Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Department of Molecular Biology and Genetics, Faculty of Arts & Science, Bursa Uludag University, Gorukle, Bursa, Turkey.
PLoS One. 2020 Dec 16;15(12):e0243919. doi: 10.1371/journal.pone.0243919. eCollection 2020.
Common variants in the hepatic lipase (LIPC) gene have been shown to be associated with plasma lipid levels; however, the distribution and functional features of rare and regulatory LIPC variants contributing to the extreme lipid phenotypes are not well known. This study was aimed to catalogue LIPC variants by resequencing the entire LIPC gene in 95 non-Hispanic Whites (NHWs) and 95 African blacks (ABs) with extreme HDL-C levels followed by in silico functional analyses. A total of 412 variants, including 43 novel variants were identified; 56 were unique to NHWs and 234 were unique to ABs. Seventy-eight variants in NHWs and 89 variants in ABs were present either in high HDL-C group or low HDL-C group. Two non-synonymous variants (p.S289F, p.T405M), found in NHWs with high HDL-C group were predicted to have damaging effect on LIPC protein by SIFT, MT2 and PP2. We also found several non-coding variants that possibly reside in the circRNA and lncRNA binding sites and may have regulatory potential, as identified in rSNPbase and RegulomeDB databases. Our results shed light on the regulatory nature of rare and non-coding LIPC variants as well as suggest their important contributions in affecting the extreme HDL-C phenotypes.
已发现肝脂酶 (LIPC) 基因中的常见变异与血浆脂质水平相关；然而，导致极端脂质表型的稀有和调节性 LIPC 变异的分布和功能特征尚不清楚。本研究旨在通过对 95 名非西班牙裔白人（NHW）和 95 名非裔黑人（AB）进行 LIPC 基因全序列重测序，对 LIPC 变异进行编目，这些个体具有极端的高密度脂蛋白胆固醇（HDL-C）水平，随后进行计算机功能分析。共鉴定出 412 种变异，包括 43 种新变异；56 种仅存在于 NHW 中，234 种仅存在于 AB 中。78 种变异存在于 NHW 的高 HDL-C 组，89 种变异存在于 AB 的低 HDL-C 组。在 NHW 的高 HDL-C 组中发现的两种非同义变异（p.S289F，p.T405M），通过 SIFT、MT2 和 PP2 预测对 LIPC 蛋白具有破坏性影响。我们还发现了一些可能位于环状 RNA 和长链非编码 RNA 结合位点的非编码变异，并且可能具有调节潜力，这些变异在 rSNPbase 和 RegulomeDB 数据库中被鉴定出来。我们的研究结果阐明了稀有和非编码 LIPC 变异的调节性质，并表明它们在影响极端 HDL-C 表型方面的重要贡献。
