An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia.
An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia.
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DOI：
10.1161/atvbaha.111.226365
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发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Hegele RA
中科院分区：
文献类型：
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作者：
Johansen CT;Wang J;Lanktree MB;McIntyre AD;Ban MR;Martins RA;Kennedy BA;Hassell RG;Visser ME;Schwartz SM;Voight BF;Elosua R;Salomaa V;O'Donnell CJ;Dallinga-Thie GM;Anand SS;Yusuf S;Huff MW;Kathiresan S;Cao H;Hegele RA
早期的研究表明，一个共同的遗传结构的基础上的临床异质性多基因弗雷德里克森高脂蛋白血症（HLP）的表型定义的高脂血症（HTG）。在这里，我们全面分析了504例HLP-HTG患者和1213例正常血脂对照，并证实了一系列常见和罕见的脂质相关变异是这种异质性的基础。首先，我们证明了血浆脂质和脂蛋白的遗传决定因素，包括来自全球脂质遗传学联盟的与血浆甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白胆固醇（LDL-C）相关的常见变体，与多种HLP-HTG表型相关。其次，我们证明了与对照组相比，所有HLP-HTG表型中由常见TG相关变体组成的加权风险评分均明显增加;加权HDL-C和LDL-C风险评分也增加，尽管某些HLP-HTG表型的增加程度不太明显。有趣的是，HDL-C和LDL-C风险评分的分解显示，多效性变体（与TG共同相关）是HDL-C和LDL-C风险评分差异最大的原因。与其他表型相比，APOE E2/E2基因型在HLP 3型中的代表性显著过高。最后，4个基因中的罕见变异在HLP-HTG表型中平均累积。HTG易感性和表型异质性均受到常见和罕见TG相关变异体积累的影响。
Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity. First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes. HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.