Solomon Terry, Smith Erin N, Matsui Hiroko, Braekkan Sigrid K, Wilsgaard Tom, Njølstad Inger, Mathiesen Ellisiv B, Hansen John-Bjarne, Frazer Kelly A
From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady's Children's Hospital, San Diego, La Jolla, CA (E.N.S., H.M., K.A.F.); Institute for Genomic Medicine, University of California, San Diego, La Jolla (K.A.F.); Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Centre (TREC) (E.N.S., S.K.B., I.N., E.B.M., J.-B.H., K.A.F.), Department of Community Medicine (T.W., I.N.), and Brain and Circulation Research Group, Department of Clinical Medicine (E.B.M.), UiT The Arctic University of Norway; and Division of Internal Medicine, University Hospital of North Norway, Tromsø (S.K.B., J.-B.H.).
Circ Cardiovasc Genet. 2016 Aug;9(4):375-83. doi: 10.1161/CIRCGENETICS.115.001327. Epub 2016 Jun 21.
Genetic variation can be used to study causal relationships between biomarkers and diseases. Here, we identify new common and rare genetic variants associated with cardiovascular-related protein levels (protein quantitative trait loci [pQTLs]). We functionally annotate these pQTLs, predict and experimentally confirm a novel molecular interaction, and determine which pQTLs are associated with diseases and physiological phenotypes.
As part of a larger case-control study of venous thromboembolism, serum levels of 51 proteins implicated in cardiovascular diseases were measured in 330 individuals from the Tromsø Study. Exonic genetic variation near each protein's respective gene (cis) was identified using sequencing and arrays. Using single site and gene-based tests, we identified 27 genetic associations between pQTLs and the serum levels of 20 proteins: 14 associated with common variation in cis, of which 6 are novel (ie, not previously reported); 7 associations with rare variants in cis, of which 4 are novel; and 6 associations in trans. Of the 20 proteins, 15 were associated with single sites and 7 with rare variants. cis-pQTLs for kallikrein and F12 also show trans associations for proteins (uPAR, kininogen) known to be cleaved by kallikrein and with NTproBNP. We experimentally demonstrate that kallikrein can cleave proBNP (NTproBNP precursor) in vitro. Nine of the pQTLs have previously identified associations with 17 disease and physiological phenotypes.
We have identified cis and trans genetic variation associated with the serum levels of 20 proteins and utilized these pQTLs to study molecular mechanisms underlying disease and physiological phenotypes.
基因变异可用于研究生物标志物与疾病之间的因果关系。在此，我们鉴定了与心血管相关蛋白水平（蛋白质定量性状位点 [pQTLs]）相关的新的常见和罕见基因变异。我们对这些 pQTLs 进行功能注释，预测并通过实验证实了一种新的分子相互作用，并确定哪些 pQTLs 与疾病和生理表型相关。
作为一项更大规模的静脉血栓栓塞病例对照研究的一部分，在来自特罗姆瑟研究的 330 名个体中测量了 51 种与心血管疾病相关的蛋白质的血清水平。使用测序和阵列鉴定了每种蛋白质各自基因附近（顺式）的外显子基因变异。通过单位点和基于基因的检测，我们鉴定了 pQTLs 与 20 种蛋白质血清水平之间的 27 种基因关联：14 种与顺式常见变异相关，其中 6 种是新发现的（即以前未报道过）；7 种与顺式罕见变异相关，其中 4 种是新发现的；以及 6 种反式关联。在这 20 种蛋白质中，15 种与单一位点相关，7 种与罕见变异相关。激肽释放酶和 F12 的顺式 pQTLs 也显示出与已知被激肽释放酶切割的蛋白质（尿激酶型纤溶酶原激活剂受体、激肽原）以及 N 末端脑钠肽前体的反式关联。我们通过实验证明激肽释放酶在体外可切割脑钠肽前体（N 末端脑钠肽前体）。其中 9 个 pQTLs 先前已被鉴定与 17 种疾病和生理表型相关。
我们鉴定了与 20 种蛋白质血清水平相关的顺式和反式基因变异，并利用这些 pQTLs 研究疾病和生理表型背后的分子机制。
