Foroughi Asl H.,Cardiovascular Genomics Group |
Talukdar H.A.,Cardiovascular Genomics Group |
Kindt A.S.D.,University of Edinburgh |
Jain R.K.,University of Tartu |
And 21 more authors.
Circulation: Cardiovascular Genetics | Year: 2015
Background-Despite recent discoveries of new genetic risk factors, the majority of risk for coronary artery disease (CAD) remains elusive. As the most proximal sensor of DNA variation, RNA abundance can help identify subpopulations of genetic variants active in and across tissues mediating CAD risk through gene expression. Methods and Results-By generating new genomic data on DNA and RNA samples from the Stockholm Atherosclerosis Gene Expression (STAGE) study, 8156 cis-acting expression quantitative trait loci (eQTLs) for 6450 genes across 7 CAD-relevant tissues were detected. The inherited risk enrichments of tissue-defined sets of these eQTLs were assessed using 2 independent genome-wide association data sets. eQTLs acting across increasing numbers of tissues were found increasingly enriched for CAD risk and resided at regulatory hot spots. The risk enrichment of 42 eQTLs acting across 5 to 6 tissues was particularly high (≤7.3-fold) and confirmed in the combined genome-wide association data from Coronary Artery Disease Genome Wide Replication And Meta-Analysis Consortium. Sixteen of the 42 eQTLs associated with 19 master regulatory genes and 29 downstream gene sets (n>30) were further risk enriched comparable to that of the 153 genome-wide association risk single-nucleotide polymorphisms established for CAD (8.4-fold versus 10-fold). Three gene sets, governed by the master regulators FLYWCH1, PSORSIC3, and G3BP1, segregated the STAGE patients according to extent of CAD, and small interfering RNA targeting of these master regulators affected cholesterol-ester accumulation in foam cells of the THP1 monocytic cell line. Conclusions-eQTLs acting across multiple tissues are significant carriers of inherited risk for CAD. FLYWCH1, PSORSIC3, and G3BP1 are novel master regulatory genes in CAD that may be suitable targets. © 2015 American Heart Association, Inc.
Hagg S.,Cardiovascular Genomics Group |
Alserius T.,Karolinska University Hospital |
Noori P.,Cardiovascular Genomics Group |
Noori P.,Karolinska Institutet |
And 8 more authors.
International Journal of Molecular Medicine | Year: 2011
New technologies to generate high-dimensional data provide unprecedented opportunities for unbiased identification of biomarkers that can be used to optimize pre-operative planning, with the goal of avoiding costly postoperative complications and prolonged hospitalization. To identify such markers, we studied the global gene expression profiles of three organs central to the metabolic and inflammatory homeostasis isolated from coronary artery disease (CAD) patients during coronary artery bypass grafting (CABG) surgery. A total of 198 whole-genome expression profiles of liver, skeletal muscle and visceral fat from 66 CAD patients of the Stockholm Atherosclerosis Gene Expression (STAGE) cohort were analyzed. Of ∼50,000 mRNAs measured in each patient, the mRNA levels of the anti-inflammatory gene, dual-specificity phosphatase-1 (DUSP1) correlated independently with post-operative stay, discriminating patients with normal (≤8 days) from those with prolonged (>8 days) hospitalization (p<0.004). To validate DUSP1 as a marker of risk for post-operative complications, we prospectively analyzed 181 patients undergoing CABG at Tartu University Hospital for DUSP1 protein levels in pre-operative blood samples. The pre-operative plasma levels of DUSP1 clearly discriminated patients with normal from those with prolonged hospitalization (p=2×10 -13; odds ratio = 5.1, p<0.0001; receiver operating characteristic area under the curve = 0.80). Taken together, these results indicate that blood levels of the anti-inflammatory protein DUSP1 can be used as a biomarker for post-operative complications leading to prolonged hospitalization after CABG and therefore merit further testing in longitudinal studies of patients eligible for CABG.