Wald David S, Law Malcolm, Morris Joan K
Department of Cardiology, Southampton General Hospital, Southampton SO16 6YD.
BMJ. 2002 Nov 23;325(7374):1202. doi: 10.1136/bmj.325.7374.1202.
To assess whether the association of serum homocysteine concentration with ischaemic heart disease, deep vein thrombosis and pulmonary embolism, and stroke is causal and, if so, to quantify the effect of homocysteine reduction in preventing them.
Meta-analyses of the above three diseases using (a) 72 studies in which the prevalence of a mutation in the MTHFR gene (which increases homocysteine) was determined in cases (n=16 849) and controls, and (b) 20 prospective studies (3820 participants) of serum homocysteine and disease risk.
Odds ratios of the three diseases for a 5 micromol/l increase in serum homocysteine concentration.
There were significant associations between homocysteine and the three diseases. The odds ratios for a 5 micromol/l increase in serum homocysteine were, for ischaemic heart disease, 1.42 (95% confidence interval 1.11 to 1.84) in the genetic studies and 1.32 (1.19 to 1.45) in the prospective studies; for deep vein thrombosis with or without pulmonary embolism, 1.60 (1.15 to 2.22) in the genetic studies (there were no prospective studies); and, for stroke, 1.65 (0.66 to 4.13) in the genetic studies and 1.59 (1.29 to 1.96) in the prospective studies.
The genetic studies and the prospective studies do not share the same potential sources of error, but both yield similar highly significant results-strong evidence that the association between homocysteine and cardiovascular disease is causal. On this basis, lowering homocysteine concentrations by 3 micromol/l from current levels (achievable by increasing folic acid intake) would reduce the risk of ischaemic heart disease by 16% (11% to 20%), deep vein thrombosis by 25% (8% to 38%), and stroke by 24% (15% to 33%).
评估血清同型半胱氨酸浓度与缺血性心脏病、深静脉血栓形成、肺栓塞及中风之间的关联是否为因果关系，若为因果关系，则量化降低同型半胱氨酸水平对预防这些疾病的效果。
对上述三种疾病进行荟萃分析，采用（a）72项研究，其中在病例组（n = 16849）和对照组中测定了MTHFR基因（可增加同型半胱氨酸）突变的患病率，以及（b）20项关于血清同型半胱氨酸与疾病风险的前瞻性研究（3820名参与者）。
血清同型半胱氨酸浓度每增加5微摩尔/升时三种疾病的比值比。
同型半胱氨酸与这三种疾病之间存在显著关联。在基因研究中，血清同型半胱氨酸每增加5微摩尔/升时，缺血性心脏病的比值比为1.42（95%置信区间1.11至1.84），在前瞻性研究中为1.32（1.19至1.45）；对于伴有或不伴有肺栓塞的深静脉血栓形成，基因研究中的比值比为1.60（1.15至2.22）（无前瞻性研究）；对于中风，基因研究中的比值比为1.65（0.66至4.13），前瞻性研究中为1.59（1.29至1.96）。
基因研究和前瞻性研究的潜在误差来源不同，但均得出了相似的高度显著结果——有力证据表明同型半胱氨酸与心血管疾病之间的关联是因果关系。在此基础上，将同型半胱氨酸浓度从当前水平降低3微摩尔/升（通过增加叶酸摄入量可实现），将使缺血性心脏病风险降低16%（11%至20%），深静脉血栓形成风险降低25%（8%至38%），中风风险降低24%（15%至33%）。
