A Mendelian Randomization Study of Plasma Homocysteine and Multiple Myeloma

Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12-6.38; P = 2.7 × 10(-2)). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs).