A common allele on chromosome 9 associated with coronary heart disease.
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ABSTRACT:
SUBMITTER: McPherson R
PROVIDER: S-EPMC2711874 | biostudies-literature | 2007 Jun
REPOSITORIES: biostudies-literature
Publications
A common allele on chromosome 9 associated with coronary heart disease.
McPherson Ruth R Pertsemlidis Alexander A Kavaslar Nihan N Stewart Alexandre A Roberts Robert R Cox David R DR Hinds David A DA Pennacchio Len A LA Tybjaerg-Hansen Anne A Folsom Aaron R AR Boerwinkle Eric E Hobbs Helen H HH Cohen Jonathan C JC
Science (New York, N.Y.) 20070503 5830
Coronary heart disease (CHD) is a major cause of death in Western countries. We used genome-wide association scanning to identify a 58-kilobase interval on chromosome 9p21 that was consistently associated with CHD in six independent samples (more than 23,000 participants) from four Caucasian populations. This interval, which is located near the CDKN2A and CDKN2B genes, contains no annotated genes and is not associated with established CHD risk factors such as plasma lipoproteins, hypertension, o ...[more]
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Project description: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 CDKN2A and CDKN2B. 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 CDKN2A and CDKN2B 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.
| S-EPMC3387158 | biostudies-literature
Project description:Coronary heart disease (CHD) remains a leading cause of death across the world. A region on chromosome 9p21.3 has been recently reported to be associated with CHD. We evaluated 3 SNPs and 3 common haplotypes in the 9p21.3 region in 1494 individuals from 580 Irish families, where at least 1 member had early-onset (males <or=55 yr, females <or=60 yr) CHD. Genotypes were determined by multiplex SNaPshot technology. Using the combined TDT/S-TDT test, the 3 single nucleotide polymorphisms (SNP), rs10757274, rs2383206 and rs1333049, were strongly associated with early-onset CHD (p = 2.7 x 10(-6), 2.7 x 10(-6), 3.8 x 10(-7), respectively). Analysis of haplotypes by the TRANSMIT program also showed that the GGC haplotype was associated with early-onset CHD (p=7.9 x 10(-7)). In conclusion, using a family-based approach in the Irish population, we have confirmed previous reports of association between a region on chromosome 9p21.3 and early-onset CHD.
| S-EPMC3827790 | biostudies-other
Project description:BackgroundGenetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.MethodsA variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.ResultsMeta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).ConclusionsIn contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
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Project description:Background. The coronary heart disease (CHD) risk locus on 21q22 (lead SNP rs9982601) lies within a "gene desert." The aim of this study was to assess if this locus is associated with CHD risk factors and to identify the functional variant(s) and gene(s) involved. Methods. A phenome scan was performed with UCLEB Consortium data. Allele-specific protein binding was studied using electrophoretic mobility shift assays. Dual-reporter luciferase assays were used to assess the impact of genetic variation on expression. Expression quantitative trait analysis was performed with Advanced Study of Aortic Pathology (ASAP) and Genotype-Tissue Expression (GTEx) consortium data. Results. A suggestive association between QT interval and the locus was observed (rs9982601 p = 0.04). One variant at the locus, rs28451064, showed allele-specific protein binding and its minor allele showed 12% higher luciferase expression (p = 4.82 × 10-3) compared to the common allele. The minor allele of rs9982601 was associated with higher expression of the closest upstream genes (SLC5A3 1.30-fold increase p = 3.98 × 10-5; MRPS6 1.15-fold increase p = 9.60 × 10-4) in aortic intima media in ASAP. Both rs9982601 and rs28451064 showed a suggestive association with MRPS6 expression in relevant tissues in the GTEx data. Conclusions. A candidate functional variant, rs28451064, was identified. Future work should focus on identifying the pathway(s) involved.
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Project description:ObjectiveThe objective of this study was to identify genetic variants on the X-chromosome associated with Parkinson disease (PD) risk.MethodsWe performed an X-chromosome-wide association study (XWAS) of PD risk by meta-analyzing results from sex-stratified analyses. To avoid spurious associations, we designed a specific harmonization pipeline for the X-chromosome and focused on a European ancestry sample. We included 11,142 cases, 280,164 controls, and 5,379 proxy cases, based on parental history of PD. Additionally, we tested the association of significant variants with (1) PD risk in an independent replication with 1,561 cases and 2,465 controls and (2) putamen volume in 33,360 individuals from the UK Biobank.ResultsIn the discovery meta-analysis, we identified rs7066890 (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 1.06-1.14, p = 2.2 × 10-9 ), intron of GPM6B, and rs28602900 (OR = 1.10, 95% CI = 1.07-1.14, p = 1.6 × 10-8 ) in a high gene density region including RPL10, ATP6A1, FAM50A, and PLXNA3. The rs28602900 association with PD was replicated (OR = 1.16, 95% CI = 1.03-1.30, p = 0.016) and shown to colocalize with a significant expression quantitative locus (eQTL) regulating RPL10 expression in the putamen and other brain tissues in the Genotype-Tissue Expression Project. Additionally, the rs28602900 locus was found to be associated with reduced brain putamen volume. No results reached genome-wide significance in the sex-stratified analyses.InterpretationWe report the first XWAS of PD and identify 2 genome-wide significant loci. The rs28602900 association was replicated in an independent PD dataset and showed concordant effects in its association with putamen volume. Critically, rs26802900 is a significant eQTL of RPL10. These results support a role for ribosomal proteins in PD pathogenesis and show that the X-chromosome contributes to PD genetic risk. ANN NEUROL 2021;90:22-34.
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Project description:OBJECTIVES:To compare the new Patient Rule Induction Method (PRIM) Score and common clinical practice with the Framingham Point Score for classification of individuals with respect to coronary heart disease (CHD) risk. METHODS AND RESULTS:PRIM Score and the Framingham Point Score were estimated for 11,444 participants from the Copenhagen City Heart Study. Gender specific cumulative incidences and 10 year absolute CHD risks were estimated for subsets defined by age, total cholesterol, high-density lipoprotein (HDL) cholesterol, blood pressure, diabetes and smoking categories. PRIM defined seven mutually exclusive subsets in women and men, with cumulative incidences of CHD from 0.01 to 0.22 in women, and from 0.03 to 0.26 in men. PRIM versus Framingham Point Score found 11% versus 4% of all women, and 31% versus 35% of all men to have 10 year CHD risks>20%. Among women ? 65 years with hypertension and/or with diabetes, 10 year CHD risk>20% was found for 100% with PRIM scoring but for only 18% with the Framingham Point Score. CONCLUSION:Compared to the PRIM Score, common clinical practice with the Framingham Point Score underestimates CHD risk in women, especially in women?65 years with hypertension and/or with diabetes.
| S-EPMC3117128 | biostudies-literature
Project description:BackgroundAssessing multiple traditional risk factors improves prediction for late-life diseases, including coronary heart disease (CHD). It appears that non-traditional risk factors can also predict risk. The objective was to investigate contributions of non-traditional risk factors to coronary heart disease risk using a deficit accumulation approach.MethodsCommunity-dwelling adults with no known history of CHD (n?=?2195, mean age 46.9±18.7 years, 51.8% women) participated in the 1995 Nova Scotia Health Survey. Three risk factor indices were constructed to quantify the proportion of deficits present in individuals: 1) a 17-item Non-Traditional Risk Factor Index (e.g. sinusitis, arthritis); 2) a 9-item Traditional Risk Factor Index (e.g. hypertension, diabetes); and 3) a frailty index (25 items combined from the other two index measures). Ten-year risks of CHD events (defined as CHD-related hospitalization and CHD-related mortality) were evaluated.ResultsThe Non-Traditional Risk Factor Index, made up of health deficits unrelated to CHD, was independently associated with incident CHD events over 10 years after controlling for age, sex, and the Traditional Risk Factor Index [adjusted {adj.} Hazard Ratio {HR}?=?1.31; Confidence Interval {CI} 1.14-1.51]. When all health deficits, both those related and unrelated to CHD, were included in a frailty index the corresponding adjusted hazard ratio was 1.61; CI 1.40-1.85.ConclusionBoth traditional and non-traditional risk factor indices are independently associated with incident CHD events. CHD risk assessment may benefit from consideration of general health information as well as from traditional risk factors.
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