Abstract
BackgroundGenome-wide association studies (GWAS) have linked common single nucleotide polymorphisms (SNPs) on chromosome 9p21 near the INK4/ARF (CDKN2A/B) tumor suppressor locus with risk of atherosclerotic diseases and type 2 diabetes mellitus. To explore the mechanism of this association, we investigated whether expression of proximate transcripts (p16INK4a, p15INK4b, ARF, ANRIL and MTAP) correlate with genotype of representative 9p21 SNPs.Methodology/Principal FindingsWe analyzed expression of 9p21 transcripts in purified peripheral blood T-cells (PBTL) from 170 healthy donors. Samples were genotyped for six selected disease-related SNPs spanning the INK4/ARF locus. Correlations among these variables were determined by univariate and multivariate analysis. Significantly reduced expression of all INK4/ARF transcripts (p15INK4b, p16INK4a, ARF and ANRIL) was found in PBTL of individuals harboring a common SNP (rs10757278) associated with increased risk of coronary artery disease, stroke and aortic aneurysm. Expression of MTAP was not influenced by rs10757278 genotype. No association of any these transcripts was noted with five other tested 9p21 SNPs.Conclusions/SignificanceGenotypes of rs10757278 linked to increased risk of atherosclerotic diseases are also associated with decreased expression in PBTL of the INK4/ARF locus, which encodes three related anti-proliferative transcripts of known importance in tumor suppression and aging.
Highlights
Recent human genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) with high minor allele frequencies near the INK4/ARF (CDKN2A/B) tumor suppressor locus on chromosome 9p21 correlate with risk of atherosclerotic diseases (coronary artery disease (CAD) [1,2,3,4,5], ischemic stroke [6,7], and abdominal aortic aneurysm[6]) and type 2 diabetes mellitus (T2DM) [8,9,10]
While no significant associations were noted between expression of any 9p21 transcript and five of the six SNPs analyzed, a strong association was noted between INK4/ARF transcript expression and rs10757278 genotype (Fig. 2 and Table S2)
While expression of p16INK4a is highly dynamic in peripheral blood T-cells (PBTL) with age, differences between genotypes were significant at all ages (Fig. 2B)
Summary
Recent human genome-wide association studies (GWAS) have shown that SNPs with high minor allele frequencies near the INK4/ARF (CDKN2A/B) tumor suppressor locus on chromosome 9p21 correlate with risk of atherosclerotic diseases (coronary artery disease (CAD) [1,2,3,4,5], ischemic stroke [6,7], and abdominal aortic aneurysm[6]) and type 2 diabetes mellitus (T2DM) [8,9,10]. The mechanism underlying the association of these SNPs with atherosclerotic diseases, is less clear It is not known if these genetic variants are associated with altered expression of cis-encoded transcripts. Genome-wide association studies (GWAS) have linked common single nucleotide polymorphisms (SNPs) on chromosome 9p21 near the INK4/ARF (CDKN2A/B) tumor suppressor locus with risk of atherosclerotic diseases and type 2 diabetes mellitus. To explore the mechanism of this association, we investigated whether expression of proximate transcripts (p16INK4a, p15INK4b, ARF, ANRIL and MTAP) correlate with genotype of representative 9p21 SNPs
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