{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T13:36:56Z","timestamp":1777901816947,"version":"3.51.4"},"reference-count":29,"publisher":"The Endocrine Society","issue":"2","license":[{"start":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T00:00:00Z","timestamp":1664755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100008880","name":"Kanae Foundation for the Promotion of Medical Science","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100008880","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005072","name":"Japanese Circulation Society","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005072","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,1,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Heterozygous familial hypercholesterolemia (HeFH) is caused by a rare pathogenic variant in the LDLR, APOB, and PCSK9 genes. However, the causative variants in these genes have not been identified in approximately 40% of HeFH patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Our aim was to identify novel (or additional) genes\/variants that contribute to HeFH.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Whole-exome sequencing was performed for 215 family members from 122 families with HeFH without pathogenic variants in the LDLR or PCSK9 genes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We could not find novel causative familial hypercholesterolemia (FH) genes\/variants by family analysis. Next, we examined all APOB variants. Twenty-four nonsynonymous APOB variants were identified. The allele frequencies of the c.2863C &amp;gt; T:p.(Pro955Ser) variant in the HeFH probands and the general Japanese population were 0.15 and 0.034, respectively [odds ratio 4.9 (95% CI 3.4-7.1); P = 6.9 \u00d7 10\u221213]. The patients harboring the c.2863C &amp;gt; T:p.(Pro955Ser) variant accounted for 9.8% (n = 63) of unrelated patients with HeFH (n = 645). The penetrance of the c.2863C &amp;gt; T:p.(Pro955Ser) variant was low in the pedigree-based genetic analysis. In an in vitro assay, low-density lipoprotein (LDL) uptake from patients with the homozygous c.2863C &amp;gt; T:p.(Pro955Ser) variant was 44% of the LDL uptake from control subjects, and it was similar to that of the LDL uptake from patients with the known pathogenic heterozygous p.(Arg3527Gln) variant.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The low-frequency APOB c.2863C &amp;gt; T:p.(Pro955Ser) variant is not an FH-causative variant, but it has a moderate effect size in HeFH. These findings suggest that the combination of the APOB c.2863C &amp;gt; T:p.(Pro955Ser) variant and age, environmental factors, or other genetic factors contributes to the severity of or variability in the HeFH phenotype.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgac572","type":"journal-article","created":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T17:29:13Z","timestamp":1664818153000},"page":"422-432","source":"Crossref","is-referenced-by-count":7,"title":["A Low-Frequency <i>APOB<\/i> p.(Pro955Ser) Variant Contributes to the Severity of\/Variability in Familial Hypercholesterolemia"],"prefix":"10.1210","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5459-6984","authenticated-orcid":false,"given":"Mika","family":"Hori","sequence":"first","affiliation":[{"name":"Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute , Suita, Osaka , Japan"},{"name":"Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University , Nagoya, Aichi , Japan"},{"name":"Department of Endocrinology, Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7099-8767","authenticated-orcid":false,"given":"Atsushi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, National Cerebral and Cardiovascular Center Research Institute , Suita, Osaka , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiminori","family":"Hosoda","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Genetics, National Cerebral and Cardiovascular Center , Suita, Osaka , Japan"},{"name":"Department of Diabetes and Lipid Metabolism, National Cerebral and Cardiovascular Center , Suita, Osaka , 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