Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town
OBJECTIVE:Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor (LDLR) mutations account for >90% of cases, apolipoprotein B (APOB) muta...
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| Veröffentlicht in: | Arteriosclerosis, thrombosis, and vascular biology thrombosis, and vascular biology, 2021-02, Vol.41 (2), p.934-943 |
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| creator | Huijgen, Roeland Blom, Dirk J. Hartgers, Merel L. Chemello, Kévin Benito-Vicente, Asier Uribe, Kepa B. Behardien, Zorena Blackhurst, Dee M. Brice, Brigitte C. Defesche, Joep C. de Jong, Annemiek G. Jooste, Rosemary J. Solomon, Gabriele A.E. Wolmarans, Karen H. Hovingh, G. Kees Martin, Cesar Lambert, Gilles Marais, A. David |
| description | OBJECTIVE:Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor (LDLR) mutations account for >90% of cases, apolipoprotein B (APOB) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 (PCSK9) gain of function mutations are rare (T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P |
| doi_str_mv | 10.1161/ATVBAHA.120.314482 |
| format | Article |
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APPROACH AND RESULTS:Patients with clinically diagnosed FH underwent genetic analysis of LDLR, and if negative, sequential testing of APOB and PCSK9. We analyzed cosegregation of hypercholesterolemia with novel PCSK9 variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous PCSK9 variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel PCSK9 variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P<0.001). In vitro studies demonstrated the pathogenicity of the G516V variant.
CONCLUSIONS:In our study, 1.14% of cases with clinical FH were clearly attributable to pathogenic variants in PCSK9. Pathogenicity is established beyond doubt for the G516V variant.</description><identifier>ISSN: 1079-5642</identifier><identifier>EISSN: 1524-4636</identifier><identifier>DOI: 10.1161/ATVBAHA.120.314482</identifier><identifier>PMID: 33147992</identifier><language>eng</language><publisher>United States: Lippincott Williams & Wilkins</publisher><subject>Life Sciences</subject><ispartof>Arteriosclerosis, thrombosis, and vascular biology, 2021-02, Vol.41 (2), p.934-943</ispartof><rights>Lippincott Williams & Wilkins</rights><rights>2020 American Heart Association, Inc.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5222-12ae2ca2a80f1aaf01bfa51abcd02d677f3e77979697c428584dabd9f042b7123</citedby><cites>FETCH-LOGICAL-c5222-12ae2ca2a80f1aaf01bfa51abcd02d677f3e77979697c428584dabd9f042b7123</cites><orcidid>0000-0003-3965-5912 ; 0000-0002-8145-1676 ; 0000-0002-9899-4634 ; 0000-0003-1653-1722 ; 0000-0002-4087-8729 ; 0000-0001-5632-0685 ; 0000-0001-5087-0651 ; 0000-0002-3865-9084</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33147992$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04465347$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Huijgen, Roeland</creatorcontrib><creatorcontrib>Blom, Dirk J.</creatorcontrib><creatorcontrib>Hartgers, Merel L.</creatorcontrib><creatorcontrib>Chemello, Kévin</creatorcontrib><creatorcontrib>Benito-Vicente, Asier</creatorcontrib><creatorcontrib>Uribe, Kepa B.</creatorcontrib><creatorcontrib>Behardien, Zorena</creatorcontrib><creatorcontrib>Blackhurst, Dee M.</creatorcontrib><creatorcontrib>Brice, Brigitte C.</creatorcontrib><creatorcontrib>Defesche, Joep C.</creatorcontrib><creatorcontrib>de Jong, Annemiek G.</creatorcontrib><creatorcontrib>Jooste, Rosemary J.</creatorcontrib><creatorcontrib>Solomon, Gabriele A.E.</creatorcontrib><creatorcontrib>Wolmarans, Karen H.</creatorcontrib><creatorcontrib>Hovingh, G. Kees</creatorcontrib><creatorcontrib>Martin, Cesar</creatorcontrib><creatorcontrib>Lambert, Gilles</creatorcontrib><creatorcontrib>Marais, A. David</creatorcontrib><title>Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town</title><title>Arteriosclerosis, thrombosis, and vascular biology</title><addtitle>Arterioscler Thromb Vasc Biol</addtitle><description>OBJECTIVE:Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor (LDLR) mutations account for >90% of cases, apolipoprotein B (APOB) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 (PCSK9) gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel PCSK9 variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays.
APPROACH AND RESULTS:Patients with clinically diagnosed FH underwent genetic analysis of LDLR, and if negative, sequential testing of APOB and PCSK9. We analyzed cosegregation of hypercholesterolemia with novel PCSK9 variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous PCSK9 variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel PCSK9 variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P<0.001). In vitro studies demonstrated the pathogenicity of the G516V variant.
CONCLUSIONS:In our study, 1.14% of cases with clinical FH were clearly attributable to pathogenic variants in PCSK9. Pathogenicity is established beyond doubt for the G516V variant.</description><subject>Life Sciences</subject><issn>1079-5642</issn><issn>1524-4636</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9UsGO0zAQjRCIXRZ-gAPycfeQYo-duDmWiFK0FVTashytSeIoASfu2knLXvlyHKXscQ_2jEfvvbHnOYreM7pgLGUfV_v7T6vNasGALjgTYgkvokuWgIhFytOXIacyi5NUwEX0xvtflFIBQF9HFzzAZZbBZfT3mz1qQ3b53W1GrnfOHpwddNuT3PZH7Qb0mtyNxdCa1ofqrf4T9v3jQZPshtyja7EfPAm1HQ6tnvKf7dCQNXaBgYZsAtSVjTXaD9qF0LVI1s52JMcgsren_m30qkbj9btzvIp-rD_v8028_f7la77axmUCADED1FAi4JLWDLGmrKgxYViUFYUqlbLmWspMZmkmSwHLZCkqLKqsDo8uJAN-Fd3Mug0adXBth-5RWWzVZrVVU40KkSZcyCML2OsZG8bxMIa7q671pTYGe21Hr0AkoZHM-CQLM7R01nun6ydtRtXkkzr7pIJPavYpkD6c9cei09UT5b8xAZDOgJM1YXD-txlP2qlGoxma55XFM8TpC_CUJjFQYBTCMQ6Lp_wfpi2u9g</recordid><startdate>20210201</startdate><enddate>20210201</enddate><creator>Huijgen, Roeland</creator><creator>Blom, Dirk J.</creator><creator>Hartgers, Merel L.</creator><creator>Chemello, Kévin</creator><creator>Benito-Vicente, Asier</creator><creator>Uribe, Kepa B.</creator><creator>Behardien, Zorena</creator><creator>Blackhurst, Dee M.</creator><creator>Brice, Brigitte C.</creator><creator>Defesche, Joep C.</creator><creator>de Jong, Annemiek G.</creator><creator>Jooste, Rosemary J.</creator><creator>Solomon, Gabriele A.E.</creator><creator>Wolmarans, Karen H.</creator><creator>Hovingh, G. Kees</creator><creator>Martin, Cesar</creator><creator>Lambert, Gilles</creator><creator>Marais, A. David</creator><general>Lippincott Williams & Wilkins</general><general>American Heart Association, Inc</general><general>American Heart Association</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0003-3965-5912</orcidid><orcidid>https://orcid.org/0000-0002-8145-1676</orcidid><orcidid>https://orcid.org/0000-0002-9899-4634</orcidid><orcidid>https://orcid.org/0000-0003-1653-1722</orcidid><orcidid>https://orcid.org/0000-0002-4087-8729</orcidid><orcidid>https://orcid.org/0000-0001-5632-0685</orcidid><orcidid>https://orcid.org/0000-0001-5087-0651</orcidid><orcidid>https://orcid.org/0000-0002-3865-9084</orcidid></search><sort><creationdate>20210201</creationdate><title>Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town</title><author>Huijgen, Roeland ; Blom, Dirk J. ; Hartgers, Merel L. ; Chemello, Kévin ; Benito-Vicente, Asier ; Uribe, Kepa B. ; Behardien, Zorena ; Blackhurst, Dee M. ; Brice, Brigitte C. ; Defesche, Joep C. ; de Jong, Annemiek G. ; Jooste, Rosemary J. ; Solomon, Gabriele A.E. ; Wolmarans, Karen H. ; Hovingh, G. Kees ; Martin, Cesar ; Lambert, Gilles ; Marais, A. David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5222-12ae2ca2a80f1aaf01bfa51abcd02d677f3e77979697c428584dabd9f042b7123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Life Sciences</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huijgen, Roeland</creatorcontrib><creatorcontrib>Blom, Dirk J.</creatorcontrib><creatorcontrib>Hartgers, Merel L.</creatorcontrib><creatorcontrib>Chemello, Kévin</creatorcontrib><creatorcontrib>Benito-Vicente, Asier</creatorcontrib><creatorcontrib>Uribe, Kepa B.</creatorcontrib><creatorcontrib>Behardien, Zorena</creatorcontrib><creatorcontrib>Blackhurst, Dee M.</creatorcontrib><creatorcontrib>Brice, Brigitte C.</creatorcontrib><creatorcontrib>Defesche, Joep C.</creatorcontrib><creatorcontrib>de Jong, Annemiek G.</creatorcontrib><creatorcontrib>Jooste, Rosemary J.</creatorcontrib><creatorcontrib>Solomon, Gabriele A.E.</creatorcontrib><creatorcontrib>Wolmarans, Karen H.</creatorcontrib><creatorcontrib>Hovingh, G. Kees</creatorcontrib><creatorcontrib>Martin, Cesar</creatorcontrib><creatorcontrib>Lambert, Gilles</creatorcontrib><creatorcontrib>Marais, A. David</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huijgen, Roeland</au><au>Blom, Dirk J.</au><au>Hartgers, Merel L.</au><au>Chemello, Kévin</au><au>Benito-Vicente, Asier</au><au>Uribe, Kepa B.</au><au>Behardien, Zorena</au><au>Blackhurst, Dee M.</au><au>Brice, Brigitte C.</au><au>Defesche, Joep C.</au><au>de Jong, Annemiek G.</au><au>Jooste, Rosemary J.</au><au>Solomon, Gabriele A.E.</au><au>Wolmarans, Karen H.</au><au>Hovingh, G. Kees</au><au>Martin, Cesar</au><au>Lambert, Gilles</au><au>Marais, A. David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town</atitle><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle><addtitle>Arterioscler Thromb Vasc Biol</addtitle><date>2021-02-01</date><risdate>2021</risdate><volume>41</volume><issue>2</issue><spage>934</spage><epage>943</epage><pages>934-943</pages><issn>1079-5642</issn><eissn>1524-4636</eissn><abstract>OBJECTIVE:Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor (LDLR) mutations account for >90% of cases, apolipoprotein B (APOB) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 (PCSK9) gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel PCSK9 variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays.
APPROACH AND RESULTS:Patients with clinically diagnosed FH underwent genetic analysis of LDLR, and if negative, sequential testing of APOB and PCSK9. We analyzed cosegregation of hypercholesterolemia with novel PCSK9 variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous PCSK9 variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel PCSK9 variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P<0.001). In vitro studies demonstrated the pathogenicity of the G516V variant.
CONCLUSIONS:In our study, 1.14% of cases with clinical FH were clearly attributable to pathogenic variants in PCSK9. Pathogenicity is established beyond doubt for the G516V variant.</abstract><cop>United States</cop><pub>Lippincott Williams & Wilkins</pub><pmid>33147992</pmid><doi>10.1161/ATVBAHA.120.314482</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-3965-5912</orcidid><orcidid>https://orcid.org/0000-0002-8145-1676</orcidid><orcidid>https://orcid.org/0000-0002-9899-4634</orcidid><orcidid>https://orcid.org/0000-0003-1653-1722</orcidid><orcidid>https://orcid.org/0000-0002-4087-8729</orcidid><orcidid>https://orcid.org/0000-0001-5632-0685</orcidid><orcidid>https://orcid.org/0000-0001-5087-0651</orcidid><orcidid>https://orcid.org/0000-0002-3865-9084</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Alma/SFX Local Collection |
| subjects | Life Sciences |
| title | Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town |
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