Identification of genetic drivers of plasma lipoprotein size in the Diversity Outbred mouse population.
Identification of genetic drivers of plasma lipoprotein size in the Diversity Outbred mouse population.
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DOI：
10.1016/j.jlr.2023.100471
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发表时间：
2023-12
影响因子：
6.5
通讯作者：
Attie, Alan D.
中科院分区：
文献类型：
--
作者：
Price, Tara R.;Emfinger, Christopher H.;Schueler, Kathryn L.;King, Sarah;Nicholson, Rebekah;Beck, Tim;Yandell, Brian S.;Summers, Scott A.;Holland, William L.;Krauss, Ronald M.;Keller, Mark P.;Attie, Alan D.
尽管在了解脂蛋白生理学方面取得了很大进展，但关于脂蛋白丰度、组成和功能的遗传驱动因素仍有很多需要了解。我们用离子迁移谱法测定了500只维持西式饮食的多样性近交系小鼠的16个血浆脂蛋白亚组分。我们鉴定出21个影响脂蛋白丰度的数量性状位点（QTL）。为了完善QTL并将它们与人类疾病风险联系起来，我们在人类全基因组关联研究中询问了位于每个QTL上的基因的人类同源物是否与脂质性状相关。将小鼠QTL与人类全基因组关联研究整合，获得了21个QTL中18个的候选基因驱动。这种方法使我们能够指定编码中性神经酰胺酶Asah2的基因作为19号染色体上大HDL颗粒（HDL-2b） QTL的新候选驱动因子。为了实验验证Asah2，我们研究了Asah2−/−小鼠的脂蛋白。与野生型小鼠相比，雌性Asah2−/−小鼠显示出几种脂蛋白的增加，包括HDL。我们的研究结果为循环脂蛋白的遗传调控以及脂蛋白亚组分可能影响人类心血管疾病风险的机制提供了见解。
Despite great progress in understanding lipoprotein physiology, there is still much to be learned about the genetic drivers of lipoprotein abundance, composition, and function. We used ion mobility spectrometry to survey 16 plasma lipoprotein subfractions in 500 Diversity Outbred mice maintained on a Western-style diet. We identified 21 quantitative trait loci (QTL) affecting lipoprotein abundance. To refine the QTL and link them to disease risk in humans, we asked if the human homologs of genes located at each QTL were associated with lipid traits in human genome-wide association studies. Integration of mouse QTL with human genome-wide association studies yielded candidate gene drivers for 18 of the 21 QTL. This approach enabled us to nominate the gene encoding the neutral ceramidase, Asah2, as a novel candidate driver at a QTL on chromosome 19 for large HDL particles (HDL-2b). To experimentally validate Asah2, we surveyed lipoproteins in Asah2−/− mice. Compared to wild-type mice, female Asah2−/− mice showed an increase in several lipoproteins, including HDL. Our results provide insights into the genetic regulation of circulating lipoproteins, as well as mechanisms by which lipoprotein subfractions may affect cardiovascular disease risk in humans.
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影响因子：
3.7
作者：
Ong WY;Ng MP;Loke SY;Jin S;Wu YJ;Tanaka K;Wong PT
通讯作者：
Wong PT
DOI：
10.1096/fj.202000194r
发表时间：
2020-06
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
de Conti A;Tryndyak V;Willett RA;Borowa-Mazgaj B;Watson A;Patton R;Khare S;Muskhelishvili L;Olson GR;Avigan MI;Cerniglia CE;Ross SA;Sanyal AJ;Beland FA;Rusyn I;Pogribny IP
通讯作者：
Pogribny IP
DOI：
10.1002/hep.31628
发表时间：
2021-03
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Gu X;Sun R;Chen L;Chu S;Doll MA;Li X;Feng W;Siskind L;McClain CJ;Deng Z
通讯作者：
Deng Z
影响因子：
6.5
作者：
Flowers, Matthew T.;Groen, Albert K.;Attie, Alan D.
通讯作者：
Attie, Alan D.
影响因子：
4.6
作者：
Kim M;Huda MN;Evans LW;Que E;Gertz ER;Maeda-Smithies N;Bennett BJ
通讯作者：
Bennett BJ