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The 9p21.3 risk locus for coronary artery disease: A 10-year search for its mechanism.

ABSTRACT: The 9p21.3 risk locus is the first locus to be associated with an increased risk of coronary artery disease (CAD)-related events and many other phenotypes. This locus contains 59 single nucleotide polymorphisms (SNPs) in a region with multiple long range enhancers and long non-coding RNAs (lncRNAs) that affect the expression of neighbouring genes, cyclin-dependent kinase 2A and 2B (CDKN2A and CDKN2B), which are required for controlling vascular smooth muscle cell proliferation and ageing. Several studies have attempted to identify the precise mechanism by which this locus exerts its pathogenic effect to increase the risk of CAD-related events. In this review, we will highlight the major advances in our understanding of the genotype-phenotype correlation at the mechanistic and phenotypic levels. The high population attributable risk of the 9p21.3 risk locus, mechanistic knowledge acquired thus far, and ongoing research efforts could facilitate the design of novel therapeutic molecules to reduce the risk of CAD and its related events.

SUBMITTER: Almontashiri NAM

PROVIDER: S-EPMC6694924 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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The 9p21.3 risk locus for coronary artery disease: A 10-year search for its mechanism.

Almontashiri Naif A M NAM

Journal of Taibah University Medical Sciences 20170425 3

The 9p21.3 risk locus is the first locus to be associated with an increased risk of coronary artery disease (CAD)-related events and many other phenotypes. This locus contains 59 single nucleotide polymorphisms (SNPs) in a region with multiple long range enhancers and long non-coding RNAs (lncRNAs) that affect the expression of neighbouring genes, cyclin-dependent kinase 2A and 2B (CDKN2A and CDKN2B), which are required for controlling vascular smooth muscle cell proliferation and ageing. Severa ...[more]

PMID: 31435240

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Project description:A chromosomal locus at 4q32.1 has been genome-wide significantly associated with coronary artery disease risk. The locus encompasses GUCY1A3, which encodes the ?1 subunit of the soluble guanylyl cyclase (sGC), a key enzyme in the nitric oxide/cGMP signaling pathway. The mechanism linking common variants in this region with coronary risk is not known.Gene expression and protein expression were analyzed with quantitative polymerase chain reaction and immunoblotting, respectively. Putative allele-specific transcription factors were identified with in silico analyses and validated via allele-specific quantification of antibody-precipitated chromatin fractions. Regulatory properties of the lead risk variant region were analyzed with reporter gene assays. To assess the effect of zinc finger E box-binding homeobox 1 transcription factor (ZEB1), siRNA-mediated knockdown and overexpression experiments were performed. Association of GUCY1A3 genotype and cellular phenotypes was analyzed with vascular smooth muscle cell migration assays and platelet aggregation analyses.Whole-blood GUCY1A3 mRNA levels were significantly lower in individuals homozygous for the lead (rs7692387) risk variant. Likewise, reporter gene assays demonstrated significantly lower GUCY1A3 promoter activity for constructs carrying this allele. In silico analyses located a DNase I hypersensitivity site to rs7692387 and predicted binding of the transcription factor ZEB1 rather to the nonrisk allele, which was confirmed experimentally. Knockdown of ZEB1 resulted in more profound reduction of nonrisk allele promoter activity and a significant reduction of endogenous GUCY1A3 expression. Ex vivo-studied platelets from homozygous nonrisk allele carriers displayed enhanced inhibition of ADP-induced platelet aggregation by the nitric oxide donor sodium nitroprusside and the phosphodiesterase 5 inhibitor sildenafil compared with homozygous risk allele carriers. Moreover, pharmacological stimulation of sGC led to reduced migration only in vascular smooth muscle cells homozygous for the nonrisk allele. In the Hybrid Mouse Diversity Panel, higher levels of GUCY1A3 expression correlated with less atherosclerosis in the aorta.Rs7692387 is located in an intronic site that modulates GUCY1A3 promoter activity. The transcription factor ZEB1 binds preferentially to the nonrisk allele, leading to an increase in GUCY1A3 expression, higher sGC levels, and higher sGC activity after stimulation. Finally, human and mouse data link augmented sGC expression to lower risk of atherosclerosis.

Dataset Information

The 9p21.3 risk locus for coronary artery disease: A 10-year search for its mechanism.

Publications

The 9p21.3 risk locus for coronary artery disease: A 10-year search for its mechanism.

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