Background In epidemiological studies, within-person variability in plasma total homocysteine (tHcy) measurements may dilute the association of ‘usual’ levels of tHcy with risk of cardiovascular disease, referred to as ‘regression dilution'. The aim of this report was to estimate the magnitude of regression dilution after varying intervals of follow-up.
Methods Regression dilution ratios (RDR) for tHcy were calculated using replicate tHcy measurements obtained after 3, 6 and 8 years from the Rotterdam, Hordaland and Framingham studies, respectively, and after 3, 6, 9 and 12 years from the United Kingdom Prospective Study of type 2 Diabetes Mellitus (UKPDS).
Results The RDR for tHcy decreased with increasing interval in the three population-based studies and in the UKPDS. Moreover, the rate of decline of the RDR in the population-based studies was similar to that obtained in the UKPDS. Using linear regression analysis for the population-based studies, these results suggest an RDR of 0.83 at 2 years, 0.71 at 6 years and 0.53 at 12 years.
Conclusions These results have important implications for the interpretation of prospective studies of tHcy and cardiovascular disease. Failure to correct for increasing regression dilution using lower RDRs for longer follow-up may underestimate the relative risks of cardiovascular disease associated with tHcy by about one-fifth after 2 years and one-half after 10 years.
SelhubJJacquesPFWilsonPWRushDRosenbergIH.Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA1993; 270:2693–2698.
2.
NygardORefsumHUelandPMVollsetSE.Major lifestyle determinants of plasma total homocysteine distribution: The Hordaland Homocysteine study. Am J Clin Nutr1998; 67:263–270.
3.
JacquesPFBostomAGWilsonPWFRichSRosenbergIHSelhubJ.Determinants of plasma total homocysteine concentration in the Framingham Offspring Cohort. Am J Clin Nutr2001; 73:613–621.
4.
BousheyCBeresfordSAAOmennGSMotulskyAG.A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: Probable benefits of increasing folic acid intakes. JAMA1995; 274:1049–1057.
5.
RefsumHUelandPMNygardOVollsetS.Homocysteine and cardiovascular disease. Ann Rev Med1988; 49:31–62.
6.
DaneshJLewingtonS.Plasma homocysteine and coronary heart disease. J Cardiovasc Risk1998; 5:229–232.
7.
EvansRWShatenBJHempelJDCutlerJAKullerLH.Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol1997; 17:1947–1953.
8.
AlfthanGPekkanenJJauhiainenMPitkaniemiJKarvonenMTuomilehtoJRelation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis1994; 106:9–19.
9.
ClarkeRWoodhousePUlvikAFrostCSherlikerPRefsumHVariability and determinants of total homocysteine concentrations in an elderly population. Clin Chem1998; 44:102–107.
10.
GargUCZhengZJFolsomARMoyerYSTsaiMYMcGovernPEckfeldtJH.Short-term and long-term variability of plasma homocysteine measurement. Clin Chem1997; 43:141–145.
11.
IsraelssonBBrattstromLRefsumH.Homocysteine in frozen plasma samples. A short cut to establish hyperhomocysteinemia as a risk factor for arteriosclerososis? Scand J Clin Lab Invest1993; 53:465–469.
12.
MacMahonSPetoRCutlerJCollinsRSorliePNeatonJBlood pressure, stroke and coronary heart disease Part 1; prolonged differences in blood pressure: Prospective observational studies corrected for the regression dilution bias. Lancet1990; 335:765–774.
13.
ClarkeRShipleyMLewingtonSYoungmanLCollinsRMarmotMPetoR.Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol1999; 150:341–353.
14.
HofmanAGrobbeeDEde JongPTVMvan den OuwelandFA.Determinants of disease and disability in the elderly: Rotterdam elderly study. Eur J Epidemiol1991; 7:403–422.
15.
de GrootJCde LeeuwFEOudkerkMHofmanAJollesJBretelerMM.Cerebral white matter lesions and cognitive function: The Rotterdam Scan Study. Ann Neurol2000; 47:145–151.
16.
NexoEEngebaakFUelandPMWestleyCOgarmanPJohnstonCEvaluation of novel assays in clinical chemistry: Quantification of plasma total homocysteine. Clin Chem2000; 46:1150–1156.
17.
UelandPMRefsumHStablerSPMalinowMRAnderssonAAllenRH.Total homocysteine in plasma or serum: Methods and clinical applications. Clin Chem1993; 39:1764–1779.
18.
ArakiASakoY.Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr1987; 422:43–52.
19.
UK Prospective Diabetes Study Group.UK Prospective Diabetes Study (UKPDS): VIII Study design, progress and performance. Diabetologia1991; 34:877–890.
20.
ManleySEStrattonIMCoullCAFrighiVEaleyEAMatthewsDREffects of three month's diet after diagnosis of type2 diabetes on plasma lipids and lipoproteins (UKPDS 45). Diabet Med2000; 17:518–523.
21.
UKPDS Group.Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet1998; 352:837–853.
