Joe Bina, Saad Yasser, Dhindaw Seema, Lee Norman H, Frank Bryan C, Achinike Ovokeraye H, Luu Truong V, Gopalakrishnan Kathirvel, Toland Edward J, Farms Phyllis, Yerga-Woolwine Shane, Manickavasagam Ezhilarasi, Rapp John P, Garrett Michael R, Coe David, Apte Suneel S, Rankinen Tuomo, Pérusse Louis, Ehret Georg B, Ganesh Santhi K, Cooper Richard S, O'Connor Ashley, Rice Treva, Weder Alan B, Chakravarti Aravinda, Rao Dabeeru C, Bouchard Claude
Physiological Genomics Laboratory, Department of Physiology and Pharmacology, University of Toledo College of Medicine, 3000 Arlington Avenue, Toledo, OH 43614-2598, USA.
Hum Mol Genet. 2009 Aug 1;18(15):2825-38. doi: 10.1093/hmg/ddp218. Epub 2009 May 7.
A previously reported blood pressure (BP) quantitative trait locus on rat Chromosome 1 was isolated in a short congenic segment spanning 804.6 kb. The 804.6 kb region contained only two genes, LOC306664 and LOC306665. LOC306664 is predicted to translate into A Disintegrin-like and Metalloproteinase with Thrombospondin Motifs-16 (Adamts16). LOC306665 is a novel gene. All predicted exons of both LOC306664 and LOC306665 were sequenced. Non-synonymous variants were identified in only one of these genes, LOC306664. These variants were naturally existing polymorphisms among inbred, outbred and wild rats. The full-length rat transcript of Adamts16 was detected in multiple tissues. Similar to ADAMTS16 in humans, expression of Adamts16 was prominent in the kidney. Renal transcriptome analysis suggested that a network of genes related to BP was differential between congenic and S rats. These genes were also differentially expressed between kidney cell lines with or without knock-down of Adamts16. Adamts16 is conserved between rats and humans. It is a candidate gene within the homologous region on human Chromosome 5, which is linked to systolic and diastolic BP in the Quebec Family Study. Multiple variants, including an Ala to Pro variant in codon 90 (rs2086310) of human ADAMTS16, were associated with human resting systolic BP (SBP). Replication study in GenNet confirmed the association of two variants of ADAMTS16 with SBP, including rs2086310. Overall, our report represents a high resolution positional cloning and translational study for Adamts16 as a candidate gene controlling BP.
一个先前报道的大鼠1号染色体上的血压（BP）数量性状基因座在一个跨越804.6 kb的短同源片段中被分离出来。这个804.6 kb的区域仅包含两个基因，LOC306664和LOC306665。LOC306664预计可翻译成含血小板反应蛋白基序的解整合素样金属蛋白酶16（Adamts16）。LOC306665是一个新基因。对LOC306664和LOC306665的所有预测外显子进行了测序。非同义变异仅在这些基因中的一个，即LOC306664中被鉴定出来。这些变异是近交系、远交系和野生大鼠中自然存在的多态性。在多个组织中检测到了Adamts16的全长大鼠转录本。与人类的ADAMTS16相似，Adamts16在肾脏中的表达很突出。肾脏转录组分析表明，同源系大鼠和S大鼠之间与血压相关的基因网络存在差异。这些基因在Adamts16敲低或未敲低的肾细胞系之间也存在差异表达。Adamts16在大鼠和人类之间是保守的。它是人类5号染色体同源区域内的一个候选基因，在魁北克家族研究中与收缩压和舒张压相关。多个变异，包括人类ADAMTS16第90密码子（rs2086310）中的丙氨酸到脯氨酸变异，与人类静息收缩压（SBP）相关。GenNet中的重复研究证实了ADAMTS16的两个变异与SBP的关联，包括rs2086310。总体而言，我们的报告代表了对作为控制血压候选基因的Adamts16进行的高分辨率定位克隆和转化研究。
