Variability and determinants of total homocysteine concentrations in plasma in an elderly population Robert Clarke, 1* Peter Woodhouse, 2 Arve Ulvik, 3 Chris Frost, 4 Paul Sherliker, 1 Helga Refsum, 3 Per M. Ueland, 3 and Kay-Tee Khaw 2 The variability of plasma total homocysteine (tHcy) was examined in 96 individuals over a 1-yr period. Blood tHcy concentrations varied from 7.1 mol/L in the bottom quintile to 14.5 mol/L in the top quintile. The mean tHcy was 10.4 mol/L, the between-person SD was 2.5 mol/L, and the within-person SD was 0.93 mol/L. There was little seasonal variation, and the reliability coefficient was 0.88. Mean tHcy concentra- tions were inversely related to mean plasma folate (r  0.36) and vitamin B 12 (r  0.35) concentrations. Median tHcy concentrations were 1 mol/L higher in men than in women and in older (70 to 74 years) than in younger (65 to 69 years) individuals and higher in those with the TT and CT genotypes for the methylenetetra- hydrofolate reductase polymorphism than in those with the CC genotype (10.7 and 10.6 vs 9.6 mol/L). Epidemi- ological studies based on single tHcy measurements may underestimate the magnitude of any risk associa- tions with disease by 10 –15%. Moderately increased concentrations of total homocys- teine (tHcy) are a strong and independent risk factor for occlusive vascular disease [1–5]. A metaanalysis of the observational studies of tHcy and vascular disease indi- cated that a prolonged 1 mol/L lower tHcy concentra- tion was associated with a 10% reduction in risk of coronary heart disease throughout the range of 10 –15 mol/L [5]. tHcy is also a sensitive indicator of folate and cobalamin deficiencies [6, 7]. These predictive and diag- nostic aspects of tHcy concentrations may be particularly relevant to the elderly, where increased tHcy concentra- tions are common [8 –12]. Blood tHcy concentrations are chiefly determined by increasing age, male sex, renal function, and folate and cobalamin status [8 –12]. The vitamin effect is related to the role of 5-methyltetrahydrofolate as a substrate and cobalamin as a coenzyme in homocysteine remethylation to methionine [13]. The most common genetic determi- nant of plasma tHcy is the C677T polymorphism in the gene that encodes the methylenetetrahydrofolate reduc- tase (MTHFR) enzyme. This genetic variant predisposes to high tHcy concentrations under conditions of impaired folate status, probably because the mutation impedes the formation of 5-methyltetrahydrofolate [14 –16]. There is extensive information on the between-person variations in tHcy concentrations [8 –12], and most clinical studies to date are based on a single determination [5]. Data on the within-person variability in tHcy concentra- tions are still sparse [17, 18], despite the fact that such knowledge is essential for accurate assessment of risk factor associations with disease. A large within-person variability will underestimate the strength of any risk associations through “regression dilution” [19 –21]. Long- term stability of tHcy concentrations should be related to seasonal variations in folate status [22]. Furthermore, susceptibility to increased tHcy concentrations in individ- uals with the C677T mutation and low folate status [23] may suggest that such individuals have a greater variabil- ity in tHcy concentrations. The aims of the present study were to examine the reliability of a single measurement of tHcy; to determine the within- and between-person variability in tHcy and the extent to which the between-person variation may be explained by differences in the vitamin or genetic deter- minants of tHcy; and to assess the seasonal variability in tHcy and compare these variations with those for serum cholesterol and systolic blood pressure in the same population. 1 Clinical Trial Service Unit and Epidemiological Studies Unit, Radcliffe Infirmary, Oxford, OX2 6HE, UK. 2 Department of Clinical Gerontology, Addenbrooke’s Hospital, Cam- bridge, CB2 2QQ, UK. 3 Department of Pharmacology, University of Bergen, Armauer Hansens Hus, 5021 Bergen, Norway. 4 Medical Statistics Unit, London School of Hygiene & Tropical Medicine, Keppel St., London, UK. * Author for correspondence. Fax (44)1865-558817; e-mail robert.clarke@ ctsu.ox.ac.uk. Received June 24, 1997; revision accepted September 19, 1997. Clinical Chemistry 44:1 102–107 (1998) Test Utilization and Outcomes 102 Downloaded from https://academic.oup.com/clinchem/article/44/1/102/5642462 by guest on 03 October 2021