Homocysteine and Incident Atrial Fibrillation: The Atherosclerosis Risk in Communities Study and the Multi-Ethnic Study of Atherosclerosis

Background: Although many studies have investigated the association of blood homocysteine with major cardiovascular diseases such as coronary heart disease and stroke, research on its association with atrial fibrillation (AF) is scarce. Methods: We analysed data from Atherosclerosis Risk in Communities (ARIC) Study (n = 492, age 45–64 years) and Multi-Ethnic Study of Atherosclerosis (MESA) (n = 6,641, age 45–84 years). Results: During the 10,106 and 67,613 person-years of follow-up, we identified 85 and 351 AF events in ARIC and MESA, respectively. An age-, sex-, and race-adjusted model showed dose-response relations between plasma homocysteine concentrations and AF incidence in both ARIC and MESA. Further adjustments for other AF risk factors did not change the associations. In the fully adjusted model, a meta-analysis of both studies showed a significant association between homocysteine and AF [hazard ratio (95% confidence interval) per 1 unit increment in log ₂ (homocysteine), 1.27 (1.01–1.61)]. Individuals with higher levels of all three B vitamins (vitamin B6 and B12, and folate) had a lower risk of AF, but those associations were not statistically significant. In the full ARIC cohort [n = 12,686 (2079 AF events)], there was no association between the C ₆₇₇ T methylenetetrahydrofolate reductase (MTHFR) mutation and AF. Conclusions: In the prospective population-based ARIC and MESA cohorts, elevated homocysteine was modestly associated with an increased risk of incident AF, but the C6 ₇₇ T MTHFR mutation was not associated with AF risk, suggesting that homocysteine may be a novel risk marker for AF rather than a causal risk factor.