Patel Riyaz S, Sun Yan V, Hartiala Jaana, Veledar Emir, Su Shaoyong, Sher Salman, Liu Ying X, Rahman Ayaz, Patel Ronak, Rab S Tanveer, Vaccarino Viola, Zafari A Maziar, Samady Habib, Tang W H Wilson, Allayee Hooman, Hazen Stanley L, Quyyumi Arshed A
Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Circ Cardiovasc Genet. 2012 Aug 1;5(4):441-9. doi: 10.1161/CIRCGENETICS.111.960229. Epub 2012 Jul 5.
Genome-wide association studies have identified multiple variants associating with coronary artery disease (CAD) and myocardial infarction (MI). Whether a combined genetic risk score (GRS) is associated with prevalent and incident MI in high-risk subjects remains to be established.
In subjects undergoing cardiac catheterization (n=2597), we identified cases with a history of MI onset at age <70 years and controls ≥70 years without prior MI and followed them for incident MI and death. Genotyping was performed for 11 established CAD/MI variants, and a GRS was calculated based on average number of risk alleles carried at each locus weighted by effect size. Replication of association findings was sought in an independent angiographic cohort (n=2702). The GRS was significantly associated with prevalent MI, occurring before age 70, compared with older controls (≥70 years of age) with no history of MI (P<0.001). This association was successfully replicated in a second cohort, yielding a pooled P value of <0.001. The GRS modestly improved the area-under-the-curve statistic in models of prevalent MI with traditional risk factors; however, the association was not statistically significant when elderly controls without MI but with s\ angiographic CAD were examined (pooled P=0.11). Finally, during a median 2.5-year follow-up, only a nonsignificant trend was noted between the GRS and incident events, which was also not significant in the replication cohort.
A GRS of 11 CAD/MI variants is associated with prevalent MI but not near-term incident adverse events in 2 independent angiographic cohorts. These findings have implications for understanding the clinical use of genetic risk scores for secondary as opposed to primary risk prediction.
全基因组关联研究已经确定了多个与冠状动脉疾病（CAD）和心肌梗死（MI）相关的变异。在高危人群中，综合遗传风险评分（GRS）是否与现患和新发MI相关仍有待确定。
在接受心脏导管插入术的受试者（n = 2597）中，我们确定了年龄<70岁时有MI发作史的病例以及年龄≥70岁且无既往MI的对照，并对他们进行新发MI和死亡情况的随访。对11个已确定的CAD/MI变异进行基因分型，并根据每个位点携带的风险等位基因平均数量乘以效应大小来计算GRS。在一个独立的血管造影队列（n = 2702）中寻求关联结果的重复验证。与无MI病史的老年对照（≥70岁）相比，GRS与70岁之前发生的现患MI显著相关（P<0.001）。这种关联在第二个队列中成功得到重复验证，合并P值<0.001。在现患MI合并传统危险因素的模型中，GRS适度改善了曲线下面积统计量；然而，在检查无MI但有血管造影CAD的老年对照时，该关联无统计学意义（合并P = 0.11）。最后，在中位2.5年的随访期间，GRS与新发事件之间仅观察到无统计学意义的趋势，在重复验证队列中也不显著。
在2个独立的血管造影队列中，11个CAD/MI变异的GRS与现患MI相关，但与近期新发不良事件无关。这些发现对于理解遗传风险评分在二级而非一级风险预测中的临床应用具有启示意义。
