Large-scale association analysis identifies new risk loci for coronary artery disease.

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci.

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.

Determinants and functional significance of myocardial perfusion reserve in severe aortic stenosis.

OBJECTIVES: The purpose of this study was to assess the functional significance of cardiac magnetic resonance (CMR) measures of left ventricular (LV) remodeling and myocardial perfusion reserve (MPR) in patients with severe aortic stenosis (AS), without obstructive coronary artery disease. BACKGROUND: Measures of stenosis severity do not correlate well with exercise intolerance in AS. LV remodeling in AS is associated with myocardial fibrosis and impaired MPR. The functional significance and determinants of MPR in AS are unclear. METHODS: Forty-six patients with isolated severe AS were prospectively studied before aortic valve replacement. The following investigations were undertaken: cardiopulmonary exercise testing to measure aerobic exercise capacity (peak VO(2)); CMR to assess left ventricular mass index (LVMI), myocardial fibrosis with late gadolinium enhancement (LGE), myocardial blood flow (MBF), and MPR; and transthoracic echocardiography to assess stenosis severity and diastolic function. RESULTS: Peak VO(2) was associated with sex (ß = -0.41), age (ß = -0.32), MPR (ß = 0.45), resting MBF (ß = -0.53), and septal transmitral flow velocity to annular velocity ratio (E/E') (ß = -0.34), but not with LVMI, LGE, or echocardiographic measures of AS severity. On stepwise regression analysis, only MPR was independently associated with age- and sex-corrected peak VO(2) (ß = 0.46, p = 0.001). MPR was also inversely related to New York Heart Association functional class (p = 0.001). Univariate associations with MPR were sex (ß = 0.38, p = 0.02), septal E/E' (ß = -0.30, p = 0.03), peak aortic valve velocity (ß = -0.34, p = 0.02), LVMI (ß = -0.51, p < 0.001), and LGE category (ß = -0.46, p = 0.002). On multivariate analysis, LVMI and LGE were independently associated with MPR. CONCLUSIONS: CMR-quantified MPR is independently associated with aerobic exercise capacity in severe AS. LV remodeling appears to be a more important determinant of impaired MPR than stenosis severity per se. Further work is required to determine how CMR assessment of MPR can aid clinical management of patients with AS.

Pathway analysis shows association between FGFBP1 and hypertension.

Variants in the gene encoding fibroblast growth factor 1 (FGF1) co-segregate with familial susceptibility to hypertension, and glomerular upregulation of FGF1 associates with hypertension. To investigate whether variants in other members of the FGF signaling pathway may also associate with hypertension, we genotyped 629 subjects from 207 Polish families with hypertension for 79 single nucleotide polymorphisms in eight genes of this network. Family-based analysis showed that parents transmitted the major allele of the rs16892645 polymorphism in the gene encoding FGF binding protein 1 (FGFBP1) to hypertensive offspring more frequently than expected by chance (P=0.005). An independent cohort of 807 unrelated Polish subjects validated this association. Furthermore, compared with normotensive subjects, hypertensive subjects had approximately 1.5- and 1.4-fold higher expression of renal FGFBP1 mRNA and protein (P=0.04 and P=0.001), respectively. By immunohistochemistry, hypertension-related upregulation of FGFBP1 was most apparent in the glomerulus and juxtaglomerular space. Taken together, these data suggest that FGFBP1 associates with hypertension and that systematic analysis of signaling pathways can identify previously undescribed genetic associations.

Large-scale candidate gene analysis of HDL particle features.

BACKGROUND: HDL cholesterol (HDL-C) is an established marker of cardiovascular risk with significant genetic determination. However, HDL particles are not homogenous, and refined HDL phenotyping may improve insight into regulation of HDL metabolism. We therefore assessed HDL particles by NMR spectroscopy and conducted a large-scale candidate gene association analysis. METHODOLOGY/PRINCIPAL FINDINGS: We measured plasma HDL-C and determined mean HDL particle size and particle number by NMR spectroscopy in 2024 individuals from 512 British Caucasian families. Genotypes were 49,094 SNPs in >2,100 cardiometabolic candidate genes/loci as represented on the HumanCVD BeadChip version 2. False discovery rates (FDR) were calculated to account for multiple testing. Analyses on classical HDL-C revealed significant associations (FDR<0.05) only for CETP (cholesteryl ester transfer protein; lead SNP rs3764261: p = 5.6*10(-15)) and SGCD (sarcoglycan delta; rs6877118: p = 8.6*10(-6)). In contrast, analysis with HDL mean particle size yielded additional associations in LIPC (hepatic lipase; rs261332: p = 6.1*10(-9)), PLTP (phospholipid transfer protein, rs4810479: p = 1.7*10(-8)) and FBLN5 (fibulin-5; rs2246416: p = 6.2*10(-6)). The associations of SGCD and Fibulin-5 with HDL particle size could not be replicated in PROCARDIS (n = 3,078) and/or the Women's Genome Health Study (n = 23,170). CONCLUSIONS: We show that refined HDL phenotyping by NMR spectroscopy can detect known genes of HDL metabolism better than analyses on HDL-C.

Genetic architecture of ambulatory blood pressure in the general population: insights from cardiovascular gene-centric array.

Genetic determinants of blood pressure are poorly defined. We undertook a large-scale, gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure. We measured 24-hour ambulatory blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains ≈ 50 000 single nucleotide polymorphisms in >2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure; each minor allele copy of rs13306560 was associated with 2.6 mm Hg lower mean 24-hour diastolic blood pressure (P = 1.2 × 10⁻8). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the Genetic Regulation of Arterial Pressure of Humans in the Community Study, the CoLaus Study, and the Silesian Cardiovascular Study (P=5.4 × 10⁻6). Additional analysis of associations between variants in gene ontology-defined pathways and mean 24-hour blood pressure in the Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency: < 0.05) among polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles. Through a large-scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure.

Common variants near TERC are associated with mean telomere length.

We conducted genome-wide association analyses of mean leukocyte telomere length in 2,917 individuals, with follow-up replication in 9,492 individuals. We identified an association with telomere length on 3q26 (rs12696304, combined P = 3.72 x 10(-14)) at a locus that includes TERC, which encodes the telomerase RNA component. Each copy of the minor allele of rs12696304 was associated with an approximately 75-base-pair reduction in mean telomere length, equivalent to approximately 3.6 years of age-related telomere-length attrition.

Dynamic cerebral autoregulation is compromised acutely following mild ischaemic stroke but not transient ischaemic attack.

BACKGROUND: Dynamic cerebral autoregulation (dCA), the process by which the cerebral blood flow (CBF) is normally maintained relatively constant despite fluctuations in beat-to-beat blood pressure (BP), is impaired acutely following major ischaemic stroke. It is uncertain if dCA is impaired acutely after mild ischaemic stroke or transient ischaemic attack (TIA). We assessed dCA in patients acutely and sub-acutely following TIA or mild ischaemic stroke. METHODS: Nineteen consecutive mild ischaemic stroke patients and 17 consecutive TIA patients underwent recordings of beat-to-beat BP, cerebral blood flow velocity (bilateral transcranial Doppler insonation of the middle cerebral artery) and heart rate a median of 36 h from onset and again a median of 96 h from onset. Dynamic autoregulatory indices (ARI) were then calculated from these data and the results compared to 22 age-, BP- and gender-matched controls. RESULTS: ARI was significantly reduced in affected hemispheres of mild stroke patients at baseline compared to controls (4.0 +/- 1.7 vs. 5.6 +/- 1.1, p < 0.01) and remained so after adjustment for significant covariates. ARI was significantly reduced in both affected (4.0 +/- 2.7 vs. 5.6 +/- 1.1, p = 0.03) and unaffected hemispheres (4.2 +/- 1.8 vs. 5.6 +/- 1.1, p = 0.01) of mild stroke patients at follow-up compared to controls. However, after adjustment for significant covariates including ipsilateral carotid stenosis these results were not significant. No reduction in ARI was seen in TIA patients. CONCLUSIONS: The impairment of cerebrovascular haemodynamic control that was observed acutely following mild ischaemic stroke may have implications for the appropriate timing of anti-hypertensive therapy acutely following mild ischaemic stroke. No impairment of cerebrovascular haemodynamic control was seen following TIA.

Longer-term follow-up of patients recruited to the REACT (Rescue Angioplasty Versus Conservative Treatment or Repeat Thrombolysis) trial.

OBJECTIVES: To evaluate the longer-term outcomes for rescue percutaneous coronary intervention (R-PCI). BACKGROUND: Thrombolysis remains an important, commonly used reperfusion therapy, yet failure to achieve complete reperfusion occurs relatively frequently. A number of recent trials have focused on the management of patients with thrombolytic failure, including the REACT (Rescue Angioplasty Versus Conservative Treatment or Repeat Thrombolysis) trial, which demonstrated a significant 6-month benefit favoring R-PCI. However, longer-term maintenance of benefit for R-PCI has not been demonstrated. METHODS: Rates of the primary composite end point (major adverse cardiac and cerebrovascular events) to 1 year and mortality to a median of 4.4 years in 427 patients included in the 3 randomized arms of the REACT trial (repeat lysis, conservative therapy, and R-PCI) were analyzed. RESULTS: One-year event-free survival for patients randomized to R-PCI was 81.5%, compared with 64.1% for repeat thrombolysis and 67.5% for conservative therapy (overall p = 0.004). Adjusted hazard ratio was 0.44 (95% confidence interval [CI]: 0.28 to 0.71; p = 0.0008) for R-PCI versus repeat thrombolysis and 0.51 (95% CI: 0.32 to 0.83; p = 0.007) for R-PCI versus conservative therapy. Adjusted hazard ratio for longer-term (median 4.4 years) overall mortality for R-PCI versus repeat thrombolysis was 0.41 (95% CI: 0.22 to 0.75; p = 0.004) and 0.43 (95% CI: 0.23 to 0.79; p = 0.006) for R-PCI versus conservative therapy. There was no difference in either analysis between repeat thrombolysis and conservative strategies. CONCLUSIONS: Rescue PCI, previously shown to be superior in the short term to both repeat thrombolysis and conservative therapy, maintains benefit in terms of long-term mortality. This strategy for failed lysis should be mandated as part of thrombolytic-based ST-segment elevation myocardial infarction protocols.

Vertical optokinetic nystagmus in Parkinson's disease.

Parkinson's disease (PD) is associated with a number of oculomotor deficits; however, little is known about changes in vertical optokinetic nystagmus (OKN) associated with PD. We recorded eye movements in 14 PD patients and 14 age-matched controls in response to large field OKN stimulation using stimulus velocities of 20 degrees /second and 40 degrees /second. We compared asymmetry of horizontal and vertical responses in the two groups. We found vertical OKN to be strongly asymmetric in PD with reduced gains for downward-moving stimuli. This asymmetry was significantly greater than that recorded in control volunteers. We postulate that this could result from an abnormal pursuit/early OKN system in PD leading to greater influence of the delayed OKN system.