Rodríguez Alejandra, Gonzalez Luis, Ko Arthur, Alvarez Marcus, Miao Zong, Bhagat Yash, Nikkola Elina, Cruz-Bautista Ivette, Arellano-Campos Olimpia, Muñoz-Hernández Linda L, Ordóñez-Sánchez Maria-Luisa, Rodriguez-Guillen Rosario, Mohlke Karen L, Laakso Markku, Tusie-Luna Teresa, Aguilar-Salinas Carlos A, Pajukanta Päivi
From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
Arterioscler Thromb Vasc Biol. 2016 Jul;36(7):1350-5. doi: 10.1161/ATVBAHA.116.307182. Epub 2016 May 19.
We recently identified a locus on chromosome 18q11.2 for high serum triglycerides in Mexicans. We hypothesize that the lead genome-wide association study single-nucleotide polymorphism rs9949617, or its linkage disequilibrium proxies, regulates 1 of the 5 genes in the triglyceride-associated region.
We performed a linkage disequilibrium analysis and found 9 additional variants in linkage disequilibrium (r(2)>0.7) with the lead single-nucleotide polymorphism. To select the variants for functional analyses, we annotated the 10 variants using DNase I hypersensitive sites, transcription factor and chromatin states and identified rs17259126 as the lead candidate variant for functional in vitro validation. Using luciferase transcriptional reporter assay in liver HepG2 cells, we found that the G allele exhibits a significantly lower effect on transcription (P<0.05). The electrophoretic mobility shift and ChIPqPCR (chromatin immunoprecipitation coupled with quantitative polymerase chain reaction) assays confirmed that the minor G allele of rs17259126 disrupts an hepatocyte nuclear factor 4 α-binding site. To find the regional candidate gene, we performed a local expression quantitative trait locus analysis and found that rs17259126 and its linkage disequilibrium proxies alter expression of the regional transmembrane protein 241 (TMEM241) gene in 795 adipose RNAs from the Metabolic Syndrome In Men (METSIM) cohort (P=6.11×10(-07)-5.80×10(-04)). These results were replicated in expression profiles of TMEM241 from the Multiple Tissue Human Expression Resource (MuTHER; n=856).
The Mexican genome-wide association study signal for high serum triglycerides on chromosome 18q11.2 harbors a regulatory single-nucleotide polymorphism, rs17259126, which disrupts normal hepatocyte nuclear factor 4 α binding and decreases the expression of the regional TMEM241 gene. Our data suggest that decreased transcript levels of TMEM241 contribute to increased triglyceride levels in Mexicans.
我们最近在墨西哥人群中发现了18号染色体q11.2上一个与高血清甘油三酯相关的基因座。我们推测全基因组关联研究中的先导单核苷酸多态性rs9949617或其连锁不平衡替代物调控甘油三酯相关区域5个基因中的1个。
我们进行了连锁不平衡分析，发现另外9个与先导单核苷酸多态性处于连锁不平衡状态（r²>0.7）的变异。为了选择用于功能分析的变异，我们利用DNA酶I超敏位点、转录因子和染色质状态对这10个变异进行注释，并确定rs17259126为体外功能验证的主要候选变异。在肝脏HepG2细胞中使用荧光素酶转录报告基因检测，我们发现G等位基因对转录的影响显著较低（P<0.05）。电泳迁移率变动分析和染色质免疫沉淀定量聚合酶链反应（ChIP-qPCR）检测证实，rs17259126的次要G等位基因破坏了一个肝细胞核因子4α结合位点。为了找到区域候选基因，我们进行了局部表达定量性状基因座分析，发现rs17259126及其连锁不平衡替代物改变了来自男性代谢综合征（METSIM）队列的795份脂肪RNA中区域跨膜蛋白241（TMEM241）基因的表达（P=6.11×10⁻⁷-5.80×10⁻⁴）。这些结果在来自多组织人类表达资源（MuTHER；n=856）的TMEM241表达谱中得到了重复。
墨西哥人群全基因组关联研究中位于18号染色体q11.2上的高血清甘油三酯信号包含一个调控性单核苷酸多态性rs17259126，它破坏了正常的肝细胞核因子4α结合并降低了区域TMEM241基因的表达。我们的数据表明TMEM241转录水平降低导致墨西哥人群甘油三酯水平升高。
