Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

?133p53 isoform promotes tumour invasion and metastasis via interleukin-6 activation of JAK-STAT and RhoA-ROCK signalling

International audienc

The Chromosome 9p21.3 Coronary Heart Disease Risk Allele Is Associated with Altered Gene Expression in Normal Heart and Vascular Tissues

<div><p>Genome-wide association studies have identified a coronary artery disease (CAD) risk locus in a non-coding region at 9p21.3, the nearest genes being <em>CDKN2A</em> and <em>CDKN2B</em>. To understand the pathways by which this locus might influence CAD susceptibility, we investigated associations between the 9p21.3 risk genotype and global gene expression in heart tissue from donors with no diagnosed heart disease (n = 108, predominant cause of death, cerebral vascular accident) and in carotid plaque (n = 106), aorta (n = 104) and mammary artery (n = 88) tissues from heart valve and carotid endarterectomy patients. Genotyping was performed with Taqman assays and Illumina arrays, and gene expression profiles generated with Affymetrix microarrays. Associations were analyzed with an additive genetic model. In heart tissue, 46 genes were putatively altered in association with the 9p21.3 risk allele (70% down-regulated, fold-change >1.1 per allele, p<0.05 adjusted for age, gender, ethnicity, cause of death). These genes were enriched for biomarkers of myocardial infarction (p = 1.53×10⁻⁹), response to wounding (p = 2.65×10⁻¹⁰) and inflammatory processes (p<1.97×10⁻⁷). Among the top 10 most down-regulated genes, 7 genes shared a set of transcription factor binding sites within conserved promoter regions (p<1.14×10⁻⁵), suggesting they may be co-regulated. Canonical pathway modelling of the most differentially expressed transcripts across all tissues (154 genes, 60% down-regulated, fold-change >1.1 per allele, p<0.01) showed that 75% of the genes could be transcriptionally regulated through the cell cycle G1 phase progression pathway (p<1.08×10⁻²⁵⁸), in which <em>CDKN2A</em> and <em>CDKN2B</em> play a regulatory role. These data suggest that the cell cycle G1 phase progression pathway is activated in individuals with the 9p21.3 risk allele. This may contribute to a proliferative phenotype that promotes adverse cardiac hypertrophy and vascular remodeling, leading to an increased CAD risk.</p> </div

Twenty top-ranked genes altered in association with the 9p21.3 risk allele in donor hearts (n = 108).

<p>Analysis was performed using a fold-change threshold of >1.1 per copy of the risk allele and p<0.05 (adjusted for age, gender, ethnicity and cause of death; not corrected for multiple comparisons). Each bar represents an individual gene, as indicated by the gene symbol. Genes are ranked in order of fold-change from greatest to smallest (left to right). Analysis of the top 10 most down-regulated genes (indicated by line below graph) identified a shared combination transcription factor binding sites within the promoter regions of 7 of these genes (genes indicated by asterisks).</p

Baseline characteristics of heart donors, heart valve patients and carotid endarterectomy patients.

*<p>mean±standard deviation.</p

Comparison of microarray data with real-time PCR for selected genes in donor hearts (n = 108).

<p>Periostin, <i>CCDC80</i> (coiled-coil domain containing 80) and <i>VCAM1</i> (vascular cell adhesion molecule 1), the most differentially expressed genes altered in association with the 9p21.3 risk allele in heart donors, gave an equivalent, statistically significant decrease in expression by microarray and RT-qPCR methods. In contrast to array data, RT-qPCR for <i>CDKN2B</i>, a gene in close proximity to the 9p21.3 risk locus, also showed a significant decrease in expression. No significant association between the 9p21.3 risk allele and expression levels of <i>ANRIL</i> or <i>CDKN2A</i> was detected in these individuals, by either method. The 9p21.3 (rs1333049) low-risk GG genotype is depicted in green; GC heterozygotes (intermediate risk) are shown in orange; the high-risk CC genotype is shown in red. Statistical analysis was performed assuming an additive genetic model and all p-values have been adjusted for age, gender, ethnicity and cause of death.</p

Canonical pathway modeling of the most significantly differentially expressed genes in donor heart (n = 108), carotid plaque (n = 106), aorta (n = 104) and mammary artery (n = 88) tissues.

<p>(A) A schematic depicting part of the cell cycle G1 phase progression pathway, indicating the regulatory role of p16^INK4 and p15, which are encoded by two genes located adjacent to the 9p21.3 risk locus (<i>CDKN2A</i> and <i>CDKN2B)</i>. The majority of the most significantly differentially expressed genes (fold-change >1.1 per copy of the risk allele, p<0.01 not corrected for multiple comparisons,) associated with the 9p21.3 risk allele in myocardial and vascular tissues were predicted to be transcriptionally regulated by this pathway, predominantly by the transcription factors E2F1, E2F4 and Sp1 (116 out of 154 genes, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039574#pone.0039574.s006" target="_blank">Table S2</a> for the list of genes associated with this pathway and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039574#pone.0039574.s002" target="_blank">Figure S2</a> for gene network analysis). More than half of these genes (58%) were down-regulated in association with the 9p21.3 risk allele, which would be concordant with lower levels of <i>ANRIL</i> expression. Green arrows indicate positive regulation; red arrows indicate negative regulation. (B) Venn diagram indicating the proportion of differentially expressed genes predicted to be regulated by E2F1, E2F4 and Sp1. The genes predicted to be regulated by each of these transcription factors is indicated by the symbols *, § and ¶ respectively, in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039574#pone.0039574.s006" target="_blank">Table S2</a>.</p

Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10−5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10−5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10−10, odds ratio 1.15 [1.10–1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04–1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression