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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #165914
Title: ASSOCIATION OF A COMMON POLYMORPHISM IN THE METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) GENE WITH BONE PHENOTYPES DEPENDS ON PLASMA FOLATE STATUS

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

Submitted to: Journal of Bone and Mineral Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/9/2003
Publication Date: 4/1/2004
Citation: Mclean, R.R., Karasik, D., Selhub, J., Tucker, K.L., Ordovas, J.M., Russo, G.T., Cupples, A.L., Jacques, P.F., Kiel, D.P. 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. 19:410-418.

Interpretive Summary: Homocysteine, a sulfur amino acid formed during methionine metabolism, is believed to be detrimental when high levels are found in circulation (hyperhomocysteinemia). It is known that individuals with severe hyperhomocysteinemia have an increased risk of osteoporosis. This suggests the possibility that mild elevations may also have adverse effects on bone. One proposed mechanism is that homocysteine interferes with the cross-linking of collagen, decreasing the structural integrity of bone. A common mutation (polymorphism) in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR), designated as C677T, can affect the conversion of homocysteine to methionine, resulting in mildly elevated plasma homocysteine concentrations (mild hyperhomocysteinemia). However, the consequences of this genetic defect are abolished among individuals with adequate plasma folate concentrations. These findings indicate that MTHFR C677T genotype and plasma folate concentration can combine to influence the development of mild hyperhomocysteinemia. Thus, individuals possessing both the homozygous form of the C677T MTHFR genotype and low plasma folate concentrations may be at greater risk of osteoporosis. Moreover, a region on chromosome 1p that has been related to bone density is known to include the MTHFR gene. Based on these observations, we examined the association of the C677T MTHFR genotype and folate status on bone density of the hip and spine in 1632 men and women who participated in the Framingham Osteoporosis Study. Our findings support the hypothesis of an association between the C677T MTHFR polymorphism and bone density that depends on folate status.

Technical Abstract: Genome-wide screens using quantitative ultrasound (QUS) and bone mineral density (BMD) phenotypes have shown suggestive linkage on chromosome 1pter-1p36.3, a region containing the methylenetetrahydrofolate reductase (MTHFR) gene. We hypothesized that 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. QUS [broadband ultrasound attenuation (BUA), speed of sound (SOS), and quantitative ultrasound index (QUI)] 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. Adjusted mean QUS and BMD measures did not differ between C677T groups. Although all participants with plasma folate concentrations >/= 4 ng/ml had ~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 C677T group (CC+CT vs. TT) were found for hip BMD (p'0.05) and BUA (p=0.11). Compared to 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/=4 ng/ml group. For both folate groups, TT participants had higher age-adjusted mean plasma tHcy versus CC+CT participants. 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 due to homocysteine effects on bone.