A routine blood measurement may be linked to who dies over the next decade—but the genetic context appears to change how strong that link is. This study follows 5,200 Chinese residents to test that connection. Homocysteine, or Hcy, is an intermediate thiol-containing nonproteinogenic amino acid derived from methionine catabolism.

It is metabolized via remethylation or trans-sulfuration into cysteine. Hcy plays a critical role in endothelial dysfunction, atherosclerosis, and thrombosis through mechanisms including inflammation, lipid peroxidation, ferroptosis, and platelet activation.

The American Heart Association has recognized that elevated Hcy levels are associated with an increased risk of stroke and other vascular events. The evidence regarding Hcy concentrations and the risk of death remains limited and conflicting, particularly for specific causes of death or populations.

A meta-analysis found that each five micromole-per-liter Hcy increment was associated with a twenty-seven percent higher risk of all-cause mortality and a thirty-two percent higher risk of cardiovascular mortality. But pooled Hcy-lowering clinical trials did not improve the causal relationships between Hcy and either all-cause or cause-specific mortality after folic acid or vitamin B supplementation.

Methylenetetrahydrofolate reductase, or MTHFR, is a crucial regulatory enzyme within the one-carbon cycle. With the C677T variant, enzyme activity drops to around sixty-seven percent in heterozygous carriers and twenty-five percent in homozygous carriers of the T allele, and these variants are associated with elevated plasma Hcy concentrations.

The MTHFR six-seven-seven-TT genotype did not have a significant effect on all-cause mortality, and a Mendelian randomization study did not provide evidence supporting a causal link between elevated plasma Hcy concentrations and all-cause or cardiovascular mortality. Few prospective studies have considered plasma Hcy concentrations and risk of death in the Chinese general population.

Important knowledge gaps include genetic background, environmental exposures, lifestyles, and nutritional status, with scarce data on the MTHFR C677T genetic polymorphism and its inheritance–metabolism interaction. The study therefore examines the association of plasma Hcy concentrations with a ten-year risk of all-cause and cardiovascular mortality in a community-based longitudinal cohort in China.

Participants came from an atherosclerosis cohort in the Pingguoyuan and Gucheng communities in Beijing, China. The initial cohort investigated 9,540 residents aged forty years or older from December 2011 to April 2012, with follow-up surveys continuing until the end of 2021.

Participants with missing follow-up information, absent plasma Hcy concentrations, or missing MTHFR C677T genotype were excluded, leaving 5,200 participants in the final analysis. Ethical approval came from the ethics committee of Peking University, and each participant signed informed consent.

Plasma Hcy was assayed at baseline by the enzymatic cycling method using the Beckman Coulter AU480 Automatic Biochemical Analyzer. Serum folate was measured by electrochemiluminescence immunoassay in a commercial laboratory. The MTHFR C677T genotype was obtained for all subjects by retrieving Asian ExomeChip, a specially designed exome array based on the Infinium Human Exome BeadChip.

Death data came from the Chinese Center for Disease Control and Prevention and the Beijing Municipal Health Commission. The International Classification of Diseases in its tenth revision was used to classify the leading cause of death. The primary endpoint was all-cause death, and the secondary endpoint was cardiovascular death, defined as codes I00 through I99.

Follow-up ran from baseline to participant death or the end of follow-up on December thirty-first, twenty twenty-one. Table one summarizes five thousand two hundred participants at baseline, divided into three plasma homocysteine groups: below ten, ten to below fifteen, and at least fifteen micromoles per liter.

The table reports differences in age, sex, folate, MTHFR genotype, kidney function, smoking, drinking, hypertension, cardiovascular disease, and medication use, while diabetes and dyslipidemia show p-values of zero point one one five and zero point five five one. It also records three hundred twenty all-cause deaths and one hundred seven cardiovascular deaths.

During a mean follow-up of nine point sixty-five years, with a standard deviation of one point eleven years, 320 deaths were documented, including 107 cardiovascular deaths. Kaplan–Meier survival curves revealed a significant dose–response relationship between Hcy and both all-cause and cardiovascular mortality.

Figure one compares cumulative mortality hazards over nearly ten years. Panels A and B, grouped by plasma homocysteine thresholds, show statistically significant separation for all-cause and cardiovascular mortality, with log-rank p values below zero point zero zero zero one.

Panels C and D, grouped by MTHFR C677T genotype, show no significant separation, with p values of zero point six two and zero point eight nine. This supports homocysteine concentration as the more informative mortality stratifier in these analyses.

The Cox proportional hazard regression analyses are summarized in Table 2. After covariate adjustment, using Hcy concentrations below ten micromole per liter as the reference, concentrations from ten to below fifteen micromole per liter were associated with a seventy-four percent increased risk of all-cause mortality.

Hcy concentrations of fifteen micromole per liter or higher were associated with a sixty-four percent increased risk of all-cause mortality. Table two uses Cox models to relate plasma homocysteine, or Hcy, and MTHFR C six hundred seventy-seven T genotype to mortality.

After adjustment for clinical factors and serum folate, Hcy of at least ten micromoles per liter was associated with all-cause mortality, with a hazard ratio of one point seven two and a p-value of zero point zero one five. For cardiovascular mortality, each one-micromole-per-liter increase in Hcy had an adjusted hazard ratio of one point zero two, while genotype associations were not statistically significant.

Restricted cubic spline analysis was conducted with fully adjusted models to show dose–response associations between Hcy and different outcomes. The smooth curves indicated rising trends for the risk of both all-cause and cardiovascular mortality as plasma Hcy concentrations increased.

Figure two uses restricted cubic splines to show how plasma homocysteine, or Hcy, relates to mortality after adjustment for clinical and treatment factors. Panel A shows a rising trend for all-cause mortality, while panel B shows a rising trend for cardiovascular mortality as Hcy increases.

The blue bands mark the ninety-five percent confidence intervals, which widen at higher concentrations and indicate greater uncertainty in those estimates. A significant modifying effect of MTHFR C677T genetic polymorphism on the association between Hcy and all-cause mortality was observed, with a p value for interaction of zero point zero three six.

Compared with the CT and TT genotypes, elevated Hcy concentrations were significantly associated with increased all-cause mortality in individuals with the MTHFR six-seven-seven-CC genotype, with a hazard ratio of five point twenty-four and a ninety-five percent confidence interval from one point twenty-seven to twenty-one point sixty-three.

The positive association appeared stronger in several subgroups, but the interaction test for a trend was not significant, with all p values for interaction greater than zero point zero five. Table three examines whether the association between plasma Hcy and all-cause mortality varies across age, sex, and body-mass-index groups, using ten micromoles per liter as the threshold.

It reports hazard ratios and confidence intervals for each subgroup, with interaction p-values of zero point five three zero for age, zero point eight zero five for sex, and zero point four nine six for BMI. This stratified view shows how consistently the association is estimated across clinically defined groups.

In this community-based longitudinal study of 5,200 Chinese residents, higher plasma Hcy concentrations, but not the MTHFR C677T genotype, were associated with an increased ten-year risk of all-cause and cardiovascular mortality. MTHFR C677T genetic polymorphism nevertheless played a vital role in the relationship between Hcy and the ten-year risk of all-cause mortality.

The study is described as the first large-scale cohort study to examine the MTHFR C677T genetic polymorphism–Hcy metabolism interaction in death endpoints through long-term follow-up among the general population. Because it is a single-center study based on a northern Chinese population, the findings need validation in other independent populations.

Plasma Hcy was measured only at baseline and may not accurately reflect long-term changes in Hcy, so the impact of changes over time requires further investigation. The study also focused on a limited range of mortality types, leaving the effects of Hcy and MTHFR C677T on non-cardiovascular mortality, such as cancer, poorly understood.

Higher plasma homocysteine concentrations were associated with higher ten-year risks of all-cause and cardiovascular mortality, while the MTHFR genotype alone was not. The genotype nevertheless modified the association with all-cause mortality.