BACKGROUND Type 2 diabetes increases the risk of coronary heart disease (CHD), yet the mechanisms involved remain poorly described. Polygenic risk scores (PRS) provide an opportunity to understand risk factors since they reflect etiologic pathways from the entire genome. We therefore tested whether a PRS for CHD influenced risk of CHD in individuals with type 2 diabetes and which risk factors were associated with this PRS. METHODS We tested the association of a CHD PRS with CHD and its traditional clinical risk factors amongst individuals with type 2 diabetes in UK Biobank (N = 21,102). We next tested the association of the CHD PRS with atherosclerotic burden in a cohort of 352 genome-wide genotyped participants with type 2 diabetes who had undergone coronary angiograms. RESULTS In the UK Biobank we found that the CHD PRS was strongly associated with CHD amongst individuals with type 2 diabetes (OR per standard deviation increase = 1.50; p = 1.5 × 10- 59). But this CHD PRS was, at best, only weakly associated with traditional clinical risk factors, such as hypertension, hyperlipidemia, glycemic control, obesity and smoking. Conversely, in the angiographic cohort, the CHD PRS was strongly associated with multivessel stenosis (OR = 1.65; p = 4.9 × 10- 4) and increased number of major stenotic lesions (OR = 1.35; p = 9.4 × 10- 3). CONCLUSIONS Polygenic predisposition to CHD is strongly associated with atherosclerotic burden in individuals with type 2 diabetes and this effect is largely independent of traditional clinical risk factors. This suggests that genetic risk for CHD acts through atherosclerosis with little effect on most traditional risk factors, providing the opportunity to explore new biological pathways.

中文翻译：

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冠心病的多基因风险通过2型糖尿病的动脉粥样硬化起作用。

背景技术2型糖尿病增加了冠心病（CHD）的风险，但是所涉及的机制仍然缺乏描述。多基因风险评分（PRS）提供了一个了解风险因素的机会，因为它们反映了整个基因组的病因学途径。因此，我们测试了CHD的PRS是否影响2型糖尿病患者的CHD风险以及与该PRS相关的危险因素。方法我们在UK Biobank（N = 21,102）中测试了2型糖尿病患者中CHD PRS与CHD及其传统临床危险因素的关联。接下来，我们在352名接受了冠状动脉造影的2型糖尿病基因组全基因型参与者队列中，测试了CHD PRS与动脉粥样硬化负担的相关性。结果在英国生物库中，我们发现2型糖尿病患者中CHD PRS与CHD密切相关（OR /标准差增加= 1.50； p = 1.5×10-59）。但是，这种CHD PRS充其量仅与传统的临床危险因素（例如高血压，高脂血症，血糖控制，肥胖和吸烟）之间存在弱关联。相反，在血管造影队列中，CHD PRS与多支血管狭窄密切相关（OR = 1.65； p = 4.9×10-4）和主要狭窄病变数量增加（OR = 1.35； p = 9.4×10-3）。结论冠心病的多基因易感性与2型糖尿病患者的动脉粥样硬化负担密切相关，这种作用在很大程度上与传统的临床危险因素无关。