血清植物甾醇水平的遗传调控与冠状动脉疾病风险

Genetic regulation of serum phytosterol levels and risk of coronary artery disease.

作者信息

Teupser Daniel, Baber Ronny, Ceglarek Uta, Scholz Markus, Illig Thomas, Gieger Christian, Holdt Lesca M, Leichtle Alexander, Greiser Karin H, Huster Dominik, Linsel-Nitschke Patrick, Schäfer Arne, Braund Peter S, Tiret Laurence, Stark Klaus, Raaz-Schrauder Dorette, Fiedler Georg M, Wilfert Wolfgang, Beutner Frank, Gielen Stephan, Grosshennig Anika, König Inke R, Lichtner Peter, Heid Iris M, Kluttig Alexander, El Mokhtari Nour E, Rubin Diana, Ekici Arif B, Reis André, Garlichs Christoph D, Hall Alistair S, Matthes Gert, Wittekind Christian, Hengstenberg Christian, Cambien Francois, Schreiber Stefan, Werdan Karl, Meitinger Thomas, Loeffler Markus, Samani Nilesh J, Erdmann Jeanette, Wichmann H-Erich, Schunkert Heribert, Thiery Joachim

机构信息

Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig, Germany.

出版信息

Circ Cardiovasc Genet. 2010 Aug;3(4):331-9. doi: 10.1161/CIRCGENETICS.109.907873. Epub 2010 Jun 7.

DOI:10.1161/CIRCGENETICS.109.907873

PMID:20529992

Abstract

BACKGROUND

Phytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD).

METHODS AND RESULTS

A genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P=1.6 x 10(-50) and 6.2 x 10(-25), respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P=0.009). Effects at the ABO locus were related to SNP rs657152 (combined P=9.4x10(-13)). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P=2.2 x 10(-6); rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4 x 10(-6)), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P=1.3 x 10(-5)).

CONCLUSION

Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.

摘要

背景

植物甾醇是从食物中摄取的植物源性甾醇，可作为胆固醇摄取的生物标志物。血清水平受到严格的基因控制。我们采用基因组方法研究血清植物甾醇水平的分子调控及其与冠状动脉疾病（CAD）的潜在联系。

方法与结果

在来自奥格斯堡地区合作研究（KORA）的基于人群的样本（n = 1495）中进行了血清植物甾醇（菜油甾醇、甾烷醇、油菜甾醇）的全基因组关联研究，随后在另外两个样本（n = 1157和n = 1760）中进行重复验证。在对11个不同样本（包括13764例CAD病例和13630例健康对照）的荟萃分析中，对重复的单核苷酸多态性（SNP）进行了与早发CAD的关联测试。ATP结合半转运体ABCG8和血型ABO位点的基因变异与血清植物甾醇显著相关。ABCG8中的效应独立于SNP rs4245791和rs41360247（联合P值分别为1.6×10⁻⁵⁰和6.2×10⁻²⁵；n = 4412）。rs4245791的每个T等位基因使血清菜油甾醇升高12%。相同的等位基因与肝脏ABCG8 mRNA表达降低40%相关（P = 0.009）。ABO位点的效应与SNP rs657152相关（联合P值 = 9.4×10⁻¹³）。与植物甾醇水平升高相关的ABCG8和ABO等位基因与CAD风险增加显著相关（rs4245791比值比，1.10；95%可信区间，1.06至1.14；P = 2.2×10⁻⁶；rs657152比值比，1.13；95%可信区间，1.07至1.19；P = 9.4×10⁻⁶），而与植物甾醇水平降低相关的ABCG8等位基因与CAD风险降低相关（rs41360247比值比，0.84；95%可信区间，0.78至0.91；P = 1.3×10⁻⁵）。