Genetic Variants of Homocysteine Metabolism, Homocysteine, and Frailty - Rugao Longevity and Ageing Study.

Abstract

Recently, elevated homocysteine was reported to be associated with frailty in cross-sectional studies. However, whether homocysteine is causally associated with frailty is unknown. Here, we explore the inter-relationships between five non-synonymous genetic variants of homocysteine metabolic four genes, plasma homocysteine levels, and frailty. Data of 1480 individuals aged 70-87 years from the ageing arm of Rugao Longevity and Ageing Study were used. Five variants of the four homocysteine metabolic enzyme genes were genotyped. Frailty was defined using Fried's phenotype criteria. The percentage of high homocysteine (>15μmol/L) is 33.3%. Two functional variants that decrease methylenetetrahydrofolate reductase (MTHFR) activities, C677T (Ala222Val, rs1801133) and A1298C (Glu429Ala, rs1801131), were significantly associated with increased homocysteine levels (β=-1.16, p=0.01; and β=1.46, p<0.001, respectively). In addition, homocysteine increase gradually from CC-CC, CC-AC, CT-AC, CT-AA, CC-AA, to TT-AA genotypes of the C677T-A1298C combinations. The five polymorphisms in the homocysteine metabolic gene was not associated with frailty. However, homocysteine was significantly associated with frailty with an OR of 2.27 (95% 1.36-3.78) for high homocysteine after adjusting for multiple confounding factors. Elevated homocysteine is not a causal factor but a biomarker that manifests greater possibility of frailty in high risk elderly individuals for prevention.