Mendelian randomization studies on fibrinogen commonly use a single genetic variant as an instrument, but this may explain only a small proportion of the total phenotypic variance. We examined the contribution of multiple common single nucleotide polymorphisms (SNPs) and haplotypes in the entire fibrinogen gene cluster to plasma fibrinogen levels in two prospective cohorts, for use as instruments in future Mendelian randomization studies. Genotypes for 20 SNPs were determined in 2,778 middle-age (49-64 years) men from the Second-Northwick-Park-Heart Study (NPHS-II). These were replicated in 3,705 men from the Whitehall-II study (WH-II). Plasma fibrinogen levels were determined six times in NPHS-II and three times in WH-II. The minor alleles of four SNPs from the FGB gene, two from the FGA gene, and one from the FGG gene were associated with higher plasma fibrinogen levels. SNP rs1800790 (-455G>A) commonly used in Mendelian randomization studies was associated with R2=1.22% of the covariate adjusted residual variance in fibrinogen level. A variable selection procedure identified one additional SNP: rs2070011 (FGA) altogether explaining R2=1.45% of the residual variance in fibrinogen level. Using these SNPs no evidence for causality between the fibrinogen levels and coronary heart diseases was found in instrumental variables analysis. In the replication cohort, WH-II, the effects of the two SNPs on fibrinogen levels were consistent with the NPHS-II results. There is statistical evidence for several functional sites in the fibrinogen gene cluster that determine an individual's plasma fibrinogen levels. Thus, a combination of several SNPs will provide a stronger instrument for fibrinogen Mendelian randomization studies.

中文翻译：

---

用于纤维蛋白原孟德尔随机化的遗传工具。

关于纤维蛋白原的孟德尔随机化研究通常使用单个遗传变异作为工具，但这可能只能解释总表型变异的一小部分。我们在两个前瞻性队列中检查了整个纤维蛋白原基因簇中多个常见单核苷酸多态性 (SNP) 和单倍型对血浆纤维蛋白原水平的贡献，以用作未来孟德尔随机化研究的工具。来自 Second-Northwick-Park-Heart 研究 (NPHS-II) 的 2,778 名中年（49-64 岁）男性确定了 20 个 SNP 的基因型。这些在 Whitehall-II 研究 (WH-II) 的 3,705 名男性中重复。血浆纤维蛋白原水平在 NPHS-II 中测定了 6 次，在 WH-II 中测定了 3 次。FGB 基因的四个 SNP 的次要等位基因，FGA 基因的两个，FGG 基因中的一种与较高的血浆纤维蛋白原水平有关。孟德尔随机化研究中常用的 SNP rs1800790 (-455G>A) 与纤维蛋白原水平的协变量调整残差方差的 R2=1.22% 相关。变量选择程序确定了一个额外的 SNP：rs2070011 (FGA)，完全解释了 R2=1.45% 的纤维蛋白原水平的残余方差。使用这些 SNP 在工具变量分析中没有发现纤维蛋白原水平与冠心病之间存在因果关系的证据。在复制队列 WH-II 中，两个 SNP 对纤维蛋白原水平的影响与 NPHS-II 结果一致。有统计证据表明纤维蛋白原基因簇中的几个功能位点决定了个体的血浆纤维蛋白原水平。因此，