{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:22:04Z","timestamp":1791638524709,"version":"4.3.4"},"reference-count":26,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2012,2]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>Rare variant accumulation studies can implicate genes in disease susceptibility when a significant burden is observed in patients versus control subjects. Such analyses might be particularly useful for candidate genes that are selected based on experiments other than genome-wide association studies (GWAS). We sought to determine whether rare variants in non-GWAS candidate genes identified from mouse models and human mendelian syndromes of hypertriglyceridemia (HTG) accumulate in patients with polygenic adult-onset HTG.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              We resequenced protein coding regions of 3 genes with established roles (\n              <jats:italic>APOC2, GPIHBP1<\/jats:italic>\n              ,\n              <jats:italic>LMF1<\/jats:italic>\n              ) and 2 genes recently implicated (\n              <jats:italic>CREB3L3<\/jats:italic>\n              and\n              <jats:italic>ZHX3<\/jats:italic>\n              ) in TG metabolism. We identified 41 distinct heterozygous rare variants, including 29 singleton variants, in the combined sample; in total, we observed 47 rare variants in 413 HTG patients versus 16 in 324 control subjects (odds ratio=2.3;\n              <jats:italic>P<\/jats:italic>\n              =0.0050). Post hoc assessment of genetic burden in individual genes using 3 different tests suggested that the genetic burden was most prominent in the established genes\n              <jats:italic>LMF1<\/jats:italic>\n              and\n              <jats:italic>APOC2<\/jats:italic>\n              , and also in the recently identified\n              <jats:italic>CREB3L3<\/jats:italic>\n              gene.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>These extensive resequencing studies show a significant accumulation of rare genetic variants in non-GWAS candidate genes among patients with polygenic HTG, and indicate the importance of testing specific hypotheses in large-scale resequencing studies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.111.960864","type":"journal-article","created":{"date-parts":[[2011,12,3]],"date-time":"2011-12-03T06:11:44Z","timestamp":1322892704000},"page":"66-72","source":"Crossref","is-referenced-by-count":91,"title":["Excess of Rare Variants in Non\u2013Genome-Wide Association Study Candidate Genes in Patients With Hypertriglyceridemia"],"prefix":"10.1161","volume":"5","author":[{"given":"Christopher T.","family":"Johansen","sequence":"first","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam D.","family":"McIntyre","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca A.","family":"Martins","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Ban","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew B.","family":"Lanktree","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murray W.","family":"Huff","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikl\u00f3s","family":"P\u00e9terfy","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarete","family":"Mehrabian","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldons J.","family":"Lusis","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sekar","family":"Kathiresan","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia S.","family":"Anand","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salim","family":"Yusuf","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann-Hwee","family":"Lee","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie H.","family":"Glimcher","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henian","family":"Cao","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Hegele","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada (C.T.J., J.W., A.D.M., R.A.M., M.R.B., M.B.L., M.W.H., H.C., R.A.H.); the Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (M.H.W., R.A.H.); Medical Genetics Institute, Cedars-Sinai Medical Center and Department of Medicine, University of California, Los Angeles (C.L.H., D.A.D., A.C.); the Department of Medicine (M.P.)..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2867"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09270"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.628"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08494"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R009720"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2481"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI113246"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2007.02.002"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2007.24"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2347"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.109.902320"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)02502-2"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp361"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2010.02.016"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.818"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.816"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.86"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1001322"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.04.005"},{"key":"e_1_3_4_22_2","first-page":"73","article-title":"An apolipoprotein CII mutation, CIILys19: Thr' identified in patients with hyperlipidemia","volume":"9","author":"Hegele RA","year":"1991","unstructured":"Hegele RA, Connelly PW, Maguire GF, Huff MW, Leiter L, Wolfe BM, Evans AJ, Little JA . 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