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

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis Pub Date : 2024-09-13 DOI:10.1016/j.atherosclerosis.2024.118596

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

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引用次数: 0

摘要

背景和目的PCSK9是低密度脂蛋白胆固醇水平的关键调节因子。PCSK9 功能增益变异（GOFV）会导致常染色体显性高胆固醇血症（ADH）。第一个描述的 PCSK9-GOFV 是 p.Ser127Arg，几乎只在法国有报道，由于创始人效应，它占 PCSK9 法国 GOFV 的 67%。南非和挪威很少有其他携带者的报道。本研究旨在估计共同祖先的生活时间，并描述 p.Ser127Arg 携带者的队列。方法对 8 个家庭和 14 个 p.Ser127Arg 携带者进行了基因分型和表型分析。利用 PCSK9 周围的 11 个微卫星和 6 个基因内单核苷酸多态性 (SNP) 构建了单倍型。为了补充生物学分析，还对另外 8 名 p.Ser127Arg 携带者、12 名其他 PCSK9-GOFVs 携带者、93 名 LDLR 功能缺失变异体 (LOFV) 携带者和 49 名非携带者进行了表型分析。结果p.Ser127Arg 的最常见祖先估计生活在 775 年前[95 % CI：575-1075]。公元1685年南特敕令废除后流亡的法国新教徒很可能将该变异体带到了南非和挪威。正如 ADH 受试者所预期的那样，LDLR-LOFV、p.Ser127Arg 或其他 PCSK9-GOFV 携带者的低密度脂蛋白胆固醇水平明显高于非携带者。有趣的是，与分泌型 PCSK9-GOFV 相比，LDLR-LOFV 和分泌减少的 p.Ser127Arg 的 LDL-C 水平更高，这表明 p.Ser127Arg 的作用更大。结论这是对一大群 PCSK9-p.Ser127Arg 携带者的首次报道，观察结果表明，与分泌型成熟蛋白相比，突变的原 PCSK9 具有更强的高胆固醇血症潜力。这项研究还提供了更多数据，支持 PCSK9 与高密度脂蛋白代谢之间的联系，并提供了分子证据，证明该变异体在公元 1248 年左右出现在法国（图解摘要 = 图 1）。

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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).

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来源期刊

Atherosclerosis 医学-外周血管病

CiteScore

9.80

自引率

3.80%

发文量

1269

审稿时长

36 days

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.