前列腺癌与血脂中的共享常见变异
Shared common variants in prostate cancer and blood lipids.
作者信息
Andreassen Ole A, Zuber Verena, Thompson Wesley K, Schork Andrew J, Bettella Francesco, Djurovic Srdjan, Desikan Rahul S, Mills Ian G, Dale Anders M
机构信息
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway, Prostate Cancer Research Group, Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway, Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA, Multimodal Imaging Laboratory, University of California at San Diego, La Jolla, CA, USA, Cognitive Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA, Center for Human Development, University of California at San Diego, La Jolla, CA, USA, the participants acknowledged in Supplementary data, available at IJE online, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway, Department of Radiology, University of California, San Diego, La Jolla, CA, USA, Department of Cancer Prevention, Institute of Cancer Research and Department of Urology, Oslo University Hospital, Oslo, Norway and Department of Neurosciences, University of California, San Diego, La Jolla, CA, USANORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway, Prostate Cancer Research Group, Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway, Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA, Multimodal Imaging Laboratory, University of California at San Diego, La Jolla, CA, USA, Cognitive Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA, Center for Human Development, University of California at San Diego, La Jolla, CA, USA, the participants acknowledged in Supplementary data, available at IJE online, Department of Medical Genetics, Oslo University Hospital, Oslo
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway, Prostate Cancer Research Group, Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway, Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA, Multimodal Imaging Laboratory, University of California at San Diego, La Jolla, CA, USA, Cognitive Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA, Center for Human Development, University of California at San Diego, La Jolla, CA, USA, the participants acknowledged in Supplementary data, available at IJE online, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway, Department of Radiology, University of California, San Diego, La Jolla, CA, USA, Department of Cancer Prevention, Institute of Cancer Research and Department of Urology, Oslo University Hospital, Oslo, Norway and Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
出版信息
Int J Epidemiol. 2014 Aug;43(4):1205-14. doi: 10.1093/ije/dyu090. Epub 2014 Apr 30.
BACKGROUND
Epidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors.
METHODS
We applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n=50 000) and CVD risk factors (n=200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR.
RESULTS
We found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR <0.01). For T2D, we detected one locus adjacent to HNF1B.
CONCLUSIONS
We found polygenic overlap between PCA predisposition and blood lipids, in particular LDL and TG, and identified 17 pleiotropic gene loci between PCA and LDL, and PCA and TG, respectively. These findings provide novel pathobiological insights and may have implications for trials using targeting lipid-lowering agents in a prevention or cancer setting.
背景
流行病学和临床研究表明前列腺癌（PCA）与心血管疾病（CVD）风险因素之间存在合并症。然而，这两种表型之间的关系仍未得到充分理解。在此，我们试图确定PCA与CVD风险因素之间共享的基因座。
方法
我们应用了一种基于联合错误发现率（FDR）的遗传流行病学方法，该方法结合了来自不同全基因组关联研究（GWAS）的汇总统计数据，并能够识别两种表型之间的遗传重叠。我们评估了来自PCA（n = 50000）和CVD风险因素（n = 200000）[甘油三酯（TG）、低密度脂蛋白（LDL）胆固醇和高密度脂蛋白（HDL）胆固醇、收缩压、体重指数、腰臀比和2型糖尿病（T2D）]的大型多中心GWA研究的汇总统计数据。使用条件分位数-分位数图和安德森-达林检验评估与PCA和CVD风险因素相关的单核苷酸多态性（SNP）的富集情况。此外，我们使用联合FDR确定了共享基因座。
结果
我们发现PCA中P值的最强富集以LDL为条件且以TG为条件。相比之下，我们发现以HDL为条件或以其他研究性状为条件时只有微弱的富集。联合FDR共鉴定出17个基因座；10个基因座与PCA和LDL相关，3个基因座与PCA和TG相关，另外4个基因座与PCA、LDL和TG共同相关（联合FDR < 0.01）。对于T2D，我们在HNF1B附近检测到一个基因座。
结论
我们发现PCA易感性与血脂之间存在多基因重叠，特别是LDL和TG，并分别在PCA与LDL以及PCA与TG之间鉴定出17个多效性基因座。这些发现提供了新的病理生物学见解，可能对在预防或癌症环境中使用靶向降脂药物的试验具有启示意义。
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