Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Sweden.
Department of Genomics of Common Disease, School of Public Health, Imperial College London, UK.
Biochem Biophys Res Commun. 2014 Apr 18;446(4):1126-31. doi: 10.1016/j.bbrc.2014.03.075. Epub 2014 Mar 25.
Risk alleles within a gene desert at the 9p21 locus constitute the most prevalent genetic determinant of cardiovascular disease. Previous research has demonstrated that 9p21 risk variants influence gene expression in vascular tissues, yet the biological mechanisms by which this would mediate atherosclerosis merits further investigation. To investigate possible influences of this locus on other tissues, we explored expression patterns of 9p21-regulated genes in a panel of multiple human tissues and found that the tumor suppressor CDKN2B was highly expressed in subcutaneous adipose tissue (SAT). CDKN2B expression was regulated by obesity status, and this effect was stronger in carriers of 9p21 risk alleles. Covariation between expression of CDKN2B and genes implemented in adipogenesis was consistent with an inhibitory effect of CDKN2B on SAT proliferation. Moreover, studies of postprandial triacylglycerol clearance indicated that CDKN2B is involved in down-regulation of SAT fatty acid trafficking. CDKN2B expression in SAT correlated with indicators of ectopic fat accumulation, including markers of hepatic steatosis. Among genes regulated by 9p21 risk variants, CDKN2B appears to play a significant role in the regulation of SAT expandability, which is a strong determinant of lipotoxicity and therefore might contribute to the development of atherosclerosis.
9p21 基因座内的风险等位基因是心血管疾病最常见的遗传决定因素。先前的研究表明，9p21 风险变体影响血管组织中的基因表达，但这种影响介导动脉粥样硬化的生物学机制值得进一步研究。为了研究该基因座对其他组织的可能影响，我们在一组多种人类组织中探索了 9p21 调控基因的表达模式，发现肿瘤抑制因子 CDKN2B 在皮下脂肪组织 (SAT) 中高度表达。CDKN2B 的表达受肥胖状态调节，而携带 9p21 风险等位基因的个体的这种影响更强。CDKN2B 表达与参与脂肪生成的基因之间的共变与 CDKN2B 对 SAT 增殖的抑制作用一致。此外，对餐后三酰甘油清除的研究表明，CDKN2B 参与下调 SAT 脂肪酸转运。SAT 中的 CDKN2B 表达与异位脂肪积累的指标相关，包括肝脂肪变性的标志物。在受 9p21 风险变体调控的基因中，CDKN2B 似乎在调节 SAT 可扩展性方面发挥着重要作用，而 SAT 可扩展性是脂毒性的一个强有力决定因素，因此可能有助于动脉粥样硬化的发展。
