背景:带9p21.3包含已建立的心血管疾病(CVD)基因组风险区。自2007年最初的惠康信托案例控制联盟研究(WTCCC)以来,不同大陆的多项研究证实了与9p21.3相关的CVD风险增加.然而,多年后,仍然没有证实9p21.3与高血压的相应关联的报告,一个主要的CV风险因素,也没有血压(BP)。
背景:在此贡献中,我们回顾了9p21.3风险位点的二分单倍型结构:一个区块缺乏蛋白质编码基因,但含有导致CVD风险的SNP,而另一个块包含细胞周期抑制剂p15基因的第一个外显子和调节DNA。我们考虑分子生物学的发现如何提供p15参与高血压病因学的可能性,p15基因的表达受到9p21.3风险位点内遗传变异的调节。
结果:我们提供了哥伦比亚一项研究的原始结果,该研究揭示了在经典的9p21.3CVD风险位点内,血压和高血压的中度但持续的关联信号。这些SNP大多局限于“高血压岛”,其跨度小于60kb,与p15单倍型区块一致。我们发现来自更大的数据得到证实,最近的欧洲BP研究,尽管效果方向相反。
结论:尽管需要更多的工作来阐明可能的机制,先前的发现和新数据促使人们重新考虑9p21.3的变化如何影响心血管风险的高血压成分的问题.
BACKGROUND: The band 9p21.3 contains an established genomic risk zone for cardiovascular disease (CVD). Since the initial 2007 Wellcome Trust Case Control Consortium study (WTCCC), the increased CVD risk associated with 9p21.3 has been confirmed by multiple studies in different continents. However, many years later there was still no confirmed report of a corresponding association of 9p21.3 with hypertension, a major CV risk factor, nor with blood pressure (BP).
BACKGROUND: In this contribution, we review the bipartite haplotype structure of the 9p21.3 risk locus: one block is devoid of protein-coding genes but contains the lead CVD risk SNPs, while the other block contains the first exon and regulatory DNA of the gene for the cell cycle inhibitor p15. We consider how findings from molecular biology offer possibilities of an involvement of p15 in hypertension etiology, with expression of the p15 gene modulated by genetic variation from within the 9p21.3 risk locus.
RESULTS: We present original results from a Colombian study revealing moderate but persistent association signals for BP and hypertension within the classic 9p21.3 CVD risk locus. These SNPs are mostly confined to a \'hypertension island\' that spans less than 60 kb and coincides with the p15 haplotype block. We find confirmation in data originating from much larger, recent European BP studies, albeit with opposite effect directions.
CONCLUSIONS: Although more work will be needed to elucidate possible mechanisms, previous findings and new data prompt reconsidering the question of how variation in 9p21.3 might influence hypertension components of cardiovascular risk.