The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans
Atherosclerotic cardiovascular disease (ASCVD) affects more than 1 in 3 American adults. Hypercholesterolemia is a major treatable risk factor for ASCVD, yet many individuals fail to reach target levels of LDL-cholesterol (LDL-C) through the use of statins and lifestyle changes. The E3 ubiquitin lig...
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| Veröffentlicht in: | The Journal of clinical investigation 2011-08, Vol.121 (8), p.3062-3071 |
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| creator | Weissglas-Volkov, Daphna Calkin, Anna C Tusie-Luna, Teresa Sinsheimer, Janet S Zelcer, Noam Riba, Laura Tino, Ana Maria Vargas Ordoñez-Sánchez, Maria Luisa Cruz-Bautista, Ivette Aguilar-Salinas, Carlos A Tontonoz, Peter Pajukanta, Päivi |
| description | Atherosclerotic cardiovascular disease (ASCVD) affects more than 1 in 3 American adults. Hypercholesterolemia is a major treatable risk factor for ASCVD, yet many individuals fail to reach target levels of LDL-cholesterol (LDL-C) through the use of statins and lifestyle changes. The E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP; also known as IDOL) is a recently identified regulator of the LDL receptor (LDLR) pathway. Genome-wide association studies (GWASs) in populations of mixed European descent have identified noncoding variants in the MYLIP region as being associated with LDL-C levels, but no underlying functional variants were pinpointed. In order to fine-map actual susceptibility variants, we studied a population demographically distinct from the discovery population to ensure a different pattern of linkage disequilibrium. Our analysis revealed that in a Mexican population, the nonsynonymous SNP rs9370867, which encodes the N342S amino acid substitution, is an underlying functional variant that was associated with high total cholesterol and accounted for one of the previous significant GWAS signals. Functional characterization showed that the Asn-encoding allele was associated with more potent LDLR degradation and decreased LDL uptake. Mutagenesis of residue 342 failed to affect intrinsic MYLIP E3 ligase activity, but it was critical for LDLR targeting. Our findings suggest that modulation of MYLIP activity can affect LDL-C levels and that pharmacologic inhibition of MYLIP activity might be a useful strategy in the treatment of dyslipidemia and ASCVD. |
| doi_str_mv | 10.1172/JCI45504 |
| format | Article |
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Hypercholesterolemia is a major treatable risk factor for ASCVD, yet many individuals fail to reach target levels of LDL-cholesterol (LDL-C) through the use of statins and lifestyle changes. The E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP; also known as IDOL) is a recently identified regulator of the LDL receptor (LDLR) pathway. Genome-wide association studies (GWASs) in populations of mixed European descent have identified noncoding variants in the MYLIP region as being associated with LDL-C levels, but no underlying functional variants were pinpointed. In order to fine-map actual susceptibility variants, we studied a population demographically distinct from the discovery population to ensure a different pattern of linkage disequilibrium. Our analysis revealed that in a Mexican population, the nonsynonymous SNP rs9370867, which encodes the N342S amino acid substitution, is an underlying functional variant that was associated with high total cholesterol and accounted for one of the previous significant GWAS signals. Functional characterization showed that the Asn-encoding allele was associated with more potent LDLR degradation and decreased LDL uptake. Mutagenesis of residue 342 failed to affect intrinsic MYLIP E3 ligase activity, but it was critical for LDLR targeting. Our findings suggest that modulation of MYLIP activity can affect LDL-C levels and that pharmacologic inhibition of MYLIP activity might be a useful strategy in the treatment of dyslipidemia and ASCVD.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI45504</identifier><identifier>PMID: 21765216</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Amino acids ; Atherosclerosis ; Biomedical research ; Cardiovascular disease ; Cardiovascular diseases ; Cholesterol ; Cholesterol - metabolism ; Complications and side effects ; Dyslipidemias - metabolism ; Genetic aspects ; Genetic Variation ; Genome-Wide Association Study ; Genomes ; Heterozygote ; Humans ; Hypercholesterolemia ; Linkage Disequilibrium ; Lipids ; Low density lipoprotein receptors ; Low density lipoproteins ; Metabolic disorders ; Mexico ; Mutagenesis ; Mutation ; Physiological aspects ; Polymorphism, Genetic ; Population ; Proteins ; Receptors, LDL - genetics ; Receptors, LDL - metabolism ; Risk Factors ; Sequence Analysis, DNA ; Single nucleotide polymorphisms ; Statins ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism</subject><ispartof>The Journal of clinical investigation, 2011-08, Vol.121 (8), p.3062-3071</ispartof><rights>COPYRIGHT 2011 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Aug 2011</rights><rights>Copyright © 2011, American Society for Clinical Investigation 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c602t-892b14c5831aebb7432c313a1513c5daf63fa9a11be00420766881952dc8f3fa3</citedby><cites>FETCH-LOGICAL-c602t-892b14c5831aebb7432c313a1513c5daf63fa9a11be00420766881952dc8f3fa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148733/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148733/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21765216$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Weissglas-Volkov, Daphna</creatorcontrib><creatorcontrib>Calkin, Anna C</creatorcontrib><creatorcontrib>Tusie-Luna, Teresa</creatorcontrib><creatorcontrib>Sinsheimer, Janet S</creatorcontrib><creatorcontrib>Zelcer, Noam</creatorcontrib><creatorcontrib>Riba, Laura</creatorcontrib><creatorcontrib>Tino, Ana Maria Vargas</creatorcontrib><creatorcontrib>Ordoñez-Sánchez, Maria Luisa</creatorcontrib><creatorcontrib>Cruz-Bautista, Ivette</creatorcontrib><creatorcontrib>Aguilar-Salinas, Carlos A</creatorcontrib><creatorcontrib>Tontonoz, Peter</creatorcontrib><creatorcontrib>Pajukanta, Päivi</creatorcontrib><title>The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Atherosclerotic cardiovascular disease (ASCVD) affects more than 1 in 3 American adults. Hypercholesterolemia is a major treatable risk factor for ASCVD, yet many individuals fail to reach target levels of LDL-cholesterol (LDL-C) through the use of statins and lifestyle changes. The E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP; also known as IDOL) is a recently identified regulator of the LDL receptor (LDLR) pathway. Genome-wide association studies (GWASs) in populations of mixed European descent have identified noncoding variants in the MYLIP region as being associated with LDL-C levels, but no underlying functional variants were pinpointed. In order to fine-map actual susceptibility variants, we studied a population demographically distinct from the discovery population to ensure a different pattern of linkage disequilibrium. Our analysis revealed that in a Mexican population, the nonsynonymous SNP rs9370867, which encodes the N342S amino acid substitution, is an underlying functional variant that was associated with high total cholesterol and accounted for one of the previous significant GWAS signals. Functional characterization showed that the Asn-encoding allele was associated with more potent LDLR degradation and decreased LDL uptake. Mutagenesis of residue 342 failed to affect intrinsic MYLIP E3 ligase activity, but it was critical for LDLR targeting. Our findings suggest that modulation of MYLIP activity can affect LDL-C levels and that pharmacologic inhibition of MYLIP activity might be a useful strategy in the treatment of dyslipidemia and ASCVD.</description><subject>Amino acids</subject><subject>Atherosclerosis</subject><subject>Biomedical research</subject><subject>Cardiovascular disease</subject><subject>Cardiovascular diseases</subject><subject>Cholesterol</subject><subject>Cholesterol - metabolism</subject><subject>Complications and side effects</subject><subject>Dyslipidemias - metabolism</subject><subject>Genetic aspects</subject><subject>Genetic Variation</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Hypercholesterolemia</subject><subject>Linkage Disequilibrium</subject><subject>Lipids</subject><subject>Low density lipoprotein receptors</subject><subject>Low density lipoproteins</subject><subject>Metabolic disorders</subject><subject>Mexico</subject><subject>Mutagenesis</subject><subject>Mutation</subject><subject>Physiological aspects</subject><subject>Polymorphism, Genetic</subject><subject>Population</subject><subject>Proteins</subject><subject>Receptors, LDL - genetics</subject><subject>Receptors, LDL - metabolism</subject><subject>Risk Factors</subject><subject>Sequence Analysis, DNA</subject><subject>Single nucleotide polymorphisms</subject><subject>Statins</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Ubiquitin-Protein Ligases - 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MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans</title><author>Weissglas-Volkov, Daphna ; Calkin, Anna C ; Tusie-Luna, Teresa ; Sinsheimer, Janet S ; Zelcer, Noam ; Riba, Laura ; Tino, Ana Maria Vargas ; Ordoñez-Sánchez, Maria Luisa ; Cruz-Bautista, Ivette ; Aguilar-Salinas, Carlos A ; Tontonoz, Peter ; Pajukanta, Päivi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c602t-892b14c5831aebb7432c313a1513c5daf63fa9a11be00420766881952dc8f3fa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Amino acids</topic><topic>Atherosclerosis</topic><topic>Biomedical research</topic><topic>Cardiovascular disease</topic><topic>Cardiovascular diseases</topic><topic>Cholesterol</topic><topic>Cholesterol - metabolism</topic><topic>Complications and side effects</topic><topic>Dyslipidemias - metabolism</topic><topic>Genetic aspects</topic><topic>Genetic Variation</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Heterozygote</topic><topic>Humans</topic><topic>Hypercholesterolemia</topic><topic>Linkage Disequilibrium</topic><topic>Lipids</topic><topic>Low density lipoprotein receptors</topic><topic>Low density lipoproteins</topic><topic>Metabolic disorders</topic><topic>Mexico</topic><topic>Mutagenesis</topic><topic>Mutation</topic><topic>Physiological aspects</topic><topic>Polymorphism, Genetic</topic><topic>Population</topic><topic>Proteins</topic><topic>Receptors, LDL - genetics</topic><topic>Receptors, LDL - metabolism</topic><topic>Risk Factors</topic><topic>Sequence Analysis, DNA</topic><topic>Single nucleotide polymorphisms</topic><topic>Statins</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Weissglas-Volkov, 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Hypercholesterolemia is a major treatable risk factor for ASCVD, yet many individuals fail to reach target levels of LDL-cholesterol (LDL-C) through the use of statins and lifestyle changes. The E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP; also known as IDOL) is a recently identified regulator of the LDL receptor (LDLR) pathway. Genome-wide association studies (GWASs) in populations of mixed European descent have identified noncoding variants in the MYLIP region as being associated with LDL-C levels, but no underlying functional variants were pinpointed. In order to fine-map actual susceptibility variants, we studied a population demographically distinct from the discovery population to ensure a different pattern of linkage disequilibrium. Our analysis revealed that in a Mexican population, the nonsynonymous SNP rs9370867, which encodes the N342S amino acid substitution, is an underlying functional variant that was associated with high total cholesterol and accounted for one of the previous significant GWAS signals. Functional characterization showed that the Asn-encoding allele was associated with more potent LDLR degradation and decreased LDL uptake. Mutagenesis of residue 342 failed to affect intrinsic MYLIP E3 ligase activity, but it was critical for LDLR targeting. Our findings suggest that modulation of MYLIP activity can affect LDL-C levels and that pharmacologic inhibition of MYLIP activity might be a useful strategy in the treatment of dyslipidemia and ASCVD.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>21765216</pmid><doi>10.1172/JCI45504</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | Journals@Ovid Ovid Autoload; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Amino acids Atherosclerosis Biomedical research Cardiovascular disease Cardiovascular diseases Cholesterol Cholesterol - metabolism Complications and side effects Dyslipidemias - metabolism Genetic aspects Genetic Variation Genome-Wide Association Study Genomes Heterozygote Humans Hypercholesterolemia Linkage Disequilibrium Lipids Low density lipoprotein receptors Low density lipoproteins Metabolic disorders Mexico Mutagenesis Mutation Physiological aspects Polymorphism, Genetic Population Proteins Receptors, LDL - genetics Receptors, LDL - metabolism Risk Factors Sequence Analysis, DNA Single nucleotide polymorphisms Statins Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism |
| title | The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans |
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