Coronary collateralization shows sex and racial-ethnic differences in obstructive artery disease patients

<div><p>Background</p><p>Coronary collateral circulation protects cardiac tissues from myocardial infarction damage and decreases sudden cardiac death. So far, it is unclear how coronary collateralization varies by race-ethnicity groups and by sex.</p><p>Methods</p><p>We assessed 868 patients with obstructive CAD. Patients were assessed for collateral grades based on Rentrop grading system, as well as other covariates. DNA samples were genotyped using the Affymetrix 6.0 genotyping array. To evaluate genetic contributions to collaterals, we performed admixture mapping using logistic regression with estimated local and global ancestry.</p><p>Results</p><p>Overall, 53% of participants had collaterals. We found difference between sex and racial-ethnic groups. Men had higher rates of collaterals than women (P-value = 0.000175). White Hispanics/Latinos showed overall higher rates of collaterals than African Americans and non-Hispanic Whites (59%, 50% and 48%, respectively, P-value = 0.017), and especially higher rates in grade 1 and grade 3 collateralization than the other two populations (P-value = 0.0257). Admixture mapping showed Native American ancestry was associated with the presence of collaterals at a region on chromosome 17 (chr17:35,243,142-41,251,931, β = 0.55, P-value = 0.000127). African ancestry also showed association with collaterals at a different region on chromosome 17 (chr17: 32,266,966-34,463,323, β = 0.38, P-value = 0.00072).</p><p>Conclusions</p><p>In our study, collateralization showed sex and racial-ethnic differences in obstructive CAD patients. We identified two regions on chromosome 17 that were likely to harbor genetic variations that influenced collateralization.</p></div

Population demographics and clinical characteristics based on collateral grades.

<p>Population demographics and clinical characteristics based on collateral grades.</p

Chromosome 17 regional plot showed peak association between local African/Native American ancestries and collateralization.

<p>Local Native American ancestry was highly associated with the presence of collaterals at a region on chromosome 17 (35,243,142-41,251,931 (hg19), min P-value = 0.000127, −log10 (P-value) = 3.90). Local African ancestry also showed association with collaterals at a different region on chromosome 17 (32,266,966-34,463,323 (hg19), min P-value = 0.00072, -log10 (P-value) = 3.14). X-axis represented the base pair location on chromosome 17; Y-axis represented −log10 P-values.</p

Manhattan plots showed associations between collateralization and local ancestry.

<p>(A) local Native American ancestry; (B) local African ancestry in admixture mapping. The peak regions of local Native American ancestry and local African ancestry were both located on chromosome 17. X-axis indicated chromosomes 1 to 22. Y-axis indicated −log10 of local Native American/African ancestry P-values.</p

Conversion of Gene Expression and GWAS Pathways.

<p>For gene expression analysis, differentially expressed genes between adjacent tissues affected in PD were identified in each individual and adjusted using average control expression profiles. Three subtractions were used to identify genes of interest in PD. The first subtraction between two adjacent tissues relates to a given PD patient (eg CASE N). The second subtraction is in controls, where a similar subtraction as above is performed, and then averaged over the four controls for the two given adjacent tissues. This is denoted as CONTROLAVG. To establish if gene X is of interest in PD between two adjacent tissues, the CONTROLAVG was subtracted from the first subtraction for each patient. An overview of the GWAS PD study is shown. Pathway analysis was performed on each of the GWAS and gene expression PD gene sets derived. Two types of convergence were performed. First, significantly over represented pathways common in both studies were identified (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016917#pone-0016917-g001" target="_blank">Figure 1</a>). Second, a meta-analysis was carried out to combine the results obtained from the gene expression and the GWAS PD pathway analyses (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016917#pone-0016917-t002" target="_blank">Table 2</a>). DMV = dorsal motor nucleus, LCER =  locus ceruleus, SNGRA =  substantia nigra, PTMN =  putamen, INSLA =  insula.</p

The Venn diagram shows 25 and 42 over-represented pathways in the GWAS (green) and the expression PD (pink) studies respectively.

<p>Twelve over-represented pathways common to both PD studies are also shown (yellow). The pathway's rank in the meta-analysis is provided in parenthesis.</p

The top ten over-represented pathways from (a) the GWAS PD study and (b) the gene expression PD study.

<p>The pathways are presented in the decreasing order of significance.</p

KEGG pathway for melanogenesis.

<p>Similar to a gene expression array, those significant genes in the GWAS study are green, those in the expression study are pink and those that are significant in both are yellow.</p

The top twenty over-represented pathways determined by the meta-analysis combining the GWAS and the gene expression PD studies.

<p>The over-represented pathways are presented in rank order.</p

KEGG pathway for MAPK.

<p>Similar to a gene expression array, those genes that are significant in the GWAS study are green, those in the expression study are pink and those that are significant in both are yellow.</p