Coronary Artery Disease Loci Research Articles

Identification of 15 novel risk loci for coronary artery disease and genetic risk of recurrent events, atrial fibrillation and heart failure

Coronary artery disease (CAD) is the major cause of morbidity and mortality in the world. Identification of novel genetic determinants may provide new opportunities for developing innovative strategies to predict, prevent and treat CAD. Therefore, we meta-analyzed independent genetic variants passing P <× 10−5 in CARDIoGRAMplusC4D with novel data made available by UK Biobank. Of the 161 genetic variants studied, 71 reached genome wide significance (p < 5 × 10−8) including 15 novel loci. These novel loci include multiple genes that are involved in angiogenesis (TGFB1, ITGB5, CDH13 and RHOA) and 2 independent variants in the TGFB1 locus. We also identified SGEF as a candidate gene in one of the novel CAD loci. SGEF was previously suggested as a therapeutic target based on mouse studies. The genetic risk score of CAD predicted recurrent CAD events and cardiovascular mortality. We also identified significant genetic correlations between CAD and other cardiovascular conditions, including heart failure and atrial fibrillation. In conclusion, we substantially increased the number of loci convincingly associated with CAD and provide additional biological and clinical insights.

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms.

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

Abstract 606: Reciprocal Gene-Gene Regulation Between GWAS Genes ADTRP and MIA3 Contributing to Susceptibility of Coronary Artery Disease

Genome-wide association studies (GWAS) have identified &gt;60 genomic loci for coronary artery disease (CAD), including ADTRP (regulator of TFPI and coagulation) and MIA3 (involved in ER trafficking of collagens). In this study, we hypothesized that some GWAS genes form a molecular regulatory network involved in the pathogenesis of CAD. Global microarray analysis showed that ADTRP regulated expression of MIA3 and PIK3R3 encoding the regulatory subunit 3 of PI3K. ADTRP -mediated up-regulation of PIK3R3 activates AKT, resulting in up-regulation of MIA3 . Knockdown of ADTRP expression promoted oxidized-LDL-mediated monocyte adhesion to endothelial cell (EC) and transendothelial migration of monocytes, inhibited EC proliferation and migration, and increased apoptosis, which was reversed by expression of constitutively active AKT1, while the over-expression of ADTRP in ECs blunted these processes. Knockdown of MIA3 expression also promoted monocyte adhesion to ECs and transendothelial migration of monocytes. However, knockdown of MIA3 increased ADTRP expression, suggesting that MIA3 negatively regulates ADTRP expression. Genetically, no significant interaction between ADTRP SNP rs6903956 and MIA3 SNP rs17465637 was detected in 2,185 CAD patients and 2,156 non-CAD controls by classical two-locus genotypic analysis, relative excess risk due to interaction or INTERSNP programs. We have recently found that one molecular mechanism for gene-gene interaction is positive cyclic cross-regulation of gene expression: Gene A positively regulates gene B, whereas gene B also positively regulates gene A. Here we have identified a different scenario in which gene A positively regulates gene B, but gene B negatively regulates gene A, thereby resulting in lack of gene-gene interaction. In conclusion, we have uncovered a novel molecular signaling pathway involving ADTRP and MIA3 for the pathogenesis of CAD. We show that ADTRP positively regulates PIK3R3 expression, which leads to activation of AKT and up-regulation of MIA3 , thereby regulating endothelial cell functions directly relevant to atherosclerosis. These results further support that positive cyclic cross-regulation of gene expression is a molecular mechanism for gene-gene interaction.

Abstract 413: Lipoprotein SCARB1 Intronic Variant Associated With Increased Coronary Heart Disease Risk Affects Cardio-Protective Gene Networks

Introduction: We previously reported a common intronic SCARB1 (12q24.31) variant, rs10846744, located in an enhancer region, to be significantly associated with coronary artery disease (CAD) in the Multi-Ethnic Study of Atherosclerosis (MESA). RNA-Seq showed expression of the immune checkpoint inhibitor lymphocyte activation gene 3 ( LAG3 , 12p13.31), to be 5-fold lower in carriers of the risk allele, while low plasma LAG3 protein levels were also significantly associated with increased CAD risk in MESA, after multivariate regression analysis. Hypothesis: That the SCARB1 rs10846744 variant disrupts long-range transcriptional regulation of LAG3 disturbing cardio-protective and anti-inflammatory gene networks to promote CAD. Methods and Results: Using functional genomics (HiC global chromatin capture, ChIP-Seq and RNA-Seq) in reference and risk EBV-transformed B lymphocytes to assess 3D chromatin architecture and gene-gene interactions at a 2.5kb resolution, we did not observe direct chromatin contacts between SCARB1 and LAG3. In the reference allele, an enhancer-rich intermediate contact (12q13.13) was found containing genes associated with cholesterol ( SOAT2 ) and NR2F2 signaling ( RARG ). This same 12q13.13 region was in direct contact with 22q12.3 ( APOLI) , an apoprotein associated with HDL and innate immunity. Micro-looping within the rs10846744 12q24.31 region showed direct contacts with other enhancers ( NCOR2 ) and cardiovascular loci ( TMEM132B ), while LAG3 micro-looping on 12p13.31 was associated with immune regulatory networks ( CD4 ). Loci associated with viral infection, cytokine production, heart failure and autoimmunity were also identified. NR2F2 disrupted contacts in the risk allele, implicating NR2F2 as a dysfunctional rs10846744 transcriptional repressor altering gene networks. The risk allele included contacts near PCSK9 , VLDLR and 2q33.1, a CAD locus. Conclusion: Functional genomics of the SCARB1 rs10846744 enhancer region identified a number of intra- and inter-chromosomal chromatin contacts in reference cells that were markedly disrupted in risk cells. Perturbing NR2F2 and/or genes disrupted in the SCARB1 -NR2F2 immuno-cardiovascular axis may protect against CAD in the rs10846744 risk population.

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

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.

Leveraging information from genetic risk scores of coronary atherosclerosis.

Genome-wide association studies (GWAS) have identified ∼60 loci for coronary artery disease (CAD). Through genetic risk scores (GRSs), investigators are leveraging this genomic information to gain insights on both the fundamental mechanisms driving these associations as well as their utility in improving risk prediction. GRSs of CAD track with the earliest atherosclerosis lesions in the coronary including fatty streaks and uncomplicated raised lesions. In multiple cohort studies, they predict incident CAD events independent of all traditional and lifestyle risk factors. The incorporation of SNPs with suggestive but not genome-wide association in GWAS into GRSs often increases the strength of these associations. GRS may also predict recurrent events and identify patients most likely to respond to statins. The effect of the GRS on discrimination metrics remains modest but the minimal degree of improvement needed for clinical utility is unknown. Most novel loci for CAD identified through GWAS facilitate the formation of coronary atherosclerosis and stratify individuals based on their underlying burden of coronary atherosclerosis. GRSs may one day be routinely used in clinical practice to not only assess the risk of incident events but also to predict who will respond best to established prevention strategies.

Identification of a molecular signaling gene-gene regulatory network between GWAS susceptibility genes ADTRP and MIA3/TANGO1 for coronary artery disease

Coronary artery disease (CAD) is the leading cause of death worldwide. GWAS have identified >50 genomic loci for CAD, including ADTRP and MIA3/TANGO1. However, it is important to determine whether the GWAS genes form a molecular network. In this study, we have uncovered a novel molecular network between ADTRP and MIA3/TANGO1 for the pathogenesis of CAD. We showed that knockdown of ADTRP expression markedly down-regulated expression of MIA3/TANGO1. Mechanistically, ADTRP positively regulates expression of PIK3R3 encoding the regulatory subunit 3 of PI3K, which leads to activation of AKT, resulting in up-regulation of MIA3/TANGO1. Both ADTRP and MIA3/TANGO1 are involved in endothelial cell (EC) functions relevant to atherosclerosis. Knockdown of ADTRP expression by siRNA promoted oxidized-LDL-mediated monocyte adhesion to ECs and transendothelial migration of monocytes, inhibited EC proliferation and migration, and increased apoptosis, which was reversed by expression of constitutively active AKT1 and MIA3/TANGO1 overexpression, while the over-expression of ADTRP in ECs blunted these processes. Knockdown of MIA3/TANGO1 expression also promoted monocyte adhesion to ECs and transendothelial migration of monocytes, and vice versa for overexpression of MIA3/TANGO1. We found that ADTRP negatively regulates the levels of collagen VII and ApoB in HepG2 and endothelial cells, which are downstream regulatory targets of MIA3/TANGOI. In conclusion, we have uncovered a novel molecular signaling pathway for the pathogenesis of CAD, which involves a novel gene-gene regulatory network. We show that ADTRP positively regulates PIK3R3 expression, which leads to activation of AKT and up-regulation of MIA3/TANGO1, thereby regulating endothelial cell functions directly relevant to atherosclerosis.

Additional Candidate Genes for Human Atherosclerotic Disease Identified Through Annotation Based on Chromatin Organization.

As genome-wide association efforts, such as CARDIoGRAM and METASTROKE, are ongoing to reveal susceptibility loci for their underlying disease-atherosclerotic disease-identification of candidate genes explaining the associations of these loci has proven the main challenge. Many disease susceptibility loci colocalize with DNA regulatory elements, which influence gene expression through chromatin interactions. Therefore, the target genes of these regulatory elements can be considered candidate genes. Applying these biological principles, we used an alternative approach to annotate susceptibility loci and identify candidate genes for human atherosclerotic disease based on circular chromosome conformation capture followed by sequencing. In human monocytes and coronary endothelial cells, we generated 63 chromatin interaction data sets for 37 active DNA regulatory elements that colocalize with known susceptibility loci for coronary artery disease (CARDIoGRAMplusC4D) and large artery stroke (METASTROKE). By circular chromosome conformation capture followed by sequencing, we identified a physical 3-dimensional interaction with 326 candidate genes expressed in at least 1 of these cell types, of which 294 have not been reported before. We highlight 16 genes based on expression quantitative trait loci. Our findings provide additional candidate-gene annotation for 37 disease susceptibility loci for human atherosclerotic disease that are of potential interest to better understand the complex pathophysiology of cardiovascular diseases.

Genome-wide meta-analysis identifies novel loci of plaque burden in carotid artery

Background and aimsCarotid artery plaque is an established marker of subclinical atherosclerosis and common patho-mechanisms with coronary artery disease (CAD) are hypothesized. We aimed to identify genetic variants associated with carotid plaque and to examine the potential shared genetic basis with CAD. MethodsAfter investigating the reliability of plaque detection, we performed a genome-wide meta-association study in two independent cohorts (LIFE-Adult, n = 4037 and LIFE-Heart, n = 3152) for carotid plaque score (PS), defined as the sum of the plaque load of common carotid artery and carotid bulb. Further, we analyzed whether previously reported CAD and stroke loci were also associated with PS. ResultsWe identified two loci with genome-wide significance for PS. One locus is the known CAD-locus at chromosome 9p21 (lead SNP rs9644862, p = 8.73 × 10−12). We also describe a novel locus on chromosome 10q24 within the SFXN2 gene as the most probable candidate (lead SNP rs2902548, p = 1.97 × 10−8). In addition, 17 out of 58 known CAD loci and six of 17 known stroke loci were associated with PS at a nominal level of significance. ConclusionsWe showed that PS is a reliable trait to analyze genetics of atherosclerosis. Two new loci of genome-wide significant association with PS were found. The observed non-random overlap of CAD and PS associations strengthens the hypothesis of a shared genetic basis for these atherosclerotic manifestations.

Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

BackgroundGenome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. ObjectivesThis study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. MethodsIn discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. ResultsWe identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10−4 with a range of other diseases/traits. ConclusionsWe identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

Genetic variation at ADAMTS7 and severity of coronary artery disease

BackgroundGenome-wide association studies have identified ADAMTS7 as a risk locus for coronary artery disease and myocardial infarction. Functional studies suggest that ADAMTS7 might promote cellular processes in atherosclerosis. We sought to examine whether carriers of a loss-of-function genetic variant exhibit favourable characteristics on plaque histology, angiographic coronary artery disease severity, and cardiovascular outcomes. MethodsThe single-nucleotide polymorphism rs3825807 was used as a marker for ADAMTS7. Human coronary atherosclerotic plaques (n=50) were genotyped, and characterised with immunohistochemical analysis. Burden of angiographic coronary artery disease was assessed by angiographic severity scores in two independent population-based cohorts—the Southampton Atherosclerosis Study (SAS, n=1359) in the UK, and the prospective Emory Genebank study (Emory GB, n=2684) in the USA. Follow-up data were collected in Emory GB over a median of 7 years. FindingsHuman coronary atherosclerotic plaques with the loss-of-function G allele exhibited thinner fibrous cap (p=0·017) and lower percentage area of α-actin (smooth muscle cell marker) in the intima (p=0·029). After adjustment for age and sex, the G allele was associated with less coronary artery disease in both SAS (odds ratio 0·82, 95% CI 0·67–0·99), and Emory GB (0·84, 0·74–0·95). Angiographic burden was further characterised with the Gensini Score (GS) and Sullivan Extent Score (SES). ADAMTS genotypes were associated with all of the angiographic severity scores in both SAS (GS p=0·026, SES p=0·029) and Emory GB (GS p<0·0001, SES p<0·0001). Outcome analysis showed lower incidence of revascularisation for G allele carriers (hazard ratio 0·77, 95% CI 0·60–0·98), but not all cause mortality (1·12, 0·92–1·35). InterpretationCarriers of the ADAMTS7 loss-of-function allele G had reduced atherosclerotic plaque progression, as demonstrated by thinner cap and smooth muscle migration. In addition there was less severe angiographic coronary artery disease in the SAS and Emory GB cohorts, as well as lower incidence of revascularisation procedure, further supporting the role of this protease in promoting atherosclerosis. FundingNone.

A survey of sub-Saharan gene flow into the Mediterranean at risk loci for coronary artery disease.

This study tries to find detectable signals of gene flow of Sub-Saharan origin into the Mediterranean in four genomic regions previously associated with coronary artery disease. A total of 366 single-nucleotide polymorphisms were genotyped in 772 individuals from 10 Mediterranean countries. Population structure analyses were performed, in which a noticeable Sub-Saharan component was found in the studied samples. The overall percentage of this Sub-Saharan component presents differences between the two Mediterranean coasts. D-statistics suggest possible Sub-Saharan introgression into one of the studied genomic regions (10q11). We also found differences in linkage disequilibrium patterns between the two Mediterranean coasts, possibly attributable to differential Sub-Saharan admixture. Our results confirm the potentially important role of human demographic history when performing epidemiological studies.

Proficiency of data interpretation: identification of signaling SNPs/specific loci for coronary artery disease.

Coronary artery disease (CAD) is a complex disorder involving both genetic and non-genetic factors. Genome-wide association studies (GWAS) have identified hundreds of single nucleotides polymorphisms (SNPs) tagging over > 40 CAD risk loci. We hypothesized that some non-coding variants might directly regulate the gene expression rather than tagging a nearby locus. We used RegulomeDB to examine regulatory functions of 58 SNPs identified in two GWAS and those SNPs in linkage disequilibrium (LD) (r2 ≥ 0.80) with the GWAS SNPs. Of the tested 1200 SNPs, 858 returned scores of 1–6 by RegulomeDB. Of these 858 SNPs, 97 were predicted to have regulatory functions with RegulomeDB score of < 3. Notably, only 8 of the 97 predicted regulatory variants were genome-wide significant SNPs (LIPA/rs2246833, RegulomeDB score = 1b; ZC3HC1/rs11556924, CYP17A1-CNNM2-NT5C2/rs12413409, APOE-APOC1/rs2075650 and UBE2Z/rs46522, each with a RegulomeDB score = 1f; ZNF259-APOA5-APOA1/rs964184, SMG6/rs2281727 and COL4A1-COL4A2/rs4773144, each with a RegulomeDB score = 2b). The remainder 89 functional SNPs were in linkage disequilibrium with GWAS SNPs. This study supports the hypothesis that some of the non-coding variants are true signals via regulation of gene expression at transcription level. Our study indicates that RegulomeDB is a useful database to examine the putative functions of large number of genetic variants and it may help to identify a true association among multiple tagged SNPs in a complex disease, such as CAD.Database URLs http://www.regulomedb.org/; https://www.broadinstitute.org/mpg/snap/

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Associations between a Genetic Risk Score for Clinical CAD and Early Stage Lesions in the Coronary Artery and the Aorta.

ObjectiveThe correlation between the extent of fatty streaks, more advanced atherosclerotic lesions, and community rates of coronary artery disease (CAD) is substantially higher for the coronary artery compared to the aorta. We sought to determine whether a genetic basis contributes to these differences.Approach and ResultsWe conducted a cluster analysis of 6 subclinical atherosclerosis phenotypes documented in 564 white participants of the Pathobiological Determinants of Atherosclerosis in Youth study including the extent of fatty streaks and raised lesions in the coronary artery (CF and CR), thoracic aorta (TF and TR), and abdominal aorta (AF and AR) followed by a genetic association analysis of the same phenotypes. Our cluster analysis grouped all raised lesions and fatty streaks in the coronary into one cluster (CF, CR, TR, and AR) and the fatty streaks in the aorta into a second cluster (TF and AF). We found a genetic risk score of high-risk alleles at 57 susceptibility loci for CAD to be variably associated with the phenotypes in the first cluster (OR: 1.30 p = 0.009 for being in top quartile of degree of involvement of CF, 1.34 p = 0.005 for CR, 1.25: p = 0.11 for TR, and 1.19 p = 0.08 for AR) but not at all with the phenotypes in the second cluster (OR: 1.01, p = 0.95 for TF and 0.98, p = 0.82 for AF).ConclusionsThe genetic determinants of fatty streaks in the aorta do not appear to overlap substantially with the genetic determinants of fatty streaks in the coronary as well as raised lesions in both the coronary and the aorta. These findings may explain why a larger fraction of fatty streaks in the aorta are less likely to progress to raised lesions compared to the coronary artery.

Bayesian variable selection for post-analytic interrogation of susceptibility loci.

Understanding the complex interplay among protein coding genes and regulatory elements requires rigorous interrogation with analytic tools designed for discerning the relative contributions of overlapping genomic regions. To this aim, we offer a novel application of Bayesian variable selection (BVS) for classifying genomic class level associations using existing large meta-analysis summary level resources. This approach is applied using the expectation maximization variable selection (EMVS) algorithm to typed and imputed SNPs across 502 protein coding genes (PCGs) and 220 long intergenic non-coding RNAs (lncRNAs) that overlap 45 known loci for coronary artery disease (CAD) using publicly available Global Lipids Gentics Consortium (GLGC) (Teslovich et al., 2010; Willer et al., 2013) meta-analysis summary statistics for low-density lipoprotein cholesterol (LDL-C). The analysis reveals 33 PCGs and three lncRNAs across 11 loci with >50% posterior probabilities for inclusion in an additive model of association. The findings are consistent with previous reports, while providing some new insight into the architecture of LDL-cholesterol to be investigated further. As genomic taxonomies continue to evolve, additional classes such as enhancer elements and splicing regions, can easily be layered into the proposed analysis framework. Moreover, application of this approach to alternative publicly available meta-analysis resources, or more generally as a post-analytic strategy to further interrogate regions that are identified through single point analysis, is straightforward. All coding examples are implemented in R version 3.2.1 and provided as supplemental material.

PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance.

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10−4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10−10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10−4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development.We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.

No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis.

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

Association study of polymorphisms in the ABO gene with ischemic stroke in the Chinese population.

BackgroundIschemic stroke is the main cause of mortality and disability in older people worldwide. Recently epidemiological studies indicate that ischemic stroke is a complex disorder with a strong genetic component. Genome-wide association studies (GWAS) identified several single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD) and myocardial infarction (MI) locus in ABO gene. Our study examined the association between four variants in the ABO gene and the risk of ischemic stroke and its subtypes, large-artery atherosclerosis (LAA) and small-vessel diseases (SVD) in the Chinese population.MethodsIn this case–control study, we recruited 1897 subjects, including 979 healthy controls and 918 ischemic stroke patients (465 with LAA and 453 with SVD). We selected four single nucleotide polymorphisms (rs579459, rs651007, rs514659 and rs529565) of the ABO gene and performed genotyping assays to assess the association with ischemic stroke and its subtypes.ResultsWe found three polymorphisms, rs579459 and rs651007 were significantly associated with LAA using additive model and rs529565 was significantly associated with LAA using additive and dominant models. And we failed to find any significant association between these SNPs and ischemic stroke and SVD in the Chinese population. However, after the Bonferroni correction for multiple comparisons, the P-values of these SNPs failed to exceed significant threshold under any models.ConclusionOur findings indicated that genetic variations of ABO gene may contribute to susceptibility of LAA but not ischemic stroke and SVD in the Chinese population. Our preliminary results should be further validated in prospective independent studies with expanded sample size.

Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci.

Coronary artery disease (CAD) is the leading cause of mortality and morbidity, driven by both genetic and environmental risk factors. Meta-analyses of genome-wide association studies have identified >150 loci associated with CAD and myocardial infarction susceptibility in humans. A majority of these variants reside in non-coding regions and are co-inherited with hundreds of candidate regulatory variants, presenting a challenge to elucidate their functions. Herein, we use integrative genomic, epigenomic and transcriptomic profiling of perturbed human coronary artery smooth muscle cells and tissues to begin to identify causal regulatory variation and mechanisms responsible for CAD associations. Using these genome-wide maps, we prioritize 64 candidate variants and perform allele-specific binding and expression analyses at seven top candidate loci: 9p21.3, SMAD3, PDGFD, IL6R, BMP1, CCDC97/TGFB1 and LMOD1. We validate our findings in expression quantitative trait loci cohorts, which together reveal new links between CAD associations and regulatory function in the appropriate disease context.