Reconciling the Evidence on Serum Homocysteine and Ischaemic Heart Disease: A Meta-Analysis

BackgroundResults from genetic epidemiological studies suggest that raised serum homocysteine is a cause of ischaemic heart disease, but the results of randomised trials suggest otherwise. We aimed to update meta-analyses on each type of study using the latest published data and test a hypothesis based on antiplatelet therapy use in the trials to explain the discrepancy.
Methods and FindingsMeta-analyses of ischaemic heart disease using (i) 75 studies in which the prevalence of a mutation (CT) in the MTHFR gene (which increases homocysteine) was determined in cases (22,068) and controls (23,618), and (ii) 14 randomised trials (39,597 participants) of homocysteine lowering and ischaemic heart disease events. The summary estimates from the two analyses were compared. Meta-analysis of the MTHFR studies showed a statistically significantly increased risk of ischaemic heart disease in TT compared with CC homozygotes; odds ratio 1.16 (1.04 to 1.29) for a 1.9 µmol/L homocysteine difference (TT minus CC). Meta-analysis of randomised trials showed no significant reduction in IHD risk from folic acid; relative risk 1.00 (0.93 to 1.08), despite a reduction in homocysteine of 3.3 µmol/L. There was a statistically significant difference in risk reduction between the 5 trials with the lowest prevalence of antiplatelet therapy (60% on average, usually aspirin), RR 0.93 (0.84 to 1.05) and the 5 trials with the highest prevalence (91% on average), RR 1.09 (1.00 to 1.19), p = 0.037 for the difference.
ConclusionDiscordant results from MTHFR studies and randomised trials could be explained by aspirin reducing or negating the anti-platelet effect of lowering homocysteine. On this basis, folic acid would have a role in the primary prevention of ischaemic heart disease, when aspirin is not taken routinely, but not in secondary prevention, when it is routine.

背景
遗传流行病学研究结果显示，血清同型半胱氨酸（serum homocysteine）水平升高是缺血性心脏病（ischaemic heart disease，IHD）的致病危险因素，但随机对照试验（randomised trials）的结果却与之相悖。本研究旨在利用最新发表的数据，对两类研究分别进行荟萃分析（meta-analyses）更新，并基于试验中抗血小板治疗（antiplatelet therapy）的使用情况验证一项假说，以解释这一矛盾结果。

方法与结果
本研究针对缺血性心脏病开展两项荟萃分析：① 纳入75项研究，检测病例组（22068例）与对照组（23618例）中亚甲基四氢叶酸还原酶（MTHFR）基因的CT突变携带率，该基因可升高同型半胱氨酸水平；② 纳入14项随机对照试验（共39597名受试者），评估降同型半胱氨酸治疗与缺血性心脏病事件的关联。对两项分析的汇总估计值进行比较。
针对MTHFR相关研究的荟萃分析显示，与CC纯合子相比，TT纯合子的缺血性心脏病发病风险显著升高；在同型半胱氨酸水平相差1.9μmol/L（TT组减CC组）的情况下，比值比（odds ratio，OR）为1.16（95%置信区间：1.04~1.29）。针对随机对照试验的荟萃分析显示，叶酸治疗并未显著降低缺血性心脏病发病风险，相对危险度（relative risk，RR）为1.00（95%置信区间：0.93~1.08），尽管该治疗可使同型半胱氨酸水平降低3.3μmol/L。进一步亚组分析显示，抗血小板治疗使用率最低的5项试验（平均使用率60%，通常为阿司匹林）中，风险降低的RR为0.93（95%置信区间：0.84~1.05）；而抗血小板治疗使用率最高的5项试验（平均使用率91%）中，RR为1.09（95%置信区间：1.00~1.19），两组间差异具有统计学意义（p=0.037）。

结论
MTHFR相关研究与随机对照试验所得结果的矛盾，可通过阿司匹林抵消或削弱降同型半胱氨酸治疗的抗血小板作用来解释。据此，当未常规服用阿司匹林时，叶酸可用于缺血性心脏病的一级预防；而当常规服用阿司匹林时，叶酸则无法发挥该二级预防作用。