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深度覆盖全基因组序列和血浆脂蛋白(a)在欧洲和非洲血统个体。

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

机构信息

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.

Yale School of Medicine, New Haven, CT, 06510, USA.

出版信息

Nat Commun. 2018 Jul 4;9(1):2606. doi: 10.1038/s41467-018-04668-w.

DOI:10.1038/s41467-018-04668-w
PMID:29973585
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6031652/
Abstract

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.

摘要

脂蛋白(a)（Lp(a)）是一种经过修饰的低密度脂蛋白颗粒，含有载脂蛋白(a)（apolipoprotein(a)），由 LPA 编码，是一种高度遗传性的心血管疾病因果风险因素，其浓度在不同种族中存在差异。在这里，我们使用欧洲和非洲裔 8392 个人的深度覆盖全基因组测序来发现和解释与 Lp(a)相关的单核苷酸变异和拷贝数（CN）变异。我们观察到欧洲人和非洲人之间的遗传决定因素有几个独特的决定因素。与 Lp(a)胆固醇相关的常见变异 rs12740374 是 SORT1 的 eQTL，与 LDL 胆固醇无关。罕见非编码变异聚集的观察到的关联在很大程度上可以用 LPA 结构变异来解释，即 LPA 环 IV 2（KIV2）-CN。最后，我们发现与直接测量的 Lp(a)相比，LPA 风险基因型赋予了更大的动脉粥样硬化性心血管疾病发病相对风险，并且与非裔美国人亚临床动脉粥样硬化的测量值显著相关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/59b06a7a19de/41467_2018_4668_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/24a55bfa0705/41467_2018_4668_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/22d930037ba7/41467_2018_4668_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/439385e8458a/41467_2018_4668_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/43af458394c6/41467_2018_4668_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/07fd9f10527c/41467_2018_4668_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/5378771e97d2/41467_2018_4668_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/59b06a7a19de/41467_2018_4668_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/24a55bfa0705/41467_2018_4668_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/22d930037ba7/41467_2018_4668_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/439385e8458a/41467_2018_4668_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/43af458394c6/41467_2018_4668_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/07fd9f10527c/41467_2018_4668_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/5378771e97d2/41467_2018_4668_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5803/6031652/59b06a7a19de/41467_2018_4668_Fig7_HTML.jpg

相似文献

[1]
Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Nat Commun. 2018-7-4

[2]
Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans.

PLoS One. 2011-1-24

[3]
LPA and PLG sequence variation and kringle IV-2 copy number in two populations.

Hum Hered. 2008

[4]
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J Hum Genet. 2015-12

[5]
Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European Americans.

J Med Genet. 2006-12

[6]
A novel but frequent variant in LPA KIV-2 is associated with a pronounced Lp(a) and cardiovascular risk reduction.

Eur Heart J. 2017-6-14

[7]
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[8]
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[9]
Admixture mapping of quantitative trait loci for blood lipids in African-Americans.

Hum Mol Genet. 2009-6-1

[10]
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本文引用的文献

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Am J Hum Genet. 2017-2-2

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Nat Neurosci. 2016-12

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Am J Hum Genet. 2016-10-6

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