Talmud Philippa J, Cooper Jackie A, Palmen Jutta, Lovering Ruth, Drenos Fotios, Hingorani Aroon D, Humphries Steve E
Centre for Cardiovascular Genetics, Department of Medicine, University College London, London, UK.
Clin Chem. 2008 Mar;54(3):467-74. doi: 10.1373/clinchem.2007.095489. Epub 2008 Feb 4.
We investigated whether chromosome 9p21.3 single-nucleotide polymorphisms (SNPs), identified in coronary heart disease (CHD) genome-wide association scans, added significantly to the predictive utility for CHD of conventional risk factors (CRF) in the Framingham risk score (FRS) algorithm.
In the Northwick Park Heart Study II of 2742 men (270 CHD events occurring during a 15-year prospective study), rs10757274 A>G [mean frequency G = 0.48 (95% CI 0.47-0.50)] was genotyped. Using the area under the ROC curve (A(ROC)) and the likelihood ratio (LR) statistic, we assessed the discriminatory performance of the FRS based on CRFs with and without genotype.
rs10757274 A>G was associated with incident CHD, with an effect size as reported previously [hazard ratio in GG vs AA men of 1.60 (95% CI 1.12-2.28)], independent of CRFs and family history of CHD. Although the A(ROC) for CRFs alone [0.62 (95% CI 0.58-0.66)] did not increase significantly (P = 0.14) when rs10757274 A>G genotype was added [0.64 (95% CI 0.60-0.68)], including genotype gave better fit (LR P = 0.01) and including rs10757274 moved 369 men (13.5% of the total) into more accurate risk categories. To model polygenic effects, 10 hypothetical, randomly assigned gene variants, with similar effect size and frequencies were added. Two variants made significant A(ROC) improvements to the FRS prediction (P = 0.01), whereas further variants had smaller incremental effects (final A(ROC) = 0.71, P <0.001 vs CRFs; LR vs CRFs P <0.0001).
Although overall, rs10757274 did not add substantially to the usefulness of the FRS for predicting future events, it did improve reclassification of CHD risk, and thus may have clinical utility.
我们研究了在冠心病（CHD）全基因组关联扫描中鉴定出的9号染色体p21.3单核苷酸多态性（SNP），是否能显著提高弗雷明汉风险评分（FRS）算法中传统风险因素（CRF）对冠心病的预测效用。
在北威克公园心脏研究II中，对2742名男性（在15年的前瞻性研究中发生270例冠心病事件）进行了rs10757274 A>G [平均G频率=0.48（95%CI 0.47 - 0.50）]基因分型。使用ROC曲线下面积（A(ROC)）和似然比（LR）统计量，我们评估了基于有无基因型的CRF的FRS的鉴别性能。
rs10757274 A>G与冠心病发病相关，效应大小如先前报道[GG与AA男性的风险比为1.60（95%CI 1.12 - 2.28）]，独立于CRF和冠心病家族史。虽然仅CRF的A(ROC)为0.62（95%CI 0.58 - 0.66），添加rs10757274 A>G基因型后[0.64（95%CI 0.60 - 0.68）]没有显著增加（P = 0.14），但包含基因型的拟合更好（LR P = 0.01），并且包含rs10757274使369名男性（占总数的13.5%）进入更准确的风险类别。为了模拟多基因效应，添加了10个假设的、随机分配的基因变异，其效应大小和频率相似。两个变异对FRS预测的A(ROC)有显著改善（P = 0.01），而其他变异的增量效应较小（最终A(ROC)=0.71，与CRF相比P <0.001；与CRF相比LR P <0.0001）。
虽然总体而言，rs10757274对FRS预测未来事件的有用性没有实质性增加，但它确实改善了冠心病风险的重新分类，因此可能具有临床效用。
