Rare Variants in <i>NOD1</i> Associated with Carotid Bifurcation Intima-Media Thickness in Dominican Republic Families

<div><p>Cardiovascular disorders including ischemic stroke (IS) and myocardial infarction (MI) are heritable; however, few replicated loci have been identified. One strategy to identify loci influencing these complex disorders is to study subclinical phenotypes, such as carotid bifurcation intima-media thickness (bIMT). We have previously shown bIMT to be heritable and found evidence for linkage and association with common variants on chromosome 7p for bIMT. In this study, we aimed to characterize contributions of rare variants (RVs) in 7p to bIMT. To achieve this aim, we sequenced the 1 LOD unit down region on 7p in nine extended families from the Dominican Republic (DR) with strong evidence for linkage to bIMT. We then performed the family-based sequence kernel association test (famSKAT) on genes within the 7p region. Analyses were restricted to single nucleotide variants (SNVs) with population based minor allele frequency (MAF) <5%. We first analyzed all exonic RVs and then the subset of only non-synonymous RVs. There were 68 genes in our analyses. Nucleotide-binding oligomerization domain (<i>NOD1)</i> was the most significantly associated gene when analyzing exonic RVs (famSKAT p = 9.2x10^-4; number of SNVs = 14). We achieved suggestive replication of <i>NOD1</i> in an independent sample of twelve extended families from the DR (p = 0.055). Our study provides suggestive statistical evidence for a role of rare variants in <i>NOD1</i> in bIMT. Studies in mice have shown Nod1 to play a role in heart function and atherosclerosis, providing biologic plausibility for a role in bIMT thus making <i>NOD1</i> an excellent bIMT candidate.</p></div

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

Polymorphic Exome Array variants passing QC in the 7p region in the 12 replication families and the NOMAS DR sample.

<p>Polymorphic Exome Array variants passing QC in the 7p region in the 12 replication families and the NOMAS DR sample.</p

Gene-based association results for rare variant analyses in the chr 7p region, for genes with p<0.05 in at least one analysis.

<p>Gene-based association results for rare variant analyses in the chr 7p region, for genes with p<0.05 in at least one analysis.</p

Polymorphic variants identified by re-sequencing of 7p region in 9 discovery families.

<p>Polymorphic variants identified by re-sequencing of 7p region in 9 discovery families.</p

Characteristics of Dominican families included in analyses for chr7 analyses.

<p>Characteristics of Dominican families included in analyses for chr7 analyses.</p

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

Pedigree of Family 5987 depicting residual bIMT value and rs5743335 genotype, our most significantly associated variant in <i>NOD1</i>.

<p>Individuals with residual bIMT value ≤ 0 are shaded gray in the upper right quadrant and individuals with residual bIMT value > 0 are shaded completely gray.</p

Single-SNP association results for rare variants in <i>NOD1</i>.

<p>Single-SNP association results for rare variants in <i>NOD1</i>.</p