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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #165304
Title: ASSOCIATION OF A COMMON POLYMORPHISM IN THE METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) GENE WITH BONE PHENOTYPES DEPENDS ON PLASMA FOLATE STATUS

Author
item MCLEAN, ROBERT - BOSTON UNIVERSITY
item KARASIK, DAVID - HEBREW REHAB CENTER
item SELHUB, JACOB - TUFTS-HNRCA
item TUCKER, KATHERINE - TUFTS-HNRCA
item ORDOVAS, JOSE - TUFTS-HNRCA
item FRISO, SIMONETTA - UNIVERSITY OF VERONA
item CUPPLES, ADRIENNE - TUFTS-HNRCA
item JACQUES, PAUL - TUFTS-HNRCA
item KIEL, DOUGLAS - HEBREW REHAB CENTER

Submitted to: Journal of Bone and Mineral Research
Publication Type: Abstract Only
Publication Acceptance Date: 10/9/2003
Publication Date: 3/1/2004
Citation: Mclean, R., Karasik, D., Selhub, J., Tucker, K., Ordovas, J., Friso, S., Cupples, A.L., Jacques, P.F., Kiel, D. 2004. Association of a common polymorphism in the methylenetetrahydrofolate reductase (mthfr) gene with bone phenotypes depends on plasma folate status. Journal of Bone and Mineral Research. S325.

Interpretive Summary:

Technical Abstract: Our previously reported genome search in the Framingham Study using a quantitative ultrasound (QUS) phenotype found suggestive linkage on chromosome 1pter-1p36.3. This region contains several candidate genes for bone status, including the MTHFR gene. MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is used for homocysteine methylation to methionine. Studies show that the homozygous form (TT) of the MTHFR C677T polymorphism (alanine-to-valine substitution) is associated with increased plasma homocysteine levels in individuals with inadequate plasma folate. Thus, we examined whether the C677T MTHFR polymorphism is associated with QUS and if it differs by folate status. We evaluated broadband ultrasound attenuation [BUA (dB/MHz)] of the calcaneus, using the SAHARA Bone Sonometer (Hologic), in 1745 men and women (mean age 60, range 32-86) who were members of the Framingham Offspring Study (1996-2001). Participants were genotyped for C677T alleles using standard PCR, digestion with HinfI, and then electrophoretic resolution of fragments to generate genotypes. Genotype frequencies in our sample were 40%, 46% and 14% for CC, CT, and TT, respectively. Plasma folate was measured using an automated chemiluminescence method. Because the homozygous mutation (TT) was of particular interest, participants were classified into two groups: 1) CC+CT and 2) TT. We used analysis of covariance to compare mean BUA between the two groups and tested for an interaction between C677T group and folate. We controlled for gender, age, BMI, smoking, physical activity, alcohol, calcium, and vitamin D intakes, and estrogen use in women. We found no difference in mean BUA between the two C677T groups [Least square means (LSM): CC+CT=75.6, TT=74.7, p=0.4]. Our test for interaction between C677T group and plasma folate was borderline statistically significant at the p=0.07 level. In the CC+CT group, there was no difference in mean BUA between the 71% of persons with high plasma folate (>/=4 ng/ml) and the 29% with low folate (<4 ng/ml) (LSM: high=75.6, low=74.7, p=0.4). However, the TT individuals with low folate (61%) had significantly lower mean BUA (LSM: high=78.4, low=73.3, p=0.03). Our findings support the hypothesis that the association between a common mutation in the MTHFR gene and BUA is dependent upon folate status. Further understanding of the underlying mechanisms for these findings in bone is warranted.