Low Dietary Riboflavin but Not Folate Predicts Increased Fracture Risk in Postmenopausal Women Homozygous for the MTHFR 677 T Allele

Abstract

The MTHFR C677T polymorphism is associated with mildly elevated homocysteine levels when folate and/or riboflavin status is low. Furthermore, a mildly elevated homocysteine level is a risk factor for osteoporotic fractures. We studied whether dietary intake of riboflavin and folate modifies the effects of the MTHFR C677T variant on fracture risk in 5035 men and women from the Rotterdam Study. We found that the MTHFR C677T variant interacts with dietary riboflavin intake to influence fracture risk in women. Introduction:The MTHFR C677T polymorphism is associated with mildly elevated homocysteine (Hcy) levels in the presence of low folate and/or riboflavin status. A mildly elevated Hcy level was recently identified as a modifiable risk factor for osteoporotic fracture. We studied whether dietary intake of riboflavin and folate modifies the effects of the MTHFR C677T polymorphism on BMD and fracture risk. Materials and Methods:We studied 5035 individuals from the Rotterdam Study, Ն55 yr of age, who had data available on MTHFR, nutrient intake, and fracture risk. We performed analysis on Hcy levels in a total of 666 individuals, whereas BMD data were present for 4646 individuals (2692women). Results: In the total population, neither the MTHFR C677T polymorphism nor low riboflavin intake was associated with fracture risk and BMD. However, in the lowest quartile of riboflavin intake, female 677-T homozygotes had a 1.8 (95% CI: 1.1-2.9, p ‫ס‬ 0.01) times higher risk for incident osteoporotic fractures and a 2.6 (95% CI: 1.3-5.1, p ‫ס‬ 0.01) times higher risk for fragility fractures compared with the 677-CC genotype (interaction, p ‫ס‬ 0.0002). This effect was not seen for baseline BMD in both men and women. No significant influence was found for dietary folate intake on the association between the MTHFR C677T genotype and fracture risk or BMD. In the lowest quartile of dietary riboflavin intake, T-homozygous individuals (men and women combined) had higher (22.5%) Hcy levels compared with C-homozygotes (mean difference ‫ס‬ 3.44 M, p ‫ס‬ 0. 01; trend, p ‫ס‬ 0.02). Conclusions: In this cohort of elderly whites, the MTHFR C677T variant interacts with dietary riboflavin intake to influence fracture risk in women.

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) .…”

“…In support of these findings, further analysis of the Danish Osteoporosis Prevention Study cohort concluded that the BMD in individuals with the TT genotype was only significantly reduced with low dietary intakes of several B-vitamins including folate, B 12 , B 6 and riboflavin (49) . In terms of fracture risk, evidence from the Rotterdam Study (n 5035) demonstrated that women with the TT genotype in the lowest quartile of riboflavin intakes had 1·8 times greater risk of osteoporotic fracture, and 2·6 times greater risk of fragility fracture (defined as a fracture at the hip, pelvis or proximal humorus), than those in the same quartile of riboflavin intakes with the CC genotype (47) . Such findings provide evidence to support a detrimental effect of the polymorphism combined with low B-vitamin intakes on robust bone health outcomes (i.e.…”

MTHFR C677T polymorphism and osteoporotic fracture in postmenopausal women: a meta-analysis

“…We excluded five studies (one without full-text, one without sufficient genotype data for extraction, 2 meta-analyses and one review). Finally, a total of 7 case-control studies met our inclusion criteria (Jorgensen et al, 2002;Abrahamsen et al, 2003;Li et al, 2004;Bathum et al, 2004;Golbahar et al, 2004;Hong et al, 2007;Yazdanpanah et al, 2008), including 4258 cases and 3454 controls. Table 1 lists the characteristics of each study.…”

A Perspective on Nutritional Genomics

“…The presence of MTR A2756G and MTHFR C>T mutant allele in BRCA carriers is associated with increased breast cancer risk. 54 Estrogen receptor/progesterone receptor status modifies the association between the MTHFR C>T polymorphism and survival. 55 Interestingly, MTHFR A>C alleles have been associated with a decreased risk of breast cancer.…”