Influence of PCSK9 polymorphisms on plasma lipids and response to atorvastatin treatment in Brazilian subjects
Background The proprotein convertase subtilisin/kexin type 9 (PCSK9) has a key role in the regulation of plasma low-density lipoprotein (LDL) cholesterol by enhancing the degradation of LDL receptor. Functional variants in PCSK9 have been associated with differences in plasma lipids and may contribu...
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| creator | Anderson, Jacqueline M., PharmD Cerda, Alvaro, PhD Hirata, Mario H., PhD Rodrigues, Alice C., PhD Dorea, Egidio L., PhD Bernik, Marcia M.S., PhD Bertolami, Marcelo C., PhD Faludi, Andre A., PhD Hirata, Rosario D.C., PhD |
| description | Background The proprotein convertase subtilisin/kexin type 9 (PCSK9) has a key role in the regulation of plasma low-density lipoprotein (LDL) cholesterol by enhancing the degradation of LDL receptor. Functional variants in PCSK9 have been associated with differences in plasma lipids and may contribute to the variability of the response to cholesterol-lowering drugs. Objective To investigate the influence of PCSK9 variants on plasma lipid profile and response to atorvastatin in Brazilian subjects. Methods PCSK9 E670G, I474V, and R46L single nucleotide polymorphisms (SNPs) and plasma lipids were evaluated in 163 hypercholesterolemics (HC) and 171 normolipidemics (NL). HC patients with indication for cholesterol-lowering drug therapy (n = 128) were treated with atorvastatin (10 mg/d/4 wk). PCSK9 SNPs were analyzed by real time polymerase chain reaction. Results Frequencies of the PCSK9 SNPs were similar between the HC and NL groups. Logistic regression analysis showed a trend of association between PCSK9 E670G and hypercholesterolemia after adjustment for covariates ( P = .059). The 670G allele was associated with high basal levels of LDL cholesterol ( P = .03) in HC patients using the extreme discordant phenotype method. No association tests were performed for R46L variant because of its very low frequency, whereas the I474V polymorphism and PCSK9 haplotypes were not related to hypercholesterolemia or variability on plasma lipids in both NL and HC groups ( P > .05). LDL cholesterol reduction in response to atorvastatin was not influenced by PCSK9 genotypes or haplotypes. Conclusions PCSK9 E670G polymorphism but not I474V contributes to the variability on plasma LDL cholesterol levels in hypercholesterolemic subjects. Both PCSK9 variants have no influence on cholesterol-lowering response to atorvastatin. |
| doi_str_mv | 10.1016/j.jacl.2014.02.008 |
| format | Article |
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Functional variants in PCSK9 have been associated with differences in plasma lipids and may contribute to the variability of the response to cholesterol-lowering drugs. Objective To investigate the influence of PCSK9 variants on plasma lipid profile and response to atorvastatin in Brazilian subjects. Methods PCSK9 E670G, I474V, and R46L single nucleotide polymorphisms (SNPs) and plasma lipids were evaluated in 163 hypercholesterolemics (HC) and 171 normolipidemics (NL). HC patients with indication for cholesterol-lowering drug therapy (n = 128) were treated with atorvastatin (10 mg/d/4 wk). PCSK9 SNPs were analyzed by real time polymerase chain reaction. Results Frequencies of the PCSK9 SNPs were similar between the HC and NL groups. Logistic regression analysis showed a trend of association between PCSK9 E670G and hypercholesterolemia after adjustment for covariates ( P = .059). The 670G allele was associated with high basal levels of LDL cholesterol ( P = .03) in HC patients using the extreme discordant phenotype method. No association tests were performed for R46L variant because of its very low frequency, whereas the I474V polymorphism and PCSK9 haplotypes were not related to hypercholesterolemia or variability on plasma lipids in both NL and HC groups ( P > .05). LDL cholesterol reduction in response to atorvastatin was not influenced by PCSK9 genotypes or haplotypes. Conclusions PCSK9 E670G polymorphism but not I474V contributes to the variability on plasma LDL cholesterol levels in hypercholesterolemic subjects. Both PCSK9 variants have no influence on cholesterol-lowering response to atorvastatin.</description><identifier>ISSN: 1933-2874</identifier><identifier>EISSN: 1876-4789</identifier><identifier>DOI: 10.1016/j.jacl.2014.02.008</identifier><identifier>PMID: 24793346</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adult ; Aged ; Atorvastatin ; Atorvastatin Calcium ; Biomarkers, Pharmacological - metabolism ; Brazil ; Cardiovascular ; Cholesterol ; Cholesterol, LDL - metabolism ; Female ; Heptanoic Acids - administration & dosage ; Humans ; Hypercholesterolemia - drug therapy ; Hypercholesterolemia - genetics ; Hypercholesterolemia - metabolism ; Male ; Middle Aged ; Mutation - genetics ; Pharmacogenomics ; Polymorphism, Single Nucleotide ; Proprotein Convertase 9 ; Proprotein convertase subtilisin/kexin type 9 (PCSK9) ; Proprotein Convertases - genetics ; Proprotein Convertases - metabolism ; Pyrroles - administration & dosage ; Serine Endopeptidases - genetics ; Serine Endopeptidases - metabolism ; Single nucleotide polymorphism ; Treatment Outcome</subject><ispartof>Journal of clinical lipidology, 2014-05, Vol.8 (3), p.256-264</ispartof><rights>National Lipid Association</rights><rights>2014 National Lipid Association</rights><rights>Copyright © 2014 National Lipid Association. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c411t-1c4017754e66a842d40d4c1d9a45429a4d2c0ade41e86bd03c77d58c3b09c48c3</citedby><cites>FETCH-LOGICAL-c411t-1c4017754e66a842d40d4c1d9a45429a4d2c0ade41e86bd03c77d58c3b09c48c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1933287414000701$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24793346$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Anderson, Jacqueline M., PharmD</creatorcontrib><creatorcontrib>Cerda, Alvaro, PhD</creatorcontrib><creatorcontrib>Hirata, Mario H., PhD</creatorcontrib><creatorcontrib>Rodrigues, Alice C., PhD</creatorcontrib><creatorcontrib>Dorea, Egidio L., PhD</creatorcontrib><creatorcontrib>Bernik, Marcia M.S., PhD</creatorcontrib><creatorcontrib>Bertolami, Marcelo C., PhD</creatorcontrib><creatorcontrib>Faludi, Andre A., PhD</creatorcontrib><creatorcontrib>Hirata, Rosario D.C., PhD</creatorcontrib><title>Influence of PCSK9 polymorphisms on plasma lipids and response to atorvastatin treatment in Brazilian subjects</title><title>Journal of clinical lipidology</title><addtitle>J Clin Lipidol</addtitle><description>Background The proprotein convertase subtilisin/kexin type 9 (PCSK9) has a key role in the regulation of plasma low-density lipoprotein (LDL) cholesterol by enhancing the degradation of LDL receptor. Functional variants in PCSK9 have been associated with differences in plasma lipids and may contribute to the variability of the response to cholesterol-lowering drugs. Objective To investigate the influence of PCSK9 variants on plasma lipid profile and response to atorvastatin in Brazilian subjects. Methods PCSK9 E670G, I474V, and R46L single nucleotide polymorphisms (SNPs) and plasma lipids were evaluated in 163 hypercholesterolemics (HC) and 171 normolipidemics (NL). HC patients with indication for cholesterol-lowering drug therapy (n = 128) were treated with atorvastatin (10 mg/d/4 wk). PCSK9 SNPs were analyzed by real time polymerase chain reaction. Results Frequencies of the PCSK9 SNPs were similar between the HC and NL groups. Logistic regression analysis showed a trend of association between PCSK9 E670G and hypercholesterolemia after adjustment for covariates ( P = .059). The 670G allele was associated with high basal levels of LDL cholesterol ( P = .03) in HC patients using the extreme discordant phenotype method. No association tests were performed for R46L variant because of its very low frequency, whereas the I474V polymorphism and PCSK9 haplotypes were not related to hypercholesterolemia or variability on plasma lipids in both NL and HC groups ( P > .05). LDL cholesterol reduction in response to atorvastatin was not influenced by PCSK9 genotypes or haplotypes. Conclusions PCSK9 E670G polymorphism but not I474V contributes to the variability on plasma LDL cholesterol levels in hypercholesterolemic subjects. Both PCSK9 variants have no influence on cholesterol-lowering response to atorvastatin.</description><subject>Adult</subject><subject>Aged</subject><subject>Atorvastatin</subject><subject>Atorvastatin Calcium</subject><subject>Biomarkers, Pharmacological - metabolism</subject><subject>Brazil</subject><subject>Cardiovascular</subject><subject>Cholesterol</subject><subject>Cholesterol, LDL - metabolism</subject><subject>Female</subject><subject>Heptanoic Acids - administration & dosage</subject><subject>Humans</subject><subject>Hypercholesterolemia - drug therapy</subject><subject>Hypercholesterolemia - genetics</subject><subject>Hypercholesterolemia - metabolism</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mutation - genetics</subject><subject>Pharmacogenomics</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Proprotein Convertase 9</subject><subject>Proprotein convertase subtilisin/kexin type 9 (PCSK9)</subject><subject>Proprotein Convertases - genetics</subject><subject>Proprotein Convertases - metabolism</subject><subject>Pyrroles - administration & dosage</subject><subject>Serine Endopeptidases - genetics</subject><subject>Serine Endopeptidases - metabolism</subject><subject>Single nucleotide polymorphism</subject><subject>Treatment Outcome</subject><issn>1933-2874</issn><issn>1876-4789</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kV-L1TAQxYso7h_9Aj5IHn1pTdK0aUEE9-Lq4oLC6nPITeZiaprUTLpw_fSm3NUHH3yZmZBzDsxvquoFow2jrH89NZM2vuGUiYbyhtLhUXXOBtnXQg7j4zKPbVvzQYqz6gJxorTrJO2eVmdcyPIl-vMq3ISDXyEYIPFAvuzuPo1kif44x7R8dzgjiYEsXuOsiXeLs0h0sCQBLjEgkByJzjHda8w6u0ByAp1nCJmUx1XSv5x3OhBc9xOYjM-qJwftEZ4_9Mvq2_X7r7uP9e3nDze7d7e1EYzlmhlBmZSdgL7Xg-BWUCsMs6MWneClWm6otiAYDP3e0tZIabvBtHs6GlH6ZfXqlLuk-HMFzGp2aMB7HSCuqFjHWdu2sh2KlJ-kJkXEBAe1JDfrdFSMqo2zmtTGWW2cFeWqcC6mlw_5634G-9fyB2wRvDkJoGx57yApNG7DbF0qIJSN7v_5b_-xG--CM9r_gCPgFNcUCj_FFBaDutsuvR2aCUqppKz9DeEVpIc</recordid><startdate>201405</startdate><enddate>201405</enddate><creator>Anderson, Jacqueline M., PharmD</creator><creator>Cerda, Alvaro, PhD</creator><creator>Hirata, Mario H., PhD</creator><creator>Rodrigues, Alice C., PhD</creator><creator>Dorea, Egidio L., PhD</creator><creator>Bernik, Marcia M.S., PhD</creator><creator>Bertolami, Marcelo C., PhD</creator><creator>Faludi, Andre A., PhD</creator><creator>Hirata, Rosario D.C., PhD</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201405</creationdate><title>Influence of PCSK9 polymorphisms on plasma lipids and response to atorvastatin treatment in Brazilian subjects</title><author>Anderson, Jacqueline M., PharmD ; Cerda, Alvaro, PhD ; Hirata, Mario H., PhD ; Rodrigues, Alice C., PhD ; Dorea, Egidio L., PhD ; Bernik, Marcia M.S., PhD ; Bertolami, Marcelo C., PhD ; Faludi, Andre A., PhD ; Hirata, Rosario D.C., PhD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c411t-1c4017754e66a842d40d4c1d9a45429a4d2c0ade41e86bd03c77d58c3b09c48c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Atorvastatin</topic><topic>Atorvastatin Calcium</topic><topic>Biomarkers, Pharmacological - metabolism</topic><topic>Brazil</topic><topic>Cardiovascular</topic><topic>Cholesterol</topic><topic>Cholesterol, LDL - metabolism</topic><topic>Female</topic><topic>Heptanoic Acids - administration & dosage</topic><topic>Humans</topic><topic>Hypercholesterolemia - drug therapy</topic><topic>Hypercholesterolemia - genetics</topic><topic>Hypercholesterolemia - metabolism</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mutation - genetics</topic><topic>Pharmacogenomics</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Proprotein Convertase 9</topic><topic>Proprotein convertase subtilisin/kexin type 9 (PCSK9)</topic><topic>Proprotein Convertases - genetics</topic><topic>Proprotein Convertases - metabolism</topic><topic>Pyrroles - administration & dosage</topic><topic>Serine Endopeptidases - genetics</topic><topic>Serine Endopeptidases - metabolism</topic><topic>Single nucleotide polymorphism</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Anderson, Jacqueline M., PharmD</creatorcontrib><creatorcontrib>Cerda, Alvaro, PhD</creatorcontrib><creatorcontrib>Hirata, Mario H., PhD</creatorcontrib><creatorcontrib>Rodrigues, Alice C., PhD</creatorcontrib><creatorcontrib>Dorea, Egidio L., PhD</creatorcontrib><creatorcontrib>Bernik, Marcia M.S., PhD</creatorcontrib><creatorcontrib>Bertolami, Marcelo C., PhD</creatorcontrib><creatorcontrib>Faludi, Andre A., PhD</creatorcontrib><creatorcontrib>Hirata, Rosario D.C., PhD</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of clinical lipidology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Anderson, Jacqueline M., PharmD</au><au>Cerda, Alvaro, PhD</au><au>Hirata, Mario H., PhD</au><au>Rodrigues, Alice C., PhD</au><au>Dorea, Egidio L., PhD</au><au>Bernik, Marcia M.S., PhD</au><au>Bertolami, Marcelo C., PhD</au><au>Faludi, Andre A., PhD</au><au>Hirata, Rosario D.C., PhD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Influence of PCSK9 polymorphisms on plasma lipids and response to atorvastatin treatment in Brazilian subjects</atitle><jtitle>Journal of clinical lipidology</jtitle><addtitle>J Clin Lipidol</addtitle><date>2014-05</date><risdate>2014</risdate><volume>8</volume><issue>3</issue><spage>256</spage><epage>264</epage><pages>256-264</pages><issn>1933-2874</issn><eissn>1876-4789</eissn><abstract>Background The proprotein convertase subtilisin/kexin type 9 (PCSK9) has a key role in the regulation of plasma low-density lipoprotein (LDL) cholesterol by enhancing the degradation of LDL receptor. Functional variants in PCSK9 have been associated with differences in plasma lipids and may contribute to the variability of the response to cholesterol-lowering drugs. Objective To investigate the influence of PCSK9 variants on plasma lipid profile and response to atorvastatin in Brazilian subjects. Methods PCSK9 E670G, I474V, and R46L single nucleotide polymorphisms (SNPs) and plasma lipids were evaluated in 163 hypercholesterolemics (HC) and 171 normolipidemics (NL). HC patients with indication for cholesterol-lowering drug therapy (n = 128) were treated with atorvastatin (10 mg/d/4 wk). PCSK9 SNPs were analyzed by real time polymerase chain reaction. Results Frequencies of the PCSK9 SNPs were similar between the HC and NL groups. Logistic regression analysis showed a trend of association between PCSK9 E670G and hypercholesterolemia after adjustment for covariates ( P = .059). The 670G allele was associated with high basal levels of LDL cholesterol ( P = .03) in HC patients using the extreme discordant phenotype method. No association tests were performed for R46L variant because of its very low frequency, whereas the I474V polymorphism and PCSK9 haplotypes were not related to hypercholesterolemia or variability on plasma lipids in both NL and HC groups ( P > .05). LDL cholesterol reduction in response to atorvastatin was not influenced by PCSK9 genotypes or haplotypes. Conclusions PCSK9 E670G polymorphism but not I474V contributes to the variability on plasma LDL cholesterol levels in hypercholesterolemic subjects. Both PCSK9 variants have no influence on cholesterol-lowering response to atorvastatin.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24793346</pmid><doi>10.1016/j.jacl.2014.02.008</doi><tpages>9</tpages></addata></record> |
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| subjects | Adult Aged Atorvastatin Atorvastatin Calcium Biomarkers, Pharmacological - metabolism Brazil Cardiovascular Cholesterol Cholesterol, LDL - metabolism Female Heptanoic Acids - administration & dosage Humans Hypercholesterolemia - drug therapy Hypercholesterolemia - genetics Hypercholesterolemia - metabolism Male Middle Aged Mutation - genetics Pharmacogenomics Polymorphism, Single Nucleotide Proprotein Convertase 9 Proprotein convertase subtilisin/kexin type 9 (PCSK9) Proprotein Convertases - genetics Proprotein Convertases - metabolism Pyrroles - administration & dosage Serine Endopeptidases - genetics Serine Endopeptidases - metabolism Single nucleotide polymorphism Treatment Outcome |
| title | Influence of PCSK9 polymorphisms on plasma lipids and response to atorvastatin treatment in Brazilian subjects |
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