Genome-Wide Association Study in a Lebanese Cohort Confirms PHACTR1 as a Major Determinant of Coronary Artery Stenosis

The manifestation of coronary artery disease (CAD) follows a well-choreographed series of events that includes damage of arterial endothelial cells and deposition of lipids in the sub-endothelial layers. Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are a crucial step in understanding global CAD pathophysiology. In this study, we report a GWAS on the genetic basis of arterial stenosis as measured by cardiac catheterization in a Lebanese population. The locus of the phosphatase and actin regulator 1 gene (PHACTR1) showed association with coronary stenosis in a discovery experiment with genome wide data in 1,949 individuals (rs9349379, OR = 1.37, p = 1.57×10−5). The association was replicated in an additional 2,547 individuals (OR = 1.31, p = 8.85×10−6), leading to genome-wide significant association in a combined analysis (OR = 1.34, p = 8.02×10−10). Results from this GWAS support a central role of PHACTR1 in CAD susceptibility irrespective of lifestyle and ethnic divergences. This association provides a plausible component for understanding molecular mechanisms involved in the formation of stenosis in cardiac vessels and a potential drug target against CAD

Association of coronary artery disease and chronic kidney disease in Lebanese population

Background: More evidence is emerging on the strong association between chronic kidney disease (CKD) and cardiovascular disease. We assessed the relationship between coronary artery disease (CAD) and renal dysfunction level (RDL) in a group of Lebanese patients. Methods: A total of 1268 patients undergoing cardiac catheterization were sequentially enrolled in a multicenter cross sectional study. Angiograms were reviewed and CAD severity scores (CADSS) were determined. Estimated glomerular filtration rate (eGFR) was calculated and clinical and laboratory data were obtained. CKD was defined as eGFR < 60 ml/min. Logistic regression model was performed using multivariate analysis including all traditional risk factors associated with both diseases. ANOVA and the Tukeytestswere used to compare subgroups of patients and to assess the impact of each disease on the severity of the other. Results: Among the 82% patients who exhibited variable degrees of CAD, 20.6% had an eGFR < 60 ml/min. Logistic regression analysis revealed a bidirectional independent association between CAD and CKD with an OR = 2.01 (P < 0.01) and an OR = 1.99 (P < 0.01) for CAD and CKD frequencies, respectively. We observed a steady increase in the CADSS mean as eGFR declined and a progressive reduction in renal function with the worsening of CAD (P < 0.05). This correlation remained highly significant despite considerable inter-patient variability and was at its highest at the most advanced stages of both diseases. Conclusions: Our results show a strong, independent and graded bidirectional relationship between CAD severity and RDL. We propose to add CAD to the list of risk factors for the development and progression of CKD

Quantile-Quantile plot of the GWAS results.

<p>In this plot, each dot corresponds to a SNP tested for association where the observed –log₁₀ p values, shown by vertical axis, were plotted by the expected –log₁₀ p values under the null hypothesis. Upper right dots with higher observed significance than expected represent candidate variants for association with the phenotype tested (CAD category 1, control subjects; CAD category 2, patients with ≤50% stenosis in any coronary artery; CAD category 3, patients with >50% stenosis in any of the coronary arteries). The genomic control ratio (λ) was 1.033, indicating the lack of strong effect of systematic error such as population stratification.</p

Map around the PHACTR1 locus on chromosome 6 showing strong evidence of association with coronary artery stenosis.

<p>The upper vertical bars correspond to the location of all markers tested from the SNP array chip in the area. The X-axis indicates the chromosomal position in base-pairs on chromosome 6. Recombination rate is presented as a continuous blue line, while individual markers are represented by a circle filled with a color corresponding to the extent of LD with the key marker rs9349379 (in red) from dark blue (r² = 0) to red (r² = 1). Grey filled circles refer to SNPs with no LD information. The lower part represents the location of the genes with corresponding exons and the direction of transcription indicated by arrows. The figure was generated with LocusZoom using CEU from HapMap release 22 as reference.</p

Association of CAD stenosis categories with conventional risk factors.

<p>Analysis was done in GWA (discovery) and replication phases separately and combined (total). No, mild, and severe correspond to CAD severity categories 1, 2 and 3. <b>¹⁾</b><i>p</i> value indicating association of risk factors with CAD categories. <b>²⁾</b><i>p</i> value indicating association of risk factors with different phases. See Methods section for details.</p

Manhattan plot showing results of a GWA analysis in 1949 Lebanese patients for 513,079 SNPs.

<p> The Y-axis corresponds to the significance of the association (-log₁₀ p-values). The X-axis represents the physical location of the variant colored by chromosome.</p