Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Liebigstr. 27, 04103 Leipzig, Germany.
Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):620-7. doi: 10.1161/ATVBAHA.109.196832. Epub 2010 Jan 7.
We tested the hypothesis that expression of transcripts adjacent to the chromosome 9p21 (Chr9p21) locus of coronary artery disease was affected by the genotype at this locus and associated with atherosclerosis risk.
We replicated the locus for coronary artery disease (P=0.007; OR=1.28) and other manifestations of atherosclerosis such as carotid plaque (P=0.003; OR=1.31) in the Leipzig Heart Study, a cohort of 1134 patients with varying degree of angiographically assessed coronary artery disease. Expression analysis in peripheral blood mononuclear cells (n=1098) revealed that transcripts EU741058 and NR_003529 of antisense noncoding RNA in the INK4 locus (ANRIL) were significantly increased in carriers of the risk haplotype (P=2.1x10(-12) and P=1.6x10(-5), respectively). In contrast, transcript DQ485454 remained unaffected, suggesting differential expression of ANRIL transcripts at Chr9p21. Results were replicated in whole blood (n=769) and atherosclerotic plaque tissue (n=41). Moreover, expression of ANRIL transcripts was directly correlated with severity of atherosclerosis (EU741058 and NR_003529; P=0.02 and P=0.001, respectively). No consistent association of Chr9p21 or atherosclerosis was found with expression of other genes such as CDKN2A, CDKN2B, C9orf53, and MTAP.
Our data provide robust evidence for an association of ANRIL but not CDKN2A, CDKN2B, C9orf53, and MTAP, with atherosclerosis and Chr9p21 genotype in a large cohort.
我们检验了这样一个假设，即毗邻染色体 9p21（Chr9p21）区域的转录本的表达受该区域基因型的影响，并与动脉粥样硬化风险相关。
我们在莱比锡心脏研究（Leipzig Heart Study）中复制了冠心病的位点（P=0.007；OR=1.28）和其他动脉粥样硬化表现，如颈动脉斑块（P=0.003；OR=1.31），这是一个包含不同程度血管造影评估的冠心病患者的队列。在外周血单核细胞（n=1098）中的表达分析显示，INK4 基因座（ANRIL）的反义非编码 RNA 的 EU741058 和 NR_003529 转录本在风险单倍型携带者中显著增加（P=2.1x10(-12)和 P=1.6x10(-5)）。相比之下，DQ485454 转录本不受影响，提示 Chr9p21 上 ANRIL 转录本的差异表达。结果在全血（n=769）和动脉粥样硬化斑块组织（n=41）中得到复制。此外，ANRIL 转录本的表达与动脉粥样硬化的严重程度直接相关（EU741058 和 NR_003529；P=0.02 和 P=0.001）。在大型队列中，没有发现 Chr9p21 或动脉粥样硬化与 CDKN2A、CDKN2B、C9orf53 和 MTAP 等其他基因的表达有一致的关联。
我们的数据为 ANRIL 而非 CDKN2A、CDKN2B、C9orf53 和 MTAP 与动脉粥样硬化和 Chr9p21 基因型的关联提供了强有力的证据。
