{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T06:45:23Z","timestamp":1768977923993,"version":"3.49.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:sec><jats:title>Background\u2014<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results\u2014<\/jats:title><jats:p>As part of a larger case\u2013control study of venous thromboembolism, serum levels of 51 proteins implicated in cardiovascular diseases were measured in 330 individuals from the Troms\u00f8 Study. Exonic genetic variation near each protein\u2019s respective gene (<jats:italic>cis<\/jats:italic>) 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<jats:italic>cis<\/jats:italic>, of which 6 are novel (ie, not previously reported); 7 associations with rare variants in<jats:italic>cis<\/jats:italic>, of which 4 are novel; and 6 associations in<jats:italic>trans<\/jats:italic>. Of the 20 proteins, 15 were associated with single sites and 7 with rare variants.<jats:italic>cis<\/jats:italic>-pQTLs for kallikrein and F12 also show<jats:italic>trans<\/jats:italic>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions\u2014<\/jats:title><jats:p>We have identified<jats:italic>cis<\/jats:italic>and<jats:italic>trans<\/jats:italic>genetic variation associated with the serum levels of 20 proteins and utilized these pQTLs to study molecular mechanisms underlying disease and physiological phenotypes.<\/jats:p><\/jats:sec>","DOI":"10.1161\/circgenetics.115.001327","type":"journal-article","created":{"date-parts":[[2016,6,22]],"date-time":"2016-06-22T19:43:08Z","timestamp":1466624588000},"page":"375-383","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Associations Between Common and Rare Exonic Genetic Variants and Serum Levels of 20 Cardiovascular-Related Proteins"],"prefix":"10.1161","volume":"9","author":[{"given":"Terry","family":"Solomon","sequence":"first","affiliation":[{"name":"From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady\u2019s Children\u2019s 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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin N.","family":"Smith","sequence":"additional","affiliation":[{"name":"From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady\u2019s Children\u2019s 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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroko","family":"Matsui","sequence":"additional","affiliation":[{"name":"From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady\u2019s Children\u2019s 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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sigrid K.","family":"Braekkan","sequence":"additional","affiliation":[{"name":"From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady\u2019s Children\u2019s 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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"INVENT Consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom","family":"Wilsgaard","sequence":"additional","affiliation":[{"name":"From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady\u2019s Children\u2019s 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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inger","family":"Nj\u00f8lstad","sequence":"additional","affiliation":[{"name":"From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady\u2019s Children\u2019s 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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellisiv B.","family":"Mathiesen","sequence":"additional","affiliation":[{"name":"From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady\u2019s Children\u2019s 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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John-Bjarne","family":"Hansen","sequence":"additional","affiliation":[{"name":"From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady\u2019s Children\u2019s 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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly A.","family":"Frazer","sequence":"additional","affiliation":[{"name":"From the Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla (T.S.), Department of Pediatrics, Rady\u2019s Children\u2019s 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..."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1502214"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08454"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/elps.1150180333"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000072"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1217238110"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds186"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa054013"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/sim.3034"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyr049"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.113.000630"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_3_4_13_2","first-page":"11.10.1","article-title":"From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline.","volume":"11","author":"Van der Auwera GA","year":"2013","unstructured":"Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, et al.. 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