Most epidemiologic studies of the role of HDL in atherosclerosis have emphasized HDL levels, but there is increasing evidence that HDL functioning may be critically important as well. It is clear that HDL from different individuals can differ strikingly in both structural and functional characteristics. In particular, there is evidence that HDL can lose its well-documented atheroprotective characteristics and even become pro-inflammatory. Studies of HDL function in humans are complicated by genetic heterogeneity and environmental factors. We propose to identify novel genes and pathways contributing to HDL functions using naturally occurring variations among inbred strains of mice. Two broad classes of HDL functioning will be examined. The first has to do with lipid transport, and particularly """"""""reverse cholesterol transport"""""""", and the second with anti-inflammatory and antioxidant properties of HDL. In preliminary studies, we have discovered large variations among inbred strains in both lipid transport functions and anti-inflammatory functions. The underlying genes and pathways will be identified using novel strategies capable of high-resolution genetic mapping and a systems-based approach that integrates genetics, gene expression and clinical traits. In contrast to classical linkage mapping in mice, our novel, association- based approach allows direct identification of likely candidate genes. We also utilize mathematical analyses to model causal relationships and entire gene networks. To validate candidate genes and pathways, we will employ a variety of in vitro and in vivo approaches, including cultured hepatocytes, transgenic mice, and gene targeted mice.
to Public Health: HDL functions as well as levels are important in conferring protection against atherosclerosis. This study will define the genetic functions and pathways affecting the HDL functions using experimental mouse models.
|Civelek, Mete; Lusis, Aldons J (2014) Systems genetics approaches to understand complex traits. Nat Rev Genet 15:34-48|
|Emert, Benjamin; Hasin-Brumshtein, Yehudit; Springstead, James R et al. (2014) HDL inhibits the effects of oxidized phospholipids on endothelial cell gene expression via multiple mechanisms. J Lipid Res 55:1678-92|
|Koeth, Robert A; Levison, Bruce S; Culley, Miranda K et al. (2014) Î³-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab 20:799-812|
|Shih, Diana M; Shaposhnik, Zory; Meng, Yonghong et al. (2013) Hyodeoxycholic acid improves HDL function and inhibits atherosclerotic lesion formation in LDLR-knockout mice. FASEB J 27:3805-17|
|Huang, Ying; Wu, Zhiping; Riwanto, Meliana et al. (2013) Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex. J Clin Invest 123:3815-28|
|van Nas, Atila; Pan, Calvin; Ingram-Drake, Leslie A et al. (2013) The systems genetics resource: a web application to mine global data for complex disease traits. Front Genet 4:84|
|Bennett, Brian J; de Aguiar Vallim, Thomas Q; Wang, Zeneng et al. (2013) Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 17:49-60|
|Martin, Lisa J; Lau, Edward; Singh, Harpreet et al. (2012) ABCC6 localizes to the mitochondria-associated membrane. Circ Res 111:516-20|
|Johansen, Christopher T; Wang, Jian; McIntyre, Adam D et al. (2012) Excess of rare variants in non-genome-wide association study candidate genes in patients with hypertriglyceridemia. Circ Cardiovasc Genet 5:66-72|
|Lusis, Aldons J (2012) Genetics of atherosclerosis. Trends Genet 28:267-75|
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