Polygenic Contribution in Individuals With Early-Onset Coronary Artery Disease
Polygenic Contribution in Individuals With Early-Onset Coronary Artery Disease
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DOI：
10.1161/circgen.117.001849
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
S. Thériault;Ricky Lali;M. Chong;J. Velianou;M. Natarajan;G. Paré
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文献类型：
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作者：
S. Thériault;Ricky Lali;M. Chong;J. Velianou;M. Natarajan;G. Paré
背景：尽管有证据表明遗传率很高，但在早发性冠状动脉疾病(EOCAD)患者中发现了一小部分单基因疾病。我们假设，一些患有EOCAD的个体携带大量常见的遗传风险变异，其综合效应类似于孟德尔形式的冠状动脉疾病，如家族性高胆固醇血症。方法和结果：为了确认多基因对EOCAD的贡献(男性⩽年龄40岁，女性⩽年龄45岁)，我们从英国生物库队列中计算了111418名英国参与者的遗传风险评分(GRS)，该评分基于存在182个与冠状动脉疾病相关的独立变异(GRS182)。96例确诊为EOCAD并接受血管重建术的患者的GRS182显著高于未行EOCAD的患者(P=3.21×10−9)。GRS182每增加1个SD，EOCAD的优势比为1.84(1.52~2.24)。与杂合性家族性高胆固醇血症相似，增加EOCAD风险的多基因因素的流行率估计为1/53。在EOCAD患者的本地队列中(n=30)，GRS182与英国生物库对照相比显著增加(P=0.001)。7名参与者(23%)的GRS182与EOCAD风险估计增加2倍相对应；没有人有与单基因血脂异常或EOCAD有关的罕见突变。结论：这些结果表明EOCAD患者存在显著的多基因致病因素，其发病率可能比家族性高胆固醇血症更为普遍。多基因风险成分的确定可以包括在EOCAD患者的诊断过程中。
Background: Despite evidence of high heritability, monogenic disorders are identified in a minor fraction of individuals with early-onset coronary artery disease (EOCAD). We hypothesized that some individuals with EOCAD carry a high number of common genetic risk variants, with a combined effect similar to Mendelian forms of coronary artery disease, such as familial hypercholesterolemia. Methods and Results: To confirm the polygenic contribution to EOCAD (age of ⩽40 years for men and ⩽45 years for women), we calculated in 111 418 British participants from the UK Biobank cohort a genetic risk score (GRS) based on the presence of 182 independent variants associated with coronary artery disease (GRS182). Participants with a diagnosis of EOCAD who underwent a revascularization procedure (n=96) had a significantly higher GRS182 (P=3.21×10−9) than those without EOCAD. An increase of 1 SD in GRS182 corresponded to an odds ratio of 1.84 (1.52–2.24) for EOCAD. The prevalence of a polygenic contribution that increased EOCAD risk similar to what is observed in heterozygous familial hypercholesterolemia was estimated at 1 in 53. In a local cohort of individuals with EOCAD (n=30), GRS182 was significantly increased compared with UK Biobank controls (P=0.001). Seven participants (23%) had a GRS182 corresponding to an estimated 2-fold increase in EOCAD risk; none had a rare mutation involved in monogenic dyslipidemia or EOCAD. Conclusions: These results suggest a significant polygenic contribution in individuals presenting with EOCAD, which could be more prevalent than familial hypercholesterolemia. Determination of the polygenic risk component could be included in the diagnostic workup of patients with EOCAD.