Ligthart Symen, Vaez Ahmad, Hsu Yi-Hsiang, Stolk Ronald, Uitterlinden André G, Hofman Albert, Alizadeh Behrooz Z, Franco Oscar H, Dehghan Abbas
Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000CA, Rotterdam, The Netherlands.
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
BMC Genomics. 2016 Jun 10;17:443. doi: 10.1186/s12864-016-2712-4.
Genome-wide association studies (GWAS) have identified multiple genetic loci for C-reactive protein (CRP) and lipids, of which some overlap. We aimed to identify genetic pleiotropy among CRP and lipids in order to better understand the shared biology of chronic inflammation and lipid metabolism.
In a bivariate GWAS, we combined summary statistics of published GWAS on CRP (n = 66,185) and lipids, including LDL-cholesterol, HDL-cholesterol, triglycerides, and total cholesterol (n = 100,184), using an empirical weighted linear-combined test statistic. We sought replication for novel CRP associations in an independent sample of 17,743 genotyped individuals, and performed in silico replication of novel lipid variants in 93,982 individuals. Fifty potentially pleiotropic SNPs were identified among CRP and lipids: 21 for LDL-cholesterol and CRP, 20 for HDL-cholesterol and CRP, 21 for triglycerides, and CRP and 20 for total cholesterol and CRP. We identified and significantly replicated three novel SNPs for CRP in or near CTSB/FDFT1 (rs10435719, Preplication: 2.6 × 10(-5)), STAG1/PCCB (rs7621025, Preplication: 1.4 × 10(-3)) and FTO (rs1558902, Preplication: 2.7 × 10(-5)). Seven pleiotropic lipid loci were replicated in the independent set of MetaboChip samples of the Global Lipids Genetics Consortium. Annotating the effect of replicated CRP SNPs to the expression of nearby genes, we observed an effect of rs10435719 on gene expression of FDFT1, and an effect of rs7621025 on PCCB.
Our large scale combined GWAS analysis identified numerous pleiotropic loci for CRP and lipids providing further insight in the genetic interrelation between lipids and inflammation. In addition, we provide evidence for FDFT1, PCCB and FTO to be associated with CRP levels.
全基因组关联研究（GWAS）已确定了多个与C反应蛋白（CRP）和脂质相关的基因位点，其中一些存在重叠。我们旨在确定CRP和脂质之间的基因多效性，以便更好地理解慢性炎症和脂质代谢的共同生物学机制。
在双变量GWAS中，我们使用经验加权线性组合检验统计量，将已发表的关于CRP（n = 66,185）和脂质（包括低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、甘油三酯和总胆固醇，n = 100,184）的GWAS汇总统计数据进行合并。我们在17,743名基因分型个体的独立样本中寻求对新的CRP关联进行复制，并在93,982名个体中对新的脂质变异进行了电子复制。在CRP和脂质之间鉴定出50个潜在的多效性单核苷酸多态性（SNP）：21个与低密度脂蛋白胆固醇和CRP相关，20个与高密度脂蛋白胆固醇和CRP相关，21个与甘油三酯和CRP相关，20个与总胆固醇和CRP相关。我们在CTSB/FDFT1（rs10435719，预复制：2.6×10^(-5)）、STAGI/PCCB（rs7621025，预复制：1.4×10^(-3)）和FTO（rs1558902，预复制：2.7×10^(-5)）中或附近鉴定并显著复制了三个新的CRP相关SNP。在全球脂质遗传学联盟的MetaboChip样本独立集中复制了七个多效性脂质基因座。将复制的CRP SNP对附近基因表达的影响进行注释后，我们观察到rs10435719对FDFT1基因表达有影响，rs7621025对PCCB有影响。
我们大规模的联合GWAS分析确定了许多与CRP和脂质相关的多效性基因座，为脂质与炎症之间的遗传相互关系提供了进一步的见解。此外，我们提供了FDFT1、PCCB和FTO与CRP水平相关的证据。
