Yara Azar , Thomas E. Ludwig , Hugo Le Bon , Thea Bismo Strøm , Olivier Bluteau , Mathilde Di-Filippo , Alain Carrié , Hedi Chtioui , Sophie Béliard , Oriane Marmontel , Annie Fonteille , Maite Gebhart , Noël Peretti , Philippe Moulin , Jean Ferrières , Alain Pradignac , Michel Farnier , Antonio Gallo , Cécile Yelnik , Dirk Blom , Mathilde Varret
{"title":"独特的法国 PCSK9-p.Ser127Arg 功能增益变体：775年前共同祖先胆固醇水平的重要影响因素","authors":"Yara Azar , Thomas E. Ludwig , Hugo Le Bon , Thea Bismo Strøm , Olivier Bluteau , Mathilde Di-Filippo , Alain Carrié , Hedi Chtioui , Sophie Béliard , Oriane Marmontel , Annie Fonteille , Maite Gebhart , Noël Peretti , Philippe Moulin , Jean Ferrières , Alain Pradignac , Michel Farnier , Antonio Gallo , Cécile Yelnik , Dirk Blom , Mathilde Varret","doi":"10.1016/j.atherosclerosis.2024.118596","DOIUrl":null,"url":null,"abstract":"<div><h3>Background and aims</h3><div>PCSK9 is a key regulator of LDL-cholesterol levels. PCSK9 gain of function variants (GOFVs) cause autosomal dominant hypercholesterolemia (ADH). The first described PCSK9-GOFV, p.Ser127Arg, almost exclusively reported in France, represents 67 % of the PCSK9 French GOFVs due to a founder effect. Few other carriers are reported in South Africa and Norway. This study aims to estimate when the common ancestor lived and to describe a cohort of p.Ser127Arg carriers.</div></div><div><h3>Methods</h3><div>Eight families and 14 p.Ser127Arg carriers were genotyped and phenotyped. Haplotypes were constructed using 11 microsatellites around <em>PCSK9</em> and 6 intragenic single nucleotide polymorphisms (SNPs). To add to the biological analysis, eight additional p.Ser127Arg carriers, 12 carriers of other PCSK9-GOFVs, 93 LDLR loss of function variant (LOFV) carriers and 49 non-carriers subjects were phenotyped.</div></div><div><h3>Results</h3><div>The most common ancestor of p.Ser127Arg was estimated to have lived 775 years ago [95 % CI: 575-1075]. French Protestants exiled after the revocation of the Edict of Nantes in 1685 AD likely brought the variant to South Africa and Norway. As expected for ADH subjects, carriers of LDLR-LOFV, the p.Ser127Arg, or other PCSK9-GOFVs showed significantly higher LDL-C levels than that of the non-carriers. Interestingly, LDL-C levels are higher for LDLR-LOFVs and for the reduced secreted p.Ser127Arg than for secreted PCSK9-GOFVs, suggesting a greater effect of the p.Ser127Arg. Conversely, HDL-C was significantly lower for LDLR-LOFV and p.Ser127Arg carriers.</div></div><div><h3>Conclusions</h3><div>This first report from a large cohort of PCSK9-p.Ser127Arg carriers provides observations suggesting a stronger hypercholesterolemic potential of the mutated pro-PCSK9 compared with the secreted mature protein. This work also provides additional data to support the association between PCSK9 and HDL metabolism, and molecular evidence that this variant appeared in France around 1248 <span>AD (Graphical Abstract = Fig. 1)</span>.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":null,"pages":null},"PeriodicalIF":4.9000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The singular French PCSK9-p.Ser127Arg gain-of-function variant: A significant player in cholesterol levels from a 775-year-old common ancestor\",\"authors\":\"Yara Azar , Thomas E. Ludwig , Hugo Le Bon , Thea Bismo Strøm , Olivier Bluteau , Mathilde Di-Filippo , Alain Carrié , Hedi Chtioui , Sophie Béliard , Oriane Marmontel , Annie Fonteille , Maite Gebhart , Noël Peretti , Philippe Moulin , Jean Ferrières , Alain Pradignac , Michel Farnier , Antonio Gallo , Cécile Yelnik , Dirk Blom , Mathilde Varret\",\"doi\":\"10.1016/j.atherosclerosis.2024.118596\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background and aims</h3><div>PCSK9 is a key regulator of LDL-cholesterol levels. PCSK9 gain of function variants (GOFVs) cause autosomal dominant hypercholesterolemia (ADH). The first described PCSK9-GOFV, p.Ser127Arg, almost exclusively reported in France, represents 67 % of the PCSK9 French GOFVs due to a founder effect. Few other carriers are reported in South Africa and Norway. This study aims to estimate when the common ancestor lived and to describe a cohort of p.Ser127Arg carriers.</div></div><div><h3>Methods</h3><div>Eight families and 14 p.Ser127Arg carriers were genotyped and phenotyped. Haplotypes were constructed using 11 microsatellites around <em>PCSK9</em> and 6 intragenic single nucleotide polymorphisms (SNPs). To add to the biological analysis, eight additional p.Ser127Arg carriers, 12 carriers of other PCSK9-GOFVs, 93 LDLR loss of function variant (LOFV) carriers and 49 non-carriers subjects were phenotyped.</div></div><div><h3>Results</h3><div>The most common ancestor of p.Ser127Arg was estimated to have lived 775 years ago [95 % CI: 575-1075]. French Protestants exiled after the revocation of the Edict of Nantes in 1685 AD likely brought the variant to South Africa and Norway. As expected for ADH subjects, carriers of LDLR-LOFV, the p.Ser127Arg, or other PCSK9-GOFVs showed significantly higher LDL-C levels than that of the non-carriers. Interestingly, LDL-C levels are higher for LDLR-LOFVs and for the reduced secreted p.Ser127Arg than for secreted PCSK9-GOFVs, suggesting a greater effect of the p.Ser127Arg. Conversely, HDL-C was significantly lower for LDLR-LOFV and p.Ser127Arg carriers.</div></div><div><h3>Conclusions</h3><div>This first report from a large cohort of PCSK9-p.Ser127Arg carriers provides observations suggesting a stronger hypercholesterolemic potential of the mutated pro-PCSK9 compared with the secreted mature protein. 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The singular French PCSK9-p.Ser127Arg gain-of-function variant: A significant player in cholesterol levels from a 775-year-old common ancestor
Background and aims
PCSK9 is a key regulator of LDL-cholesterol levels. PCSK9 gain of function variants (GOFVs) cause autosomal dominant hypercholesterolemia (ADH). The first described PCSK9-GOFV, p.Ser127Arg, almost exclusively reported in France, represents 67 % of the PCSK9 French GOFVs due to a founder effect. Few other carriers are reported in South Africa and Norway. This study aims to estimate when the common ancestor lived and to describe a cohort of p.Ser127Arg carriers.
Methods
Eight families and 14 p.Ser127Arg carriers were genotyped and phenotyped. Haplotypes were constructed using 11 microsatellites around PCSK9 and 6 intragenic single nucleotide polymorphisms (SNPs). To add to the biological analysis, eight additional p.Ser127Arg carriers, 12 carriers of other PCSK9-GOFVs, 93 LDLR loss of function variant (LOFV) carriers and 49 non-carriers subjects were phenotyped.
Results
The most common ancestor of p.Ser127Arg was estimated to have lived 775 years ago [95 % CI: 575-1075]. French Protestants exiled after the revocation of the Edict of Nantes in 1685 AD likely brought the variant to South Africa and Norway. As expected for ADH subjects, carriers of LDLR-LOFV, the p.Ser127Arg, or other PCSK9-GOFVs showed significantly higher LDL-C levels than that of the non-carriers. Interestingly, LDL-C levels are higher for LDLR-LOFVs and for the reduced secreted p.Ser127Arg than for secreted PCSK9-GOFVs, suggesting a greater effect of the p.Ser127Arg. Conversely, HDL-C was significantly lower for LDLR-LOFV and p.Ser127Arg carriers.
Conclusions
This first report from a large cohort of PCSK9-p.Ser127Arg carriers provides observations suggesting a stronger hypercholesterolemic potential of the mutated pro-PCSK9 compared with the secreted mature protein. This work also provides additional data to support the association between PCSK9 and HDL metabolism, and molecular evidence that this variant appeared in France around 1248 AD (Graphical Abstract = Fig. 1).
期刊介绍：
Atherosclerosis has an open access mirror journal Atherosclerosis: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review.
Atherosclerosis brings together, from all sources, papers concerned with investigation on atherosclerosis, its risk factors and clinical manifestations. Atherosclerosis covers basic and translational, clinical and population research approaches to arterial and vascular biology and disease, as well as their risk factors including: disturbances of lipid and lipoprotein metabolism, diabetes and hypertension, thrombosis, and inflammation. The Editors are interested in original or review papers dealing with the pathogenesis, environmental, genetic and epigenetic basis, diagnosis or treatment of atherosclerosis and related diseases as well as their risk factors.
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