血清脂质水平、体重指数及其在冠状动脉钙化中的作用：一项多基因分析。
Serum lipid levels, body mass index, and their role in coronary artery calcification: a polygenic analysis.
作者信息
van Setten Jessica, Išgum Ivana, Pechlivanis Sonali, Tragante Vinicius, de Jong Pim A, Smolonska Joanna, Platteel Mathieu, Hoffmann Per, Oudkerk Matthijs, de Koning Harry J, Nöthen Markus M, Moebus Susanne, Erbel Raimund, Jöckel Karl-Heinz, Viergever Max A, Mali Willem P Th M, de Bakker Paul I W
机构信息
From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
出版信息
Circ Cardiovasc Genet. 2015 Apr;8(2):327-33. doi: 10.1161/CIRCGENETICS.114.000496. Epub 2015 Jan 10.
BACKGROUND
Coronary artery calcification (CAC) is widely regarded as a cumulative lifetime measure of atherosclerosis, but it remains unclear what is the relationship between calcification and traditional risk factors for coronary artery disease (CAD) and myocardial infarction (MI). This study characterizes the genetic architecture of CAC by evaluating the overall impact of common alleles associated with CAD/MI and its traditional risk factors.
METHODS AND RESULTS
On the basis of summary-association results from the CARDIoGRAMplusC4D study of CAD/MI, we calculated polygenic risk scores in 2599 participants of the Dutch and Belgian Lung Cancer Screening (NELSON) trial, in whom quantitative CAC levels (Agatston scores) were determined from chest computerized tomographic imaging data. The most significant polygenic model explained ≈14% of the observed CAC variance (P=1.6×10(-11)), which points to a residual effect because of many as yet unknown loci that overlap between CAD/MI and CAC. In addition, we constructed risk scores based on published single-nucleotide polymorphism associations for traditional cardiovascular risk factors and tested these scores for association with CAC. We found nominally significant associations for genetic risk scores of low-density lipoprotein-cholesterol, total cholesterol, and body mass index, which were successfully replicated in 2182 individuals of the Heinz Nixdorf Recall Study.
CONCLUSIONS
Pervasive polygenic sharing between CAC and CAD/MI suggests that a substantial fraction of the heritable risk for CAD/MI is mediated through arterial calcification. We also provide evidence that genetic variants associated with serum lipid levels and body mass index influence CAC levels.
背景
冠状动脉钙化（CAC）被广泛认为是动脉粥样硬化的终生累积指标，但钙化与冠状动脉疾病（CAD）和心肌梗死（MI）的传统危险因素之间的关系仍不明确。本研究通过评估与CAD/MI及其传统危险因素相关的常见等位基因的总体影响，来描述CAC的遗传结构。
方法与结果
基于CAD/MI的CARDIoGRAMplusC4D研究的汇总关联结果，我们在荷兰和比利时肺癌筛查（NELSON）试验的2599名参与者中计算了多基因风险评分，这些参与者的定量CAC水平（阿加斯顿评分）由胸部计算机断层扫描成像数据确定。最显著的多基因模型解释了约14%的观察到的CAC变异（P=1.6×10⁻¹¹），这表明由于CAD/MI和CAC之间重叠的许多未知位点存在残余效应。此外，我们基于已发表的传统心血管危险因素的单核苷酸多态性关联构建了风险评分，并测试了这些评分与CAC的关联。我们发现低密度脂蛋白胆固醇、总胆固醇和体重指数的遗传风险评分存在名义上显著的关联，这些关联在海因茨·尼克斯多夫召回研究的2182名个体中成功得到复制。
结论
CAC与CAD/MI之间普遍存在多基因共享，这表明CAD/MI的很大一部分遗传风险是通过动脉钙化介导的。我们还提供证据表明，与血清脂质水平和体重指数相关的基因变异会影响CAC水平。
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