in our 1899 Chinese postmenopausal women. The C677T T-allele frequency in this population was 39.2%. The distribution of the MTHFR genotypes followed the Hardy-Weinberg equilibrium. BMD at total body, total hip or femoral neck did not significantly vary with MTHFR C677T genotype. The T-allele carrier tended to have higher risk of having osteoporosis or osteopenia, but the difference was statistically insignificant. However, Poisson regression analysis revealed that the T-allele carriers had an increased risk of fractures (RR=1.7, 95%CI=1.1-2.7, p=0.01) which occurred before or after menopause. As far as fracture incidence after menopause was concerned, the CT or TT genotype had more than twice the risk of the CC genotype (RR=2.5, 95%CI=1.2-4.9, P=0.009). This association was independent of age, physical activity, occupation, passive smoking, height, weight, years since menopause, and total hip BMD.Our data show that the MTHFR C677T polymorphism is an independent predictor of fracture risk, although it only had a weak effect on BMD. Further study on the mechanistic role that this polymorphism plays in the development of fractures may lead to better understanding of the etiology of osteoporotic fracture.

Susceptibility genes for osteoporotic fracture in postmenopausal chinese women

“…Variants in ADAMTS18, ESR1, ITGA1, LRP4, LRP5, MTHFR, SPTBN1, SPP1, TNFRSF11A, and TNFRSF11B have been reported to be associated with osteoporotic fracture in GWASs, meta-analysis studies, and population studies. Note that only variants in ADAMTS18, (16) rs11898505 in SPTBN1, (12) and rs1801133 in MTHFR (26) have been further replicated in the Chinese population. Therefore, although none of these variants met the GWAS level, the replication study of potential genetic loci for osteoporotic fracture in the Chinese population is still of great importance.…”

“…Among these genes, the association between variants in MTHFR, particularly rs1801133 (C677T), and fracture risk has been verified in Chinese and Danish postmenopausal women. (26,48) In 2010, Agueda and colleagues (49) confirmed that A222V in MTHFR was associated with vertebral fracture in Spanish postmenopausal women. Unfortunately, in this study, no variants in MTHFR were associated with osteoporotic fracture in postmenopausal women.…”

“…The 113 candidate SNPs from the 16 potential genetic risk loci were selected based on the following criteria: (1) SNPs found to be associated with BMD and/or osteoporotic fracture, including rs11898505 in SPTBN1, (5,7,12,18) rs2229580, rs2229579, rs2502992, and rs2501432 in CNR2, (21,35) rs1801133 in MTHFR, (21,26,36,37) rs7529452 in PLOD, (21) rs2302685 in LRP6, (19) rs3018362 in a region near TNFRSF11A, (5,12) rs11859065, rs16945612, rs11860781, and rs11864477 in ADAMTS18, (16) rs2073618 in TNFRSF11B, (14) rs6993813 near TNFRSF11B, (5,12) rs2234693 (38,39) and rs3798577 (39) in ESR1, rs3736228 near LRP5, (6,12,18,36,40,41) and rs6696981 in ZBTB40 (12,18) ; or (2) tag SNPs of the 16 selected genes based on the HapMap Data Rel 24/phase II Nov08 with r 2 > 0.8.…”

“…(5) Furthermore, SNPs from LRP5, SPP1, and TNFRSF11A were verified as genetic risk loci for osteoporotic fracture in a large-scale meta-analysis of genomewide association data. (8) Among the aforementioned osteoporosis candidate genes, only variants in ADAMTS18, (16) rs11898505 in SPTBN1, (12) and rs1801133 in MTHFR (26) were associated with osteoporotic fracture in the Chinese population.…”

B-vitamins and bone in health and disease: the current evidence

“…Epidemiological studies investigating the relationship between the MTHFR 677C T polymorphism and bone health add further evidence to support the view that impaired folate metabolism (and the related phenotypes of elevated homocysteine and lower folate concentrations (19,20) ) may be implicated in adverse outcomes (Table 3) (39,(47)(48)(49)(50)(51)(52)(53) . Convincingly evidence from a recent meta-analysis of twenty studies (3525 cases and 17 909 controls) found that the 677C T polymorphism was associated with BMD at all measured sites, and with a 23 % increased risk for all fractures in individuals with the MTHFR 677TT genotype compared with those with the CT or CC genotypes (13) .…”